6-7-dihydroxyflavone and Disease-Models--Animal

Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and the most common cause of autism spectrum disorders. FXS patients exhibit severe syndromic features and behavioral alterations, including anxiety, hyperactivity, impulsivity, and aggression, in addition to cognitive impairment and seizures. At present, there are no effective treatments or cures for FXS. Previously, we have found the divergence of BDNF-TrkB signaling trajectories is associated with spine defects in early postnatal developmental stages of Fmr1 KO mice. Here, young fragile X mice were intraperitoneal injection with 7,8-Dihydroxyflavone (7,8-DHF), a high affinity tropomyosin receptor kinase B (TrkB) agonist. 7,8-DHF ameliorated morphological abnormities in dendritic spine and synaptic structure and rescued synaptic and hippocampus-dependent cognitive dysfunction. These observed improvements of 7,8-DHF involved decreased protein levels of BDNF, p-TrkB

Topics: Animals; Brain-Derived Neurotrophic Factor; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Mice; Receptor, trkB; Tropomyosin

Oligodendrogenesis is the process by which new oligodendrocytes are produced in the CNS. Oligodendrocytes form myelin, which has a vital role in neural signal transmission and integration. Here we tested mice with reduced adult oligodendrogenesis in the Morris water maze, a test of spatial learning. These mice were found to have impaired long-term (28 d) spatial memory. However, when 7,8-dihydroxyflavone (7,8-DHF) was administered immediately after each training session, their long-term spatial memory impairment was rescued. An increase in the number of newly formed oligodendrocytes in the corpus callosum was also observed. 7,8-DHF has previously been shown to improve spatial memory in animal models of Alzheimer's disease, post-traumatic stress disorder, Wolfram syndrome and Down syndrome, as well as in normal aging. Understanding the underlying mechanisms of the effect of this drug on spatial memory is therefore helpful in assessing it for clinical relevance and development.

Topics: Alzheimer Disease; Animals; Disease Models, Animal; Flavones; Maze Learning; Memory Disorders; Memory, Long-Term; Mice; Spatial Memory

Astrocytic functions and brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) signaling pathways are impaired in stress-related neuropsychiatric diseases. Previous studies have reported neuroprotective effects of 7,8-dihydroxyflavone (7,8-DHF), a TrkB activator. Here, we investigated the molecular mechanisms underlying pathogenesis of post-traumatic stress disorder (PTSD) using a modified single-prolonged stress (SPS&S) model and the potential beneficial effects of 7,8-DHF. SPS&S reduced the hippocampal expression of glial fibrillary acidic protein (GFAP), a marker of astrocytes, and induced morphological changes in astrocytes. From the perspective of synaptic function, the SPS&S model displayed reduced expression of BDNF, p-TrkB, postsynaptic density protein 95 (PSD95), AMPA receptor subunit GluR1 (GluA1), NMDA receptor subunit N2A/N2B ratio, calpain-1, phosphorylated protein kinase B (Akt) and phosphorylated mammalian target of rapamycin (mTOR) and conversely, higher phosphatase and tension homolog (PTEN) expression in the hippocampus. Acute or continuous intraperitoneal administration of 7,8-DHF (5 mg/kg) after SPS&S procedures prevented SPS&S-induced fear memory generalization and anxiety-like behaviors as well as abnormalities of hippocampal oscillations. Most importantly, 7,8-DHF attenuated SPS&S-induced abnormal BDNF-TrkB signaling and calpain-1-dependent cascade of synaptic deficits. Furthermore, treatment with a TrkB inhibitor completely blocked while an mTOR inhibitor partially blocked the effects of 7,8-DHF on behavioral changes of SPS&S model mice. Our collective findings suggest that 7,8-DHF effectively alleviates PTSD-like symptoms, including fear generalization and anxiety-like behavior, potentially by preventing astrocytic and synaptic deficits in the hippocampus through targeting of TrkB.

Topics: Animals; Anxiety; Astrocytes; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Fear; Flavones; Glial Fibrillary Acidic Protein; Hippocampus; Male; Mice, Inbred C57BL; Receptor, trkB; Stress Disorders, Post-Traumatic; Synapses

Temporal lobe epilepsy often manifests months or even years after an initial epileptogenic insult (e.g., stroke, trauma, status epilepticus) and, therefore, may be preventable. However, no such preventive treatment is currently available. Aim of this study was to test an antioxidant agent, 7,8-dihydroxyflavone (7,8-DHF), that is well tolerated and effective in preclinical models of many neurological disorders, as an anti-epileptogenic drug. However, 7,8-DHF also acts as a TrkB receptor agonist and, based on the literature, this effect may imply an anti- or a pro-epileptogenic effect. We found that low- (5 mg/kg), but not high-dose 7,8-DHF (10 mg/kg) can exert strong anti-epileptogenic effects in the lithium-pilocarpine model (i.e., highly significant reduction in the frequency of spontaneous seizures and in the time to first seizure after status epilepticus). The mechanism of these different dose-related effects remains to be elucidated. Nonetheless, considering its excellent safety profile and antioxidant properties, as well as its putative effects on TrkB receptors, 7,8-DHF represents an interesting template for the development of effective and well-tolerated anti-epileptogenic drugs.

Topics: Animals; Antioxidants; Disease Models, Animal; Epilepsy; Flavones; Receptor, trkB; Seizures; Status Epilepticus

The combined antiretroviral therapy era has significantly increased the lifespan of people with HIV (PWH), turning a fatal disease to a chronic one. However, this lower but persistent level of HIV infection increases the susceptibility of HIV-associated neurocognitive disorder (HAND). Therefore, research is currently seeking improved treatment for this complication of HIV. In PWH, low levels of brain derived neurotrophic factor (BDNF) has been associated with worse neurocognitive impairment. Hence, BDNF administration has been gaining relevance as a possible adjunct therapy for HAND. However, systemic administration of BDNF is impractical because of poor pharmacological profile. Therefore, we investigated the neuroprotective effects of BDNF-mimicking 7,8 dihydroxyflavone (DHF), a bioactive high-affinity TrkB agonist, in the memory-involved hippocampus and brain cortex of Tg26 mice, a murine model for HAND. In these brain regions, we observed astrogliosis, increased expression of chemokine HIV-1 coreceptors CXCR4 and CCR5, neuroinflammation, and mitochondrial damage. Hippocampi and cortices of DHF treated mice exhibited a reversal of these pathological changes, suggesting the therapeutic potential of DHF in HAND. Moreover, our data indicates that DHF increases the phosphorylation of TrkB, providing new insights about the role of the TrkB-Akt-NFkB signaling pathway in mediating these pathological hallmarks. These findings guide future research as DHF shows promise as a TrkB agonist treatment for HAND patients in adjunction to the current antiviral therapies.

Topics: AIDS Dementia Complex; Animals; Brain; Disease Models, Animal; Flavones; Gliosis; Membrane Glycoproteins; Mice; Neuroprotective Agents; Phosphorylation; Protein-Tyrosine Kinases

Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family which has been extensively studied for its roles in neural development, long-term memory, brain injury, and neurodegenerative diseases. BDNF signaling through tropomyosin receptor kinase B (TrkB) stimulates neuronal cell survival. For this reason, small molecule TrkB agonists are under pre-clinical develoment for the treatment of a range of neurodegenerative diseases and injuries. Our laboratory recently reported BDNF is secreted by pro-regenerative endothelial progenitor cells (EPCs) which support hematopoietic reconstitution following total body irradiation (TBI). Here we report BDNF-TrkB signaling plays a novel regenerative role in bone marrow and thymic regeneration following radiation injury. Exogenous administration of BDNF or TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) following myelosuppressive radiation injury promoted faster recovery of mature blood cells and hematopoietic stem cells capable of multi-lineage reconstitution. BDNF promotes hematopoietic regeneration via activation of PDGFRα+ bone marrow mesenchymal stem cells (MSCs) which increase secretion of hematopoietic cytokines interleukin 6 (IL-6) and leukemia inhibitory factor (LIF) in response to TrkB activation. These data suggest pharmacologic activation of the BDNF pathway with either BDNF or 7,8-DHF may be beneficial for treatment of radiation or chemotherapy induced myelosuppression.

Topics: Animals; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Female; Flavones; Immune Reconstitution; Interleukin-6; Leukemia Inhibitory Factor; Male; Mesenchymal Stem Cells; Mice; Radiation Injuries; Receptor, trkB; Signal Transduction; Thymus Gland

Retinopathy of prematurity (ROP) is one of the main causes of blindness in children worldwide. Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), play critical protective roles in the development and function of neurons and vasculature. Lack of BDNF expression results in increased endothelial cell apoptosis and reduced endothelial cell-cell contact. Premature babies who develop ROP tend to have lower serum BDNF levels. BDNF expression is also significantly lower in mouse retinas following exposure to hyperoxia compared to those reared in room air. Specifically, BDNF promotes angiogenic tube formation of endothelial cells (EC), and it is considered an EC survival factor required for stabilization of intramyocardial vessels. We hypothesized that the activation of TrkB receptor protects retinal vasculature in the mice during oxygen-induced ischemic retinopathy (OIR), a model of ROP. To test this hypothesis, we treated neonatal mice with 7,8-dihydroxyflavone (DHF) (5 mg/kg body weight), a TrkB receptor agonist. We examined its potential protective effects on retinal vessel obliteration and neovascularization, two hallmarks of ROP and OIR. We found that retinas from DHF treated postnatal day 8 (P8) and P12 mice have similar levels of vessel obliteration as retinas from age-matched control mice subjected to OIR. Similarly, DHF showed no significant effect on mitigation of retinal neovascularization during OIR in P17 mice. Collectively, our studies demonstrate that the TrkB receptor agonist DHF provides no significant protective effects during OIR.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Flavones; Ischemia; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Oxygen; Receptor, trkB; Retinal Neovascularization; Retinopathy of Prematurity

Alcohol use-associated disorders are highly comorbid with anxiety disorders; however, their mechanism remains unknown. The amygdala plays a central role in anxiety. We recently found that 7,8-dihydroxyflavone (7,8-DHF) significantly reduces withdrawal symptoms in a rat model of chronic intermittent alcohol (ethanol) exposure. This study aimed to determine the role of 7,8-DHF in regulating anxiety induced by chronic alcohol exposure and its associated underlying mechanism. Male C57BL/6J mice were exposed to chronic intermittent alcohol for 3 weeks followed by alcohol withdrawal for 12 h with or without 7,8-DHF administered intraperitoneally. All mice were tested using an open field test and elevated plus maze to assess anxiety-like behaviors. Synaptic activity and intrinsic excitability in basal and lateral amygdala (BLA) neurons were assessed using electrophysiological recordings. 7,8-DHF alleviated alcohol-induced anxiety-like behavior and attenuated alcohol-induced enhancement of activities in BLA pyramidal neurons. Furthermore, 7,8-DHF prevented alcohol withdrawal-evoked augmentation of glutamatergic transmission in the amygdala and had no effect on GABAergic transmission in the amygdala, as demonstrated by unaltered frequency and amplitude of spontaneous inhibitory postsynaptic currents. Microinjection of K252a, a tropomyosin-related kinase B (TrkB) antagonist, into the BLA blocked the effects of 7,8-DHF on anxiety-like behavior and neuronal activity in the BLA. Our findings suggest that 7,8-DHF alleviates alcohol-induced anxiety-like behavior induced by chronic alcohol exposure through regulation of glutamate transmission involving TrKB in the BLA.

Topics: Amygdala; Animals; Anxiety; Behavior, Animal; Carbazoles; Disease Models, Animal; Ethanol; Excitatory Postsynaptic Potentials; Flavones; gamma-Aminobutyric Acid; Glutamic Acid; Indole Alkaloids; Inhibitory Postsynaptic Potentials; Male; Mice, Inbred C57BL; Pyramidal Cells; Receptor, trkB; Substance Withdrawal Syndrome; Synaptic Transmission

TrkB agonist drugs are shown here to have a significant effect on the regeneration of afferent cochlear synapses after noise-induced synaptopathy. The effects were consistent with regeneration of cochlear synapses that we observed in vitro after synaptic loss due to kainic acid-induced glutamate toxicity and were elicited by administration of TrkB agonists, amitriptyline, and 7,8-dihydroxyflavone, directly into the cochlea via the posterior semicircular canal 48 hours after exposure to noise. Synaptic counts at the inner hair cell and wave 1 amplitudes in the auditory brainstem response (ABR) were partially restored 2 weeks after drug treatment. Effects of amitriptyline on wave 1 amplitude and afferent auditory synapse numbers in noise-exposed ears after systemic (as opposed to local) delivery were profound and long-lasting; synapses in the treated animals remained intact 1 year after the treatment. However, the effect of systemically delivered amitriptyline on synaptic rescue was dependent on dose and the time window of administration: it was only effective when given before noise exposure at the highest injected dose. The long-lasting effect and the efficacy of postexposure treatment indicate a potential broad application for the treatment of synaptopathy, which often goes undetected until well after the original damaging exposures.

Topics: Amitriptyline; Animals; Auditory Threshold; Cochlea; Cochlear Nerve; Coculture Techniques; Disease Models, Animal; Evoked Potentials, Auditory, Brain Stem; Flavones; Hair Cells, Auditory, Inner; Hearing Loss, Noise-Induced; Membrane Glycoproteins; Mice; Mice, Inbred CBA; Protein-Tyrosine Kinases; Regeneration; Synapses

Wolfram syndrome (WS) is a monogenic progressive neurodegenerative disease and is characterized by various neurological symptoms, such as optic nerve atrophy, loss of vision, cognitive decline, memory impairment, and learning difficulties. GLP1 receptor agonist liraglutide and BDNF mimetic 7,8-dihydroxyflavone (7,8-DHF) have had protective effect to visual pathway and to learning and memory in different rat models of neurodegenerative disorders. Although synergistic co-treatment effect has not been reported before and therefore the aim of the current study was to investigate liraglutide, 7,8-DHF and most importantly for the first time their co-treatment effect on degenerative processes in WS rat model. We took 9 months old WS rats and their wild-type (WT) control animals and treated them daily with liraglutide, 7,8-DHF or with the combination of liraglutide and 7,8-DHF up to the age of 12.5 months (n = 47, 5-8 per group). We found that liraglutide, 7,8-DHF and their co-treatment all prevented lateral ventricle enlargement, improved learning in Morris Water maze, reduced neuronal inflammation, delayed the progression of optic nerve atrophy, had remyelinating effect on optic nerve and thereby improved visual acuity in WS rats compared to WT controls. Thus, the use of the liraglutide, 7,8-DHF and their co-treatment could potentially be used as a therapeutic intervention to induce neuroprotection or even neuronal regeneration.

Topics: Animals; Blindness; Blood Glucose; Body Weight; Calmodulin-Binding Proteins; Cognitive Dysfunction; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Fasting; Flavones; Gene Expression Regulation; Gene Knockout Techniques; Glucagon-Like Peptide-1 Receptor; Hippocampus; Hyperglycemia; Learning; Liraglutide; Male; Membrane Proteins; Nerve Degeneration; Optic Nerve; Rats; Remyelination; Visual Acuity; Wolfram Syndrome

Whether 7,8-dihydroxyflavone (7,8-DHF), a tyrosine kinase receptor B (TrkB) agonist, modulates colonic smooth muscle motility and/or alleviates constipation has not yet been studied.. Here, we aimed to determine how 7,8-DHF influences carbachol (CCh)-stimulated contraction of colonic strips and the in vivo effect of 7,8-DHF on constipation.. Muscle strips were isolated from rat colons for recording contractile tension and performing western blotting. Constipation was induced in rats with loperamide.. Although it specifically activated TrkB, 7,8-DHF applied alone neither activated PLCγ1 in the colonic strips nor induced colonic strip contraction. However, 7,8-DHF enhanced CCh-stimulated PLCγ1 activation and strip contraction. The PLCγ1 antagonist U73122 suppressed both CCh-stimulated and 7,8-DHF-enhanced/CCh-stimulated contraction. While clarifying the underlying mechanism, we revealed that 7,8-DHF augmented muscarinic M3 receptor expression in the colonic strips. The M3-selective antagonist tarafenacin specifically inhibited the 7,8-DHF-enhanced/CCh-stimulated contraction of the colonic strips. Since 7,8-DHF increased Akt phosphorylation, and LY294002 (an antagonist of PI3K upstream of Akt) dramatically inhibited both 7,8-DHF-augmented M3 expression and 7,8-DHF-enhanced/CCh-stimulated contractions, we assumed that 7,8-DHF/TrkB/Akt was associated with the modulation of M3 expression in the colonic strips. ANA-12, a specific TrkB antagonist, not only inhibited TrkB activation by 7,8-DHF but also suppressed 7,8-DHF-enhanced cholinergic contraction, 7,8-DHF/CCh-mediated activation of PLCγ1/Akt, and M3 overexpression in colonic strips. In vivo 7,8-DHF, also by promoting intestinal motility and M3 expression, significantly alleviated loperamide-induced functional constipation in rats.. Our results suggest that 7,8-DHF regulates colonic motility possibly via a TrkB/Akt/M3 pathway and may be applicable for alleviating constipation.

Topics: Animals; Colon; Constipation; Defecation; Disease Models, Animal; Flavones; Gastrointestinal Motility; In Vitro Techniques; Loperamide; Muscarinic Agonists; Muscle Contraction; Muscle, Smooth; Phospholipase C gamma; Proto-Oncogene Proteins c-akt; Receptor, Muscarinic M3; Receptor, trkB; Signal Transduction

Neurogenesis impairment is a key determinant of intellectual disability in Down syndrome (DS), a genetic pathology due to triplication of chromosome 21. Since neurogenesis ceases after birth, apart in the hippocampus and olfactory bulb, the only means to tackle the problem of neurogenesis impairment in DS at its root is to intervene during gestation. A few studies in DS mouse models show that this is possible, although the drugs used may raise caveats in terms of safety. We previously found that neonatal treatment with 7,8-dihydroxyflavone (7,8-DHF), a flavonoid present in plants, restores hippocampal neurogenesis in the Ts65Dn model of DS. The goal of the current study was to establish whether prenatal treatment with 7,8-DHF improves/restores overall brain proliferation potency. Pregnant Ts65Dn females received 7,8-DHF from embryonic day 10 until delivery. On postnatal day 2 (P2) the pups were injected with BrdU and were killed after either 2 h or 52-60 days (P52-60). Evaluation of the number of proliferating (BrdU+) cells in various forebrain neurogenic niches of P2 mice showed that in treated Ts65Dn mice proliferation potency was improved or even restored in most of the examined regions, including the hippocampus. Quantification of the surviving BrdU+ cells in the dentate gyrus of P52-60 mice showed no difference between treated and untreated Ts65Dn mice. At P52-60, however, treated Ts65Dn mice exhibited a larger number of granule cells in comparison with their untreated counterparts, although their number did not reach that of euploid mice. Results show that 7,8-DHF has a widespread impact on prenatal proliferation potency in Ts65Dn mice and exerts mild long-term effects. It remains to be established whether treatment extending into the neonatal period can lead to an improvement in brain development that is retained in adulthood.

Topics: Animals; Animals, Newborn; Brain; Bromodeoxyuridine; Cell Proliferation; Disease Models, Animal; Down Syndrome; Female; Flavones; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitosis; Neurogenesis; Neurons; Pregnancy; Prenatal Care; Treatment Outcome

Intracerebroventricular (ICV) streptozotocin (STZ) mimics sporadic Alzheimer's disease (SAD) characterized by tau pathology and neurodegeneration arising from oxidative stress, mitochondrial dysfunction, and insulin resistance. 7,8-Dihydroxyflavone (7,8-DHF) is a flavonoid having antioxidant property interlinked with mitochondrial functioning and insulin actions.. To evaluate the neuroprotective and cognitive enhancement properties of 7,8-DHF in an ICV-STZ rat model of SAD.. ICV-STZ (3 mg/kg) was injected into male Wistar rats. Cognitive functions were evaluated by Morris water maze (MWM) and novel object recognition (NOR). 7,8-DHF (5 mg/kg, 10 mg/kg, and 20 mg/kg) and rivastigmine (2 mg/kg) were given orally for 21 days. Reduced glutathione (GSH), catalase, superoxide dismutase (SOD), glutathione peroxidase (GPX), lipid peroxidation (LPO), protein carbonylation (PCO), and nitrite assays were performed. Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were determined. ELISA for the insulin-degrading enzyme (IDE) and p-tau was done. Histopathology was investigated by hematoxylin and eosin staining.. 7,8-DHF treatment attenuated ICV-STZ-induced cognitive deficit in MWM and NOR. Moreover, in the cortex and hippocampus regions of the brain, GSH, catalase, SOD, GPX, LPO, PCO, and nitrite levels were reversed. Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were also normalized. IDE and p-tau protein were found to be significantly altered. 7,8-DHF provided protection from neuronal cell death examined in histopathology.. Conclusively, 7,8-DHF was found to be neuroprotective in the ICV-STZ rat model by ameliorating oxidative stress, mitochondrial dysfunction, and insulin resistance, thereby improving cognitive functions evident with the behavioral results.

Topics: Alzheimer Disease; Animals; Cognition; Disease Models, Animal; Dose-Response Relationship, Drug; Flavones; Injections, Intravenous; Insulin Resistance; Male; Maze Learning; Mitochondria; Oxidative Stress; Rats; Rats, Wistar; Streptozocin

Reduced brain-derived neurotrophic factor (BDNF) signalling has been implicated in schizophrenia endophenotypes, including deficits in prepulse inhibition (PPI). Maternal immune activation (MIA) is a widely used neurodevelopmental animal model for schizophrenia but it is unclear if BDNF and its receptor, tropomyosin receptor kinase B (TrkB), are involved in PPI regulation in this model. Pregnant Long Evans rats were treated with the viral mimetic, polyinosinic-polycytidylic acid (poly I:C; 4 mg/kg i.v.), and nine male offspring from these dams were compared in adulthood to 11 male Long Evans controls. Offspring underwent PPI testing following injection with the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) (10 mg/kg i.p.), with or without the dopamine receptor agonist, apomorphine (APO; 1 mg/kg s.c.), or the dopamine releasing drug, methamphetamine (METH; 2 mg/kg s.c.). Acute administration of APO and METH caused the expected significant reduction of PPI. Acute administration of 7,8-DHF did not alter PPI on its own; however, it significantly reversed the effect of APO on PPI in poly I:C rats, but not in controls. A similar trend was observed in combination with METH. Western blot analysis of frontal cortex revealed significantly increased levels of BDNF protein, but not TrkB or phosphorylated TrkB/TrkB levels, in poly I:C rats. These findings suggest that, selectively in MIA offspring, 7,8-DHF has the ability to reverse PPI deficits caused by dopaminergic stimulation. This effect could be associated with increased BDNF expression in the frontal cortex. These data suggest that targeting BDNF signalling may have therapeutic potential for the treatment of certain symptoms of schizophrenia.

Topics: Animals; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Drug Discovery; Flavones; Frontal Lobe; Male; Prepulse Inhibition; Rats; Rats, Long-Evans; Receptor, trkB; Schizophrenia; Signal Transduction

Imbalances in bone formation and resorption cause osteoporosis. Mounting evidence supports that brain-derived neurotrophic factor (BDNF) implicates in this process. 7,8-Dihydroxyflavone (7,8-DHF), a plant-derived small molecular TrkB agonist, mimics the functions of BDNF. We show that both BDNF and 7,8-DHF promoted the proliferation, osteogenic differentiation, and mineralization of MC3T3-E1 cells. These effects might be attributed to the activation of the Wnt/β-catenin signaling pathway as the expression of cyclin D1, phosphorylated-glycogen synthase kinase-3β (p-GSK3β), β-catenin, Runx2, Osterix, and osteoprotegerin (OPG) was all significantly up-regulated. Knockdown of β-catenin restrained the up-regulation of Runx2 and Osterix stimulated by 7,8-DHF. In particular, blocking TrkB by its specific inhibitor K252a suppressed 7,8-DHF-induced osteoblastic proliferation, differentiation, and expression of osteoblastogenic genes. Moreover, BDNF and 7,8-DHF repressed osteoclastic differentiation of RAW264.7 cells. The transcription factor c-fos and osteoclastic genes such as tartrate-resistant acid phosphatase (TRAP), matrix metalloprotein-9 (MMP-9), Adamts5 were inhibited by 7,8-DHF. More importantly, 7,8-DHF attenuated bone loss, improved trabecular microarchitecture, tibial biomechanical properties, and bone biochemical indexes in an ovariectomy (OVX) rat model. The current work highlights the dual regulatory effects that 7,8-DHF exerts on bone remodeling.

Topics: Animals; beta Catenin; Bone and Bones; Bone Remodeling; Cell Differentiation; Cell Proliferation; Core Binding Factor Alpha 1 Subunit; Cyclin D1; Disease Models, Animal; Female; Flavones; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Osteoprotegerin; Ovariectomy; Rats; Sp7 Transcription Factor; Wnt Signaling Pathway

Neuroplasticity is a fundamental property of the respiratory control system, enabling critical adaptations in breathing to meet the challenges, but little is known whether neonates express neuroplasticity similar to adults. We tested the hypothesis that, similar to adults, tyrosine receptor kinase B (TrkB) or adenosine A2a receptor activation in neonates are independently sufficient to elicit respiratory motor facilitation, and that co-induction of TrkB and A2a receptor-dependent plasticity undermines respiratory motor facilitation. TrkB receptor activation with 7,8-dihydroxyflavone (DHF) in neonatal brainstem-spinal cord preparations induced a long-lasting increase in respiratory motor output in 55 % of preparations, whereas adenosine A2a receptor activation with CGS21680 only sporadically induced respiratory motor plasticity. CGS21680 and DHF co-application prevented DHF-dependent respiratory motor facilitation, whereas co-application of MSX-3 (adenosine A2a receptor antagonist) and DHF more rapidly induced respiratory motor plasticity. Collectively, these data suggest that mechanisms underlying respiratory neuroplasticity may be only partially operational in early neonatal life, and that adenosine A2a receptor activation undermines TrkB-induced respiratory plasticity.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Animals; Animals, Newborn; Brain Stem; Disease Models, Animal; Flavones; Neuronal Plasticity; Phenethylamines; Rats; Receptor, Adenosine A2A; Receptor, trkB; Respiratory Physiological Phenomena; Spinal Cord

Parkinson's disease (PD) is caused by neurodegeneration of nigrostriatal neurons, resulting in dopamine (DA) stimulated motor deficits. Like brain derived neurotrophic factor (BDNF), 7,8-dihydroxyflavone (DHF) is an agonist of the tropomyosin receptor kinase-B (TrkB) and stimulates the same secondary cascades that promote neuronal growth, survival and differentiation. We used our progressive mouse model of PD by administering increasing doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over 4 weeks (5 days/week), and then treated mice with DHF for 4 weeks after the cessation of the toxin injections (i.e., restoration). Mice treated with DHF recovered motorically, even after MPTP administration. Despite a 75% loss of tyrosine hydroxylase (TH) expression in the dorsolateral (DL) striatum in the MPTP group, mice treated with DHF had a recovery comparable to that found in the respective control. There was no recovery of DA tissue levels within the DL striatum. In both the DL striatum and substantia nigra (SN)/midbrain, phosphorylated TrkB and secondary messengers were significantly increased following DHF compared to the MPTP only group. Expression of the sprouting biomarker, superior cervical ganglion 10 (SCG10), was increased ∼20% in the DL striatum and 66% in the SN/midbrain in mice treated with DHF compared to the MPTP only group. We report that after 4 weeks of progressive MPTP administration, DHF can restore motor deficits and TH within the DL striatum in a TrkB-dependent manner. Our data suggests that DHF may help alleviate motor symptoms of PD and restore the loss of DA terminals within the striatum.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Corpus Striatum; Disease Models, Animal; Flavones; Gait; Mice; Mice, Inbred C57BL; Parkinson Disease; Parkinsonian Disorders; Substantia Nigra; Tyrosine; Tyrosine 3-Monooxygenase

Although endogenous analgesia plays an important role in controlling pain states, chronic pain patients exhibit decreased endogenous analgesia compared to healthy individuals. In rats, noxious stimulus-induced analgesia (NSIA), which is an indicator of endogenous analgesia, diminished 6 weeks after spinal nerve ligation (SNL6W). A recent study in rats with deleted noradrenergic fibers demonstrated that the noradrenergic fibers were essential to NSIA. It has also been reported that brain-derived neurotrophic factor increased spinal noradrenergic fibers. Therefore, this study examined the effect of TrkB activation, which is the receptor for brain-derived neurotrophic factor, on impaired NSIA in SNL6W rats. In addition, we also examined the effect of endogenous analgesia on acute incisional pain.. After 5 daily intraperitoneal injections of 7,8-dihydroxyflavone (7,8-DHF, TrkB agonist, 5 mg/kg), NSIA was examined by measuring the withdrawal threshold increment in the left (contralateral to nerve ligation) hindpaw at 30 minutes after capsaicin injection (250 μg) in the forepaw. K252a (TrkB antagonist, 2 μg) was administrated intrathecally for 5 days. Idazoxan (α2 adrenoceptor antagonist, 30 μg), atropine (muscarinic antagonist, 30 μg), and propranolol (nonselective β adrenoceptor antagonist, 30 μg) were administered intrathecally for 15 minutes before capsaicin injection. Microdialysis and immunohistochemistry were performed to examine the noradrenergic plasticity in the spinal dorsal horn. A hindpaw incision was performed on the left (contralateral to nerve ligation) hindpaw. Data were analyzed by 1-way analyses of variance or 2-way repeated-measures 1-way analysis of variance followed by a Student t test with Bonferroni correction.. Five daily intraperitoneal injections of 7,8-DHF restored the attenuated NSIA in SNL6W rats (n = 7, P = .002; estimated treatment effect [95% CI]: 62.9 [27.0-98.7] g), with this effect blocked by 5 daily intrathecal coadministrations of K252a (n = 6, P < .001; -57.8 [-78.3 to -37.2] g). This effect was also inhibited by a single intrathecal administration of idazoxan (n = 8, P < .001; -61.6 [-92.4 to -30.9] g) and atropine (n = 8, P = .003; -52.6 [-73.3 to -31.9] g), but not by propranolol. Furthermore, 7,8-DHF increased the noradrenergic fiber in the spinal dorsal horn and the noradrenaline release in response to the capsaicin injection in the forepaw in SNL6W rats. In addition, repeated injections of 7,8-DHF prevented delayed recovery from incisional pain in SNL6W rats.. Spinal activation of TrkB may recover the attenuated endogenous analgesia by improving the adrenergic plasticity, thereby leading to prevention of pain prolongation after surgery.

Topics: Adrenergic Fibers; Analgesics; Animals; Disease Models, Animal; Enzyme Activation; Flavones; Male; Neuralgia; Neuronal Plasticity; Norepinephrine; Pain Threshold; Rats, Sprague-Dawley; Receptor, trkB; Signal Transduction; Spinal Cord Dorsal Horn

A rat model of neuropathic pain at 6 weeks after spinal nerve ligation (SNL6w) exhibits both mechanical hypersensitivity and impaired noxious stimuli-induced analgesia (NSIA). Repeated treatment with antidepressants can produce antihypersensitivity and restore NSIA. To examine the involvement of a brain-derived neurotrophic factor-mediated mechanism, a tropomyosin receptor kinase B (TrkB) agonist, 7,8-dihydroxyflavone (DHF), was administered to SNL6w rats (5 mg/kg/d for 5 days). Mechanical hypersensitivity was evaluated using the von Frey filament test and paw pressure test. NSIA was examined by measuring the change in the hind paw withdrawal threshold 30 minutes after painful stimulation induced by capsaicin injection into the fore paw. Changes in the concentrations of glutamate and GABA in the locus coeruleus area were measured by in vivo microdialysis. DHF treatment did not affect mechanical hypersensitivity, although it restored NSIA by reducing GABA release in response to the fore paw capsaicin injection. DHF treatment did not alter the baseline concentration of glutamate or GABA. These findings suggest that DHF treatment restored the stimuli-response activity of the locus coeruleus without affecting the tonic activity of the locus coeruleus. The brain-derived neurotrophic factor-TkB signaling is also involved in the NSIA-restoring effect of amitriptyline. PERSPECTIVE: This article demonstrates that repeated treatment with TrkB agonist, DHF, restored endogenous analgesia. Repeated amitriptyline treatment showed similar effect via TrkB-mediated mechanisms, and the effect may be independent from the effect of antihypersensitivity. This effect of TrkB activation is promising for patients with chronic pain with impaired descending inhibition.

Topics: Analgesics; Animals; Disease Models, Animal; Flavones; gamma-Aminobutyric Acid; Glutamic Acid; Hyperalgesia; Locus Coeruleus; Male; Neuralgia; Pregabalin; Random Allocation; Rats, Sprague-Dawley; Receptor, trkB; Spinal Nerves

Childhood lead (Pb2+) intoxication is a public health problem of global proportion. Lead exposure during development produces multiple effects on the central nervous system including impaired synapse formation, altered synaptic plasticity, and learning deficits. In primary hippocampal neurons in culture and hippocampal slices, Pb2+ exposure inhibits vesicular release and reduces the number of fast-releasing sites, an effect associated with Pb2+ inhibition of NMDA receptor-mediated trans-synaptic Brain-Derived Neurotrophic Factor (BDNF) signaling. The objective of this study was to determine if activation of TrkB, the cognate receptor for BDNF, would rescue Pb2+-induced impairments of vesicular release. Rats were chronically exposed to Pb2+ prenatally and postnatally until 50 days of age. This chronic Pb2+ exposure paradigm enhanced paired-pulse facilitation of synaptic potentials in Schaffer collateral-CA1 synapses in the hippocampus, a phenomenon indicative of reduced vesicular release probability. Decreased vesicular release probability was confirmed by both mean-variance analysis and direct 2-photon imaging of vesicular release from hippocampal slices of rats exposed to Pb2+in vivo. We also found a Pb2+-induced impairment of calcium influx in Schaffer collateral-CA1 synaptic terminals. Intraperitoneal injections of Pb2+ rats with the TrkB receptor agonist 7,8-dihydroxyflavone (5 mg/kg) for 14-15 days starting at postnatal day 35, reversed all Pb2+-induced impairments of presynaptic transmitter release at Schaffer collateral-CA1 synapses. This study demonstrates for the first time that in vivo pharmacological activation of TrkB receptors by small molecules such as 7,8-dihydroxyflavone can reverse long-term effects of chronic Pb2+ exposure on presynaptic terminals, pointing to TrkB receptor activation as a promising therapeutic intervention in Pb2+-intoxicated children.

Topics: Animals; CA1 Region, Hippocampal; Calcium Signaling; Disease Models, Animal; Evoked Potentials; Female; Flavones; Lead; Lead Poisoning, Nervous System, Childhood; Neuronal Plasticity; Patch-Clamp Techniques; Presynaptic Terminals; Pyramidal Cells; Rats, Long-Evans; Synaptic Transmission; Synaptic Vesicles

The BDNF mimetic compound 7,8-dihydroxyflavone (7,8-DHF), a potent small molecular TrkB agonist, displays prominent therapeutic efficacy against Alzheimer's disease (AD). However, 7,8-DHF has only modest oral bioavailability and a moderate pharmacokinetic (PK) profile. To alleviate these preclinical obstacles, we used a prodrug strategy for elevating 7,8-DHF oral bioavailability and brain exposure, and found that the optimal prodrug R13 has favorable properties and dose-dependently reverses the cognitive defects in an AD mouse model. We synthesized a large number of 7,8-DHF derivatives via ester or carbamate group modification on the catechol ring in the parent compound. Using in vitro absorption, distribution, metabolism, and excretion assays, combined with in vivo PK studies, we identified a prodrug, R13, that prominently up-regulates 7,8-DHF PK profiles. Chronic oral administration of R13 activated TrkB signaling and prevented Aβ deposition in 5XFAD AD mice, inhibiting the pathological cleavage of APP and Tau by AEP. Moreover, R13 inhibited the loss of hippocampal synapses and ameliorated memory deficits in a dose-dependent manner. These results suggest that the prodrug R13 is an optimal therapeutic agent for treating AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Disease Models, Animal; Flavones; Humans; Male; Membrane Glycoproteins; Mice; Mice, Transgenic; Prodrugs; Protein-Tyrosine Kinases

Interest in brain-derived neurotrophic factor (BDNF) was greatly enhanced when it was recognized that its expression is reduced in neurodegenerative disorders, especially in Alzheimer's disease (AD). BDNF signaling through the TrkB receptor has a central role in promoting synaptic transmission, synaptogenesis, and facilitating synaptic plasticity making the BDNF-TrkB signaling pathway an attractive candidate for targeted therapies. Here we investigated the early effect of the small molecule TrkB agonist, 7,8 dihydroxyflavone (7,8-DHF), on AD-related pathology, dendritic arborization, synaptic density, and neurochemical changes in the 5xFAD mouse model of AD. We treated 5xFAD mice with 7,8-DHF for 2 months beginning at 1 month of age. We found that, in this model of AD, 7,8-DHF treatment decreased cortical Aβ plaque deposition and protected cortical neurons against reduced dendritic arbor complexity but had no significant impact on the density of dendritic spines. In addition 7,8-DHF treatment protected against hippocampal increase in the level of choline-containing compounds and glutamate loss, but had no significant impact on hippocampal neurogenesis.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Dendritic Spines; Disease Models, Animal; Flavones; Hippocampus; Mice; Neuroprotective Agents; Peptide Fragments

Brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB) signaling plays a key role in the brain neurodevelopment. The exposure of pregnant mice to polyinosinic-polycytidylic acid [poly(I:C)] causes cognitive deficits in adult offspring. Supplementation with a TrkB agonist, 7,8-dihydroxyflavone, in poly(I:C)-treated pregnant mice from pregnancy to weaning could prevent the onset of cognitive deficits and reduced BDNF-TrkB signaling in the prefrontal cortex of their adult offspring. These findings suggest that supplementation with a TrkB agonist in pregnant women with an ultra-high risk of psychosis may reduce the development of psychosis in their offspring.

Topics: Analysis of Variance; Animals; Brain; Brain-Derived Neurotrophic Factor; Cognition Disorders; Disease Models, Animal; Drug Administration Schedule; Female; Flavones; Interferon Inducers; Locomotion; Male; Mice; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; Receptor, trkB; Recognition, Psychology; Signal Transduction

Huntington's disease (HD) is a fatal neurodegenerative disease with motor, cognitive and psychiatric impairment. Dysfunctions in HD models have been related to reduced levels of striatal brain-derived neurotrophic factor (BDNF) and imbalance between its receptors TrkB and p75(NTR). Thus, molecules with activity on the BDNF/TrkB/p75 system can have therapeutic potential. 7,8-Dihydroxyflavone (7,8-DHF) was described as a TrkB agonist in several models of neuro-degenerative diseases, however, its TrkB activation profile needs further investigation due to its pleiotropic properties and divergence from BDNF effect. To investigate this, we used in vitro and in vivo models of HD to dissect TrkB activation upon 7,8-DHF treatment. 7,8-DHF treatment in primary cultures showed phosphorylation of TrkBY816 but not TrkBY515 with activation of the PLCγ1 pathway leading to morphological and functional improvements. Chronic administration of 7,8-DHF delayed motor deficits in R6/1 mice and reversed deficits on the Novel Object Recognition Test (NORT) at 17 weeks. Morphological and biochemical analyses revealed improved striatal levels of enkephalin, and prevention of striatal volume loss. We found a TrkBY816 but not TrkBY515 phosphorylation recovery in striatum concordant with in vitro results. Additionally, 7,8-DHF normalized striatal levels of induced and neuronal nitric oxide synthase (iNOS and nNOS, respectively) and ameliorated the imbalance of p75/TrkB. Our results provide new insights into the mechanism of action of 7,8-DHF suggesting that its effect through the TrkB receptor in striatum is via selective phosphorylation of its Y816 residue and activation of PLCγ1 pathway, but pleiotropic effects of the drug also contribute to its therapeutic potential.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cognition; Corpus Striatum; Disease Models, Animal; Flavones; Hippocampus; Huntington Disease; Mice; Mice, Transgenic; Motor Neurons; Phospholipase C gamma; Phosphorylation; Receptor, trkB; Signal Transduction

Intellectual disability is the unavoidable hallmark of Down syndrome (DS), with a heavy impact on public health. Reduced neurogenesis and impaired neuron maturation are considered major determinants of altered brain function in DS. Since the DS brain starts at a disadvantage, attempts to rescue neurogenesis and neuron maturation should take place as soon as possible. The brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a key role in brain development by specifically binding to tropomyosin-related kinase receptor B (TrkB). Systemic BDNF administration is impracticable because BDNF has a poor blood-brain barrier penetration. Recent screening of a chemical library has identified a flavone derivative, 7,8-dihydroxyflavone (7,8-DHF), a small-molecule that crosses the blood-brain barrier and binds with high affinity and specificity to the TrkB receptor. The therapeutic potential of TrkB agonists for neurogenesis improvement in DS has never been examined. The goal of our study was to establish whether it is possible to restore brain development in the Ts65Dn mouse model of DS by targeting the TrkB receptor with 7,8-DHF. Ts65Dn mice subcutaneously injected with 7,8-DHF in the neonatal period P3-P15 exhibited a large increase in the number of neural precursor cells in the dentate gyrus and restoration of granule cell number, density of dendritic spines and levels of the presynaptic protein synaptophysin. In order to establish the functional outcome of treatment, mice were treated with 7,8-DHF from P3 to adolescence (P45-50) and were tested with the Morris Water Maze. Treated Ts65Dn mice exhibited improvement of learning and memory, indicating that the recovery of the hippocampal anatomy translated into a functional rescue. Our study in a mouse model of DS provides novel evidence that treatment with 7,8-DHF during the early postnatal period restores the major trisomy-linked neurodevelopmental defects, suggesting that therapy with 7,8-DHF may represent a possible breakthrough for Down syndrome.

Topics: Animals; Animals, Newborn; Brain-Derived Neurotrophic Factor; Cells, Cultured; Disease Models, Animal; Down Syndrome; Female; Flavones; Flavonoids; Hippocampus; Male; Memory; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Neurogenesis; Pilot Projects; Receptor, trkB

Down syndrome (DS) is caused by the triplication of human chromosome 21 and represents the most frequent genetic cause of intellectual disability. The trisomic Ts65Dn mouse model of DS shows synaptic deficits and reproduces the essential cognitive disabilities of the human syndrome. Aerobic exercise improved various neurophysiological dysfunctions in Ts65Dn mice, including hippocampal synaptic deficits, by promoting synaptogenesis and neurotransmission at glutamatergic terminals. Most importantly, the same intervention also prompted the recovery of hippocampal adult neurogenesis and synaptic plasticity and restored cognitive performance in trisomic mice. Additionally, the expression of brain-derived neurotrophic factor (BDNF) was markedly decreased in the hippocampus of patients with DS. Since the positive effect of exercise was paralleled by increased BDNF expression in trisomic mice, we investigated the effectiveness of a BDNF-mimetic treatment with 7,8-dihydroxyflavone at alleviating intellectual disabilities in the DS model. Pharmacological stimulation of BDNF signaling rescued synaptic plasticity and memory deficits in Ts65Dn mice. Based on our findings, Ts65Dn mice benefit from interventions aimed at promoting brain plasticity, and we provide evidence that BDNF signaling represents a potentially new pharmacological target for treatments aimed at rescuing cognitive disabilities in patients with DS.

Topics: Animals; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Down Syndrome; Excitatory Postsynaptic Potentials; Female; Flavones; Hippocampus; Humans; Learning; Male; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurogenesis; Neuronal Plasticity; Physical Conditioning, Animal; Signal Transduction

7,8-Dihydroxyflavone (DHF), is a recently described TrkB agonist that readily crosses the blood brain barrier. We treated C57Bl/6 mice with MOG--induced EAE daily with DHF starting on the day of disease induction. Clinical severity of impairment was reduced throughout the course of disease. Pathological examination of brains and spinal cords on day 28 showed that DHF treatment increased the phosphorylation of TrkB and activated downstream signaling pathways including AKT and STAT3 and reduced inflammation, demyelination and axonal loss compared to EAE controls. DHF treatment duplicated the central nervous system effects of brain derived neurotrophic factor in the EAE.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Apoptosis; bcl-2-Associated X Protein; Brain; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Flavones; Humans; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Severity of Illness Index; Signal Transduction; Spinal Cord; Time Factors

Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic situations and it is characterized by cognitive deficits that include impaired explicit memory. The neurobiological bases of such PTSD-associated memory alterations are yet to be elucidated and no satisfactory treatment for them exists. To address this issue, we first studied whether a single exposure of young adult rats (60 days) to immobilization on boards (IMO), a putative model of PTSD, produces long-term behavioral effects (2-8 days) similar to those found in PTSD patients. Subsequently, we investigated whether the administration of the TrkB agonist 7,8-dihydroxyflavone (DHF) 8 h after stress (therapeutic window) ameliorated the PTSD-like effect of IMO and the associated changes in synaptic plasticity. A single IMO exposure induced a spatial memory impairment similar to that found in other animal models of PTSD or in PTSD patients. IMO also increased spine density and long-term potentiation (LTP) in the CA3-CA1 pathway. Significantly, DHF reverted both spatial memory impairment and the increase in LTP, while it produced no effect in the controls. These data provide novel insights into the possible neurobiological substrate for explicit memory impairment in PTSD patients, supporting the idea that the activation of the BDNF/TrkB pathway fulfils a protective role after severe stress. Administration of DHF in the aftermath of a traumatic experience might be relevant to prevent its long-term consequences. © 2016 Wiley Periodicals, Inc.

Topics: Animals; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Dendritic Spines; Disease Models, Animal; Flavones; Long-Term Potentiation; Male; Memory Disorders; Psychotropic Drugs; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, trkB; Restraint, Physical; Spatial Memory; Stress Disorders, Post-Traumatic; Stress, Psychological; Tissue Culture Techniques

Parkinson disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and diminished dopamine content in the striatum, which is at least partly associated with α-synuclein protein overexpression in these neurons. Recent reports show that 7,8-dihydroxyflavone (DHF), a TrkB agonist, has beneficial effects in animal model of PD. However, it is unclear whether the therapeutic effects of DHF are associated with the expression of α-synuclein.. In this study, we investigated the protective effects of DHF on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced deficit of motor functions, the loss of dopaminergic neurons and the expression of α-synuclein as well as antioxidative activity in the C57BL/6 mice.. Mice were treated with MPTP (30 mg/kg, i.p.) once a day for 5 days to induce dopaminergic neuron death in the SN. DHF (5 mg/kg, i.p.) was administrated once a day from the first day of MPTP injection until 9 days after the last injection of MPTP. Behavioral tests showed that DHF succeeded in ameliorating the impaired motor functions in the MPTP-treated mice. The immunohistochemical assay showed that the amelioration of motor function was accompanied by a reduction in the loss of dopaminergic neurons in the SN and striatum. Western blot analyses showed that DHF prevented the inactivation of TrkB and suppressed α-synuclein overexpression in the SN and striatum following MPTP treatment. Antioxidative activity detection revealed that DHF prevented MPTP-induced reduction in glutathione and total superoxide dismutase activity in the SN and striatum.. Taken together, these results indicate that DHF treatment may suppress the accumulation of α-synuclein and oxidative stress via activating TrkB and subsequently block the loss of dopaminergic neurons in the SN and striatum, thereby ameliorating MPTP-induced motor deficits in the C57BL/6 mice.

Topics: alpha-Synuclein; Analysis of Variance; Animals; Antiparkinson Agents; Cell Death; Disease Models, Animal; Flavones; Gene Expression Regulation; Mice; Mice, Inbred C57BL; Movement; MPTP Poisoning; Oxidative Stress; Psychomotor Performance; Receptor, trkA; Rotarod Performance Test; Tyrosine 3-Monooxygenase

The α7 subtype of nicotinic acetylcholine receptor (nAChR) plays a role in the inflammation which is implicated in depression. This study was undertaken to examine the role of α7 nAChR in depression using α7 nAChR knock-out (KO) mice. Serum levels of tumor necrosis factor-α and interlukin-1β in KO mice were higher than wild-type mice, suggesting an inflammatory process in KO mice. α7 nAChR KO mice showed depression-like phenotype. Furthermore, KO mice showed increased brain-derived neurotrophic factor (BDNF) and its receptor TrkB signaling, as well as increased synaptogenesis and spine density in the nucleus accumbens (NAc), although BDNF-TrkB signaling and synaptogenesis were not altered in the prefrontal cortex and hippocampus. Systemic administration of the TrkB antagonist ANA-12, but not the TrkB agonist 7,8-dihydroxyflavone and the selective serotonin reuptake inhibitor fluoxetine, showed a rapid antidepressant effect in KO mice by normalizing increased synaptogenesis in the NAc. In addition, bilateral infusion of ANA-12 into NAc promoted a rapid antidepressant effect in KO mice by normalizing increased synaptogenesis in the NAc. These findings suggest that increased BDNF-TrkB signaling and synaptogenesis in the NAc by deletion of α7 nAChR plays a key role in depression.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Antidepressive Agents; Azepines; Behavior, Animal; Benzamides; Brain-Derived Neurotrophic Factor; Dendritic Spines; Depression; Dexamethasone; Disease Models, Animal; Flavones; Fluoxetine; Gene Deletion; Hippocampus; Inflammation; Interleukin-1beta; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nucleus Accumbens; Phenotype; Receptor, trkB; Selective Serotonin Reuptake Inhibitors; Signal Transduction; Tumor Necrosis Factor-alpha

Prenatal infection and subsequent abnormal neurodevelopment of offspring is involved in the etiology of schizophrenia. Brain-derived neurotrophic factor (BDNF) and its high affinity receptor, tropomyosin receptor kinase B (TrkB) signaling plays a key role in the neurodevelopment. Pregnant mice exposed to polyriboinosinic-polyribocytidylic acid [poly(I:C)] causes schizophrenia-like behavioral abnormalities in their offspring at adulthood. Here we found that the juvenile offspring of poly(I:C)-treated mice showed cognitive deficits, as well as reduced BDNF-TrkB signaling in the prefrontal cortex (PFC). Furthermore, the adult offspring of poly(I:C)-treated mice showed cognitive deficits, prepulse inhibition (PPI) deficits, reduced BDNF-TrkB signaling, immunoreactivity of parvalbumin (PV) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in the prelimbic (PrL) of medial PFC and CA1 of hippocampus. Supplementation of a TrkB agonist 7,8-dihydroxyflavone (1 mg/mL in drinking water) during juvenile and adolescent stages could prevent these behavioral abnormalities, reduced BDNF-TrkB signaling in PFC and CA1, and immunoreactivity of PV and PGC-1α in the PrL of medial PFC and CA1 in the adult offspring from poly(I:C)-treated mice. These findings suggest that early intervention by a TrkB agonist in subjects with ultra-high risk for psychosis may reduce the risk of subsequent transition to schizophrenia.

Topics: Adult Children; Animals; Disease Models, Animal; Flavones; Hippocampus; Mice; Prefrontal Cortex; Psychotic Disorders; Receptor, trkB

Fragile X syndrome (FXS) is characterized by immature dendritic spine architectures and cognitive impairment. 7, 8-Dihydroxyflavone (7, 8-DHF) has recently been identified as a high affinity tropomyosin receptor kinase B (TrkB) agonist. The purpose of this paper was to examine the utility of 7, 8-DHF as an effective pharmacotherapeutic agent that targets dendritic pathology and cognitive impairments in FXS mutant. We synthesized pharmacologic, behavioral, and biochemical approaches to examine the effects of 7, 8-DHF on spatial and fear memory functions, and morphological spine abnormalities in fragile X mental retardation 1 (Fmr1) gene knock-out mice. The study found that 4 weeks of treatment with 7, 8-DHF improved spatial and fear memory, and ameliorated morphological spine abnormalities including the number and elongation of spines in the hippocampus and amygdala. Further mechanism analysis revealed that 7, 8-DHF enhanced the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluA1 receptor, but reduced the normal levels of GluA2 at the synapses in Fmr1. Potentially related to drug-induced changes in AMPA receptor subunits, 7, 8-DHF at the synapses led to phosphorylation of specific serine sites on subunits Ser818 and Ser813 of GluA1, and Ser880 of GluA2, as well as phosphorylation of TrkB, calcium/calmodulin-dependent protein kinase II, and protein kinase C. However, 7, 8-DHF neither affected behavioral performance nor increased TrkB phosphorylation in WT mice, which suggested that it had FXS-specific correcting effect. Altogether, these results demonstrated that 7, 8-DHF improved learning and memory, and reduced abnormalities in spine morphology, thus providing a potential pharmacotherapeutic strategy for FXS.

Topics: Animals; Cognition Disorders; Dendritic Spines; Disease Models, Animal; Flavones; Fragile X Syndrome; Gene Expression Regulation; Male; Mice; Mice, Knockout; Receptors, AMPA; Synapses

It is reported that 7,8-dihydroxyflavone (DHF), a TrkB agonist, has beneficial effects on neuronal excitotoxicity, stroke, and Parkinson disease in animal models by enhancing axon regeneration, muscle reinnervation and neuromuscular transmission. The effect of DHF on AD neuropathology remains not well defined. In this study we examined whether DHF affects APP processing and cognitive functions in vitro and in vivo. We found that DHF had no significant effect on amyloid β precursor protein (APP), BACE1 and amyloid β protein (Aβ). DHF had little effect on APP processing in cell cultures. DHF treatment did not reduce the deposition of Aβ to form neuritic plaques in the brain of AD model mice APP23/PS45. Furthermore, DHF did not alleviate learning and memory impairments in the AD model mice. Our study suggest that further extensive and careful studies are warranted for considering DHF as a new therapeutic agent for reducing amyloid pathology and alleviating cognitive deficits for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Antipsychotic Agents; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Flavones; HEK293 Cells; Humans; Maze Learning; Mice; Mice, Transgenic; Mutation; Peptide Fragments; Presenilin-1; RNA, Messenger; Time Factors; Transfection

Accumulation of stressful events can render individuals susceptible to develop epilepsy and comorbidities. Whether such vulnerability can be predicted and reversed is not known. Here we show that social defeat, although not producing depression by itself, produced in 50% of rats reduced threshold for status epilepticus (SE), accelerated epileptogenesis, and once epilepsy was induced, depression-like profile and cognitive deficits. Low serum brain-derived neurotrophic factor (BDNF) levels measured before SE identified this vulnerable population. Treatment with a BDNF analog before SE prevented the occurrence of comorbidities. Thus, vulnerability to comorbidities after epilepsy onset due to unresolved past stressful events may be predicted and reversed.

Topics: Allostasis; Animals; Brain-Derived Neurotrophic Factor; Cognition Disorders; Depression; Disease Models, Animal; Epilepsy; Excitatory Amino Acid Agonists; Flavones; Hypothalamo-Hypophyseal System; Kainic Acid; Male; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Social Environment; Status Epilepticus; Stress, Psychological

Previous studies in rodents have shown that after a moderate traumatic brain injury (TBI) with a controlled cortical impact (CCI) device, the adult-born immature granular neurons in the dentate gyrus are the most vulnerable cell type in the hippocampus. There is no effective approach for preventing immature neuron death after TBI. We found that tyrosine-related kinase B (TrkB), a receptor of brain-derived neurotrophic factor (BDNF), is highly expressed in adult-born immature neurons. We determined that the small molecule imitating BDNF, 7, 8-dihydroxyflavone (DHF), increased phosphorylation of TrkB in immature neurons both in vitro and in vivo. Pretreatment with DHF protected immature neurons from excitotoxicity-mediated death in vitro, and systemic administration of DHF before moderate CCI injury reduced the death of adult-born immature neurons in the hippocampus 24 hours after injury. By contrast, inhibiting BDNF signaling using the TrkB antagonist ANA12 attenuated the neuroprotective effects of DHF. These data indicate that DHF may be a promising chemical compound that promotes immature neuron survival after TBI through activation of the BDNF signaling pathway.

Topics: Animals; Animals, Newborn; Azepines; Benzamides; Brain Injuries; Cell Death; Disease Models, Animal; Dose-Response Relationship, Drug; Flavones; Fluoresceins; Hippocampus; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Phosphorylation; Receptor, trkB; Signal Transduction

Brain-derived neurotrophic factor (BDNF) and signaling at its receptor, tropomyosin-related kinase B (TrkB), are implicated in the rapid and long-lasting antidepressant effects of ketamine. Moreover, a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), and/or TrkB antagonist, ANA-12, shows antidepressant effects in animal models of depression.. The objective of this study is to compare the influence of ketamine, 7,8-DHF, and ANA-12 on antidepressant activity in the social defeat stress model.. In the tail suspension and forced swimming tests, ketamine, 7,8-DHF, or ANA-12 markedly attenuated the increased immobility time in depressed mice compared with the vehicle-treated group. In the sucrose preference test, all drugs significantly improved the reduced preference in depressed mice at both 1 and 3 days after a single dose. Antidepressant effect of ketamine, but not 7,8-DHF or ANA-12, was still detectable 7 days after a single dose. Western blot analyses showed that ketamine, but not 7,8-DHF or ANA-12, markedly attenuated reduced levels of BDNF and postsynaptic density protein 95 (PSD-95) in the prefrontal cortex (PFC), dentate gyrus (DG), and CA3 of the hippocampus in depressed mice 8 days after a single dose. Furthermore, ketamine markedly increased reduced levels of GluA1 in the PFC and DG of depressed mice. In contrast, ketamine showed no effect against increased levels of BDNF, PSD-95, and GluA1 observed in the nucleus accumbens of depressed mice.. Compared with 7,8-DHF and ANA-12, ketamine is a longer-lasting antidepressant in the social defeat stress model, and synaptogenesis may be required for the mechanisms that promote sustained antidepressant effects of ketamine.

Topics: Animals; Antidepressive Agents; Azepines; Benzamides; Brain-Derived Neurotrophic Factor; Depression; Disease Models, Animal; Flavones; Hindlimb Suspension; Hippocampus; Ketamine; Male; Mice; Mice, Inbred C57BL; Nucleus Accumbens; Prefrontal Cortex; Stress, Psychological; Swimming

Role of brain-derived neurotrophic factor (BDNF)-TrkB signaling in a learned helplessness (LH) model of depression was investigated. LH rats showed a reduction of BDNF in the medial prefrontal cortex (mPFC), CA3, and dentate gyrus (DG) of the hippocampus, whereas LH rats showed an increase in BDNF in the nucleus accumbens (NAc). Furthermore, levels of proBDNF, a BDNF precursor, were higher in the mPFC, but lower in the NAc, of LH rats. A single bilateral infusion of a TrkB agonist 7,8-DHF, but not a TrkB antagonist ANA-12, into the infralimbic (IL) of mPFC, DG, and CA3, but not the prelimbic (PrL) of mPFC, exerted antidepressant effects in LH rats. In contrast, a single bilateral infusion of ANA-12, but not 7,8-DHF, into the core and shell of NAc exerted antidepressant-like effects in LH rats, with more potent effects observed for the NAc core than for NAc shell. Interestingly, a single administration of 7,8-DHF (10mg/kg, i.p.) significantly improved a decreased phosphorylation of TrkB in the mPFC, CA3, and DG of LH rats. Additionally, ANA-12 (0.5mg/kg, i.p.) significantly improved an increased phosphorylation of TrkB in the NAc of LH rats. In conclusion, these results suggest that LH causes depression-like behavior by altering BDNF in the brain regions, and that proBDNF-BDNF processing and transport may be altered in the mPFC-NAc circuit of LH rats. Therefore, TrkB agonists might exert antidepressant effects by stimulating TrkB in the IL, CA3, and DG, while TrkB antagonists might exert antidepressant effects by blocking TrkB in the NAc.

Topics: Analysis of Variance; Animals; Antidepressive Agents; Azepines; Benzamides; Brain; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Dose-Response Relationship, Drug; Flavones; Helplessness, Learned; Male; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptor, trkB; Stress, Psychological; Time Factors

Synaptic loss in the brain correlates well with disease severity in Alzheimer disease (AD). Deficits in brain-derived neurotrophic factor/tropomyosin-receptor-kinase B (TrkB) signaling contribute to the synaptic dysfunction of AD. We have recently identified 7,8-dihydroxyflavone (7,8-DHF) as a potent TrkB agonist that displays therapeutic efficacy toward various neurological diseases. Here we tested the effect of 7,8-DHF on synaptic function in an AD model both in vitro and in vivo. 7,8-DHF protected primary neurons from Aβ-induced toxicity and promoted dendrite branching and synaptogenesis. Chronic oral administration of 7,8-DHF activated TrkB signaling and prevented Aβ deposition in transgenic mice that coexpress five familial Alzheimer's disease mutations (5XFAD mice). Moreover, 7,8-DHF inhibited the loss of hippocampal synapses, restored synapse number and synaptic plasticity, and prevented memory deficits. These results suggest that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antipsychotic Agents; Apoptosis; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Female; Flavones; Hippocampus; Humans; In Vitro Techniques; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neurons; Plaque, Amyloid; Synapses

Although 7,8-dihydroxyflavone (7,8-DHF) has been demonstrated to be potently neuroprotective, its effect on vascular function remains unknown.. The effect of 7,8-DHF on phenylephrine (PE)-induced preconstriction was examined with aortic rings isolated from normal rats. Its effective mechanisms were studied with blockers, Western blotting, and primarily cultured vascular smooth myocytes. The blood pressure (BP) of rats was measured with a tail cuff method.. 7,8-DHF dose-dependently dilated the PE-preconstricted, endothelia-intact aortic rings with concentration for 50% of maximal effect (EC50) of approximately 24 µM. Both Nω-nitro-L-arginine methyl ester hydrochloride, a nitric oxide synthase inhibitor, and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a soluble guanylyl cyclase blocker, significantly reduced the vasorelaxing effect of 7,8-DHF. Western blotting showed that 7,8-DHF increased the aortic endothelial nitric oxide synthase protein expression and phosphorylation. With endothelia removed, 7,8-DHF also dilated the PE-preconstricted rings but with EC50 of approximately 104 µM. Ca(2+) imaging experiments detected that 7,8-DHF probably blocked both intracellular Ca(2+) release and extracellular Ca(2+) influx. Therefore, the mechanisms of 7,8-DHF dilating effect might be stimulating the nitric oxide/cGMP production and blocking the Ca(2+) signaling pathway instead of tropomyosin receptor kinase B receptors because ANA-12, its specific antagonist, did not show any effect against 7,8-DHF. When administered intravenously, 7,8-DHF significantly reduced the BP of the spontaneously hypertensive rats. However, when used orally, there was only a slight but significant reduction in the diastolic pressure.. The results suggest that neuro-protective 7,8-DHF is also a vasorelaxing and antihypertensive substance in rats.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Aorta, Thoracic; Calcium Signaling; Cells, Cultured; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Flavones; Hypertension; Injections, Intravenous; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Rats, Inbred SHR; Vasodilation; Vasodilator Agents

Scopolamine (Sco) can induce amyloid β (Aβ) deposition, oxidative stress, synaptic dysfunction, and learning/memory impairment as observed in Alzheimer's disease (AD), the most common form of dementia affecting more than 25 million elderly people worldwide. Herein we explored the protective effect of 7,8-dihydroxyflavone (7,8-DHF) on Sco-induced Aβ deposition, oxidative stress, synaptic dysfunction, and learning/memory defects. Rats were randomly divided into four groups (n=12 for each group). The control group received normal saline (NS); the Sco group received Sco (1 mg/kg per day) intraperitoneally (i.p.) for 2 weeks. Mice in the Sco+7,8-DHF group received 1 mg/kg per day 7,8-DHF i.p. for 2 weeks, followed by Sco (1 mg/kg per day)+1 mg/kg per day 7,8-DHF (i.p.) for another 2 weeks. The 7,8-DHF group received 1 mg/kg per day 7,8-DHF (i.p.) for 4 weeks. Results showed that the supplement of 7,8-DHF significantly reversed Aβ deposition, oxidative stress, synaptic dysfunction, and cognitive defects. Our data suggest that 7,8-DHF might serve as a promising therapeutic candidate for attenuating Sco-induced AD-like pathological dysfuntion.

Topics: Alzheimer Disease; Animals; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Flavones; Male; Maze Learning; Oxidative Stress; Rats; Rats, Sprague-Dawley; Scopolamine

Augmenting BDNF/TrkB signaling has been demonstrated to be a promising strategy for reversing cognitive deficits in preclinical models of Alzheimer disease (AD). Although these studies highlight the potential of targeting BDNF/TrkB signaling, this strategy has not yet been tested in a model that develops the disease features that are most closely associated with cognitive decline in AD: severe synaptic and neuronal loss. In the present study, we investigated the impact of 7,8-dihydroxyflavone (DHF), a TrkB agonist, in CaM/Tet-DTA mice, an inducible model of severe neuronal loss in the hippocampus and cortex. Systemic 7,8-DHF treatment significantly improved spatial memory in lesioned mice, as measured by water maze. Analysis of GFP-labeled neurons in CaM/Tet-DTA mice revealed that 7,8-DHF induced a significant and selective increase in the density of thin spines in CA1 of lesioned mice, without affecting mushroom or stubby spines. These findings suggest chronic upregulation of TrkB signaling with 7,8-DHF may be an effective and practical strategy for improving function in AD, even after substantial neuronal loss has occurred.

Topics: Alzheimer Disease; Animals; Calmodulin; Dendritic Spines; Disease Models, Animal; Flavones; Green Fluorescent Proteins; Mice; Neurons; Pyramidal Cells; Receptor, trkB; Spatial Memory

Cognitive deficits are the core symptoms of schizophrenia and major contributors to disability in schizophrenic patients, but effective treatments are still lacking. Previous studies have demonstrated that impaired BDNF/TrkB signaling is associated with the cognitive impairments of schizophrenia. 7,8-Dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the blood-brain barrier after oral or intraperitoneal administration. The present study aimed to assess the effect of 7,8-DHF on the cognitive and synaptic impairments of schizophrenia. A brief disruption of NMDA receptors with MK-801 during early development serves as an animal model for cognitive deficits of schizophrenia. We found that MK-801-treated rats showed significant deficits in working learning ability and hippocampal synaptic plasticity, as well as reduction of BDNF, TrkB, and phosphorylated TrkB in the hippocampus. After intraperitoneal administration with 7,8-DHF (5 mg/kg) once daily for a consecutive 14days, we found that chronic 7,8-DHF treatment significantly enhanced the activation of phosphorylated TrkB at the Y515 and Y816 sites, increased the phosphorylation levels of TrkB downstream signal cascades including ERK1/2, CaMKII, CREB and GluR1, and promoted hippocampal synaptic plasticity, which in turn rescued performance in spatial working learning. Our results thus demonstrate that activation of TrkB signaling can reverse the cognitive deficits of schizophrenia and strongly suggest a potential usefulness for 7,8-DHF or a TrkB agonist in treating schizophrenia-related cognitive impairments.

Topics: Animals; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Flavones; Hippocampus; Male; Neuronal Plasticity; Organ Culture Techniques; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, trkB; Schizophrenia

Tropomyosin-related kinase B (TrkB) signaling is critical for promoting neuronal survival following brain damage. The present study investigated the effects and underlying mechanisms of TrkB activation by the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) on traumatic brain injury (TBI). Mice subjected to controlled cortical impact received intraperitoneal 7,8-DHF or vehicle injection 10 min post-injury and subsequently daily for 3 days. Behavioral studies, histology analysis and brain water content assessment were performed. Levels of TrkB signaling-related molecules and apoptosis-related proteins were analyzed. The protective effect of 7,8-DHF was also investigated in primary neurons subjected to stretch injury. Treatment with 20 mg/kg 7,8-DHF attenuated functional deficits and brain damage up to post-injury day 28. 7,8-DHF also reduced brain edema, neuronal death, and apoptosis at day 4. These changes were accompanied by a significant decrease in cleaved caspase-3 and increase in Bcl-2/Bax ratio. 7,8-DHF enhanced phosphorylation of TrkB, Akt (Ser473/Thr308), and Bad at day 4, but had no effect on Erk 1/2 phosphorylation. Moreover, 7,8-DHF increased brain-derived neurotrophic factor levels and promoted cAMP response element-binding protein (CREB) activation. This beneficial effect was attenuated by inhibition of TrkB or PI3K/Akt. 7,8-DHF also promoted survival and reduced apoptosis in cortical neurons subjected to stretch injury. Remarkably, delayed administration of 7,8-DHF at 3 h post-injury reduced brain tissue damage. Our study demonstrates that activation of TrkB signaling by 7,8-DHF protects against TBI via the PI3K/Akt but not Erk pathway, and this protective effect may be amplified via the PI3K/Akt-CREB cascades.

Topics: Animals; Apoptosis; Brain Edema; Brain Injuries; Cell Death; Disease Models, Animal; Flavones; Gene Expression Regulation; Injections, Intraperitoneal; MAP Kinase Signaling System; Mice; Neurons; Neuroprotective Agents; Receptor, trkB

It has been recognized that the risk of cognitive decline during aging can be reduced if one maintains strong social connections, yet the neural events underlying this beneficial effect have not been rigorously studied. Here, we show that amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice demonstrate improvement in memory after they are cohoused with wild-type mice. The improvement was associated with increased protein and mRNA levels of BDNF in the hippocampus. Concomitantly, the number of BrdU(+)/NeuN(+) cells in the hippocampal dentate gyrus was significantly elevated after cohousing. Methylazoxymethanol acetate, a cell proliferation blocker, markedly reduced BrdU(+) and BrdU/NeuN(+) cells and abolished the effect of social interaction. Selective ablation of mitotic neurons using diphtheria toxin (DT) and a retrovirus vector encoding DT receptor abolished the beneficial effect of cohousing. Knockdown of BDNF by shRNA transfection blocked, whereas overexpression of BDNF mimicked the memory-improving effect. A tropomyosin-related kinase B agonist, 7,8-dihydroxyflavone, occluded the effect of social interaction. These results demonstrate that increased BDNF expression and neurogenesis in the hippocampus after cohousing underlie the reversal of memory deficit in APP/PS1 mice.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Dentate Gyrus; Diphtheria Toxin; Disease Models, Animal; Flavones; Gene Knockdown Techniques; Hippocampus; Housing, Animal; Male; Memory Disorders; Methylazoxymethanol Acetate; Mice; Mice, Transgenic; Neurogenesis; Presenilin-1; Social Behavior

Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), signaling represent potential therapeutic targets for major depressive disorder. The purpose of this study is to examine whether TrkB ligands show antidepressant effects in an inflammation-induced model of depression.. In this study, we examined the effects of TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist ANA-12 on depression-like behavior and morphological changes in mice previously exposed to lipopolysaccharide (LPS). Protein levels of BDNF, phospho-TrkB (p-TrkB), and TrkB in the brain regions were also examined.. LPS caused a reduction of BDNF in the CA3 and dentate gyrus (DG) of the hippocampus and prefrontal cortex (PFC), whereas LPS increased BDNF in the nucleus accumbens (NAc). Dexamethason suppression tests showed hyperactivity of the hypothalamic-pituitary-adrenal axis in LPS-treated mice. Intraperitoneal (i.p.) administration of 7,8-DHF showed antidepressant effects on LPS-induced depression-like behavior, and i.p. pretreatment with ANA-12 blocked its antidepressant effects. Surprisingly, ANA-12 alone showed antidepressant-like effects on LPS-induced depression-like behavior. Furthermore, bilateral infusion of ANA-12 into the NAc showed antidepressant effects. Moreover, LPS caused a reduction of spine density in the CA3, DG, and PFC, whereas LPS increased spine density in the NAc. Interestingly, 7,8-DHF significantly attenuated LPS-induced reduction of p-TrkB and spine densities in the CA3, DG, and PFC, whereas ANA-12 significantly attenuated LPS-induced increases of p-TrkB and spine density in the NAc.. The results suggest that LPS-induced inflammation may cause depression-like behavior by altering BDNF and spine density in the CA3, DG, PFC, and NAc, which may be involved in the antidepressant effects of 7,8-DHF and ANA-12, respectively.

Topics: Animals; Antidepressive Agents; Azepines; Benzamides; Brain-Derived Neurotrophic Factor; Dendritic Spines; Depressive Disorder; Disease Models, Animal; Flavones; Hippocampus; Lipopolysaccharides; Male; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred C57BL; Multiprotein Complexes; Nucleus Accumbens; Phosphorylation; Prefrontal Cortex; Receptor, trkB; TOR Serine-Threonine Kinases

Huntington's disease (HD) is a fatal neurodegenerative disease characterized by abnormal motor coordination, cognitive decline and psychiatric disorders. This disease is caused by an expanded CAG trinucleotide repeat in the gene encoding the protein huntingtin. Reduced levels of brain-derived neurotrophic factor (BDNF) in the brain, which results from transcriptional inhibition and axonal transport deficits mediated by mutant huntingtin, have been suggested as critical factors underlying selective neurodegeneration in both HD patients and HD mouse models. BDNF activates its high-affinity receptor TrkB and promotes neuronal survival; restoring BDNF signaling is thus of particular therapeutic interest. In the present study, we evaluated the ability of a small-molecule TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and its synthetic derivative 4'-dimethylamino-7,8- dihydroxyflavone (4'-DMA-7,8-DHF) to protect neurons in the well-characterized N171-82Q HD mouse model. We found that chronic administration of 7, 8-DHF (5 mg/kg) or 4'-DMA-7,8-DHF (1 mg/kg) significantly improved motor deficits, ameliorated brain atrophy and extended survival in these N171-82Q HD mice. Moreover, 4'-DMA-7,8-DHF preserved DARPP32 levels in the striatum and rescued mutant huntingtin-induced impairment of neurogenesis in the N171-82Q HD mice. These data highlight consideration of TrkB as a therapeutic target in HD and suggest that small-molecule TrkB agonists that penetrate the brain have high potential to be further tested in clinical trials of HD.

Topics: Animals; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Female; Flavones; Humans; Huntington Disease; Male; Mice; Mice, Transgenic; Motor Activity; Neurons; Receptor, trkB; Signal Transduction; Survival

There are significant sex differences in vulnerability to develop fear-related anxiety disorders. Females exhibit twice the rate of post-traumatic stress disorder (PTSD) as males and sex differences have been observed in fear extinction learning in both humans and rodents, with a failure to inhibit fear emerging as a precipitating factor in the development of PTSD. Here we report that female mice are resistant to fear extinction, and exhibit increased DNA methylation of Bdnf exon IV and a concomitant decrease in mRNA expression within the medial prefrontal cortex. Activation of BDNF signaling by the trkB agonist 7,8-dihydroxyflavone blocks the return of fear in female mice after extinction training, and thus represents a novel approach to treating fear-related anxiety disorders that are characterized by a resistance to extinction and increased propensity for renewal.

Topics: Animals; Anxiety Disorders; Brain-Derived Neurotrophic Factor; Disease Models, Animal; DNA Methylation; Exons; Extinction, Psychological; Fear; Female; Flavones; Mice; Prefrontal Cortex; RNA, Messenger; Signal Transduction

Increasing evidence suggests that reductions in brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) may have a role in the pathogenesis of Alzheimer's disease (AD). However, the efficacy and safety profile of BDNF therapy (eg, gene delivery) remains to be established toward clinical trials. Here, we evaluated the effects of 7,8-dihydroxyflavone (7,8-DHF), a recently identified small-molecule TrkB agonist that can pass the blood-brain barrier, in the 5XFAD transgenic mouse model of AD. 5XFAD mice at 12-15 months of age and non-transgenic littermate controls received systemic administration of 7,8-DHF (5 mg/kg, i.p.) once daily for 10 consecutive days. We found that 7,8-DHF rescued memory deficits of 5XFAD mice in the spontaneous alternation Y-maze task. 5XFAD mice showed impairments in the hippocampal BDNF-TrkB pathway, as evidenced by significant reductions in BDNF, TrkB receptors, and phosphorylated TrkB. 7,8-DHF restored deficient TrkB signaling in 5XFAD mice without affecting endogenous BDNF levels. Meanwhile, 5XFAD mice exhibited elevations in the β-secretase enzyme (BACE1) that initiates amyloid-β (Aβ) generation, as observed in sporadic AD. Interestingly, 7,8-DHF blocked BACE1 elevations and lowered levels of the β-secretase-cleaved C-terminal fragment of amyloid precursor protein (C99), Aβ40, and Aβ42 in 5XFAD mouse brains. Furthermore, BACE1 expression was decreased by 7,8-DHF in wild-type mice, suggesting that BDNF-TrkB signaling is also important for downregulating baseline levels of BACE1. Together, our findings indicate that TrkB activation with systemic 7,8-DHF can ameliorate AD-associated memory deficits, which may be, at least in part, attributable to reductions in BACE1 expression and β-amyloidogenesis.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Brain; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Female; Flavones; Humans; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred Strains; Mice, Transgenic; Peptide Fragments; Phosphorylation; Receptor, trkB; Signal Transduction

Rett syndrome (RTT), caused by mutations in the methyl-CpG binding protein 2 gene (MECP2), is a debilitating autism spectrum developmental disorder predominantly affecting females. Mecp2 mutant mice have reduced levels of brain-derived neurotrophic factor (BDNF) in the brain; conditional deletion and overexpression of BDNF in the brain accelerates and slows, respectively, disease progression in Mecp2 mutant mice. Thus we tested the hypothesis that 7,8-dihydroxyflavone (7,8-DHF), a small molecule reported to activate the high affinity BDNF receptor (TrkB) in the CNS, would attenuate disease progression in Mecp2 mutant mice. Following weaning, 7,8-DHF was administered in drinking water throughout life. Treated mutant mice lived significantly longer compared with untreated mutant littermates (80 ± 4 and 66 ± 2 days, respectively). 7,8-DHF delayed body weight loss, increased neuronal nuclei size and enhanced voluntary locomotor (running wheel) distance in Mecp2 mutant mice. In addition, administration of 7,8-DHF partially improved breathing pattern irregularities and returned tidal volumes to near wild-type levels. Thus although the specific mechanisms are not completely known, 7,8-DHF appears to reduce disease symptoms in Mecp2 mutant mice and may have potential as a therapeutic treatment for RTT patients.

Topics: Animals; Body Mass Index; Body Weight; Cell Nucleus; Disease Models, Animal; Flavones; Hippocampus; Methyl-CpG-Binding Protein 2; Mice; Mice, Inbred C57BL; Motor Activity; Mutation; Receptor, trkB; Respiration; Rett Syndrome; Tidal Volume

Topics: Amygdala; Animals; Brain-Derived Neurotrophic Factor; Conditioning, Classical; Disease Models, Animal; Extinction, Psychological; Flavones; Genetic Therapy; Humans; Learning; Memory; Mental Disorders; Mice; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Receptor, trkB; Signal Transduction