6-7-dihydroxyflavone and Alzheimer-Disease

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

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

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

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

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

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

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

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