minocycline and Cognitive-Dysfunction

Topics: Animals; Antiretroviral Therapy, Highly Active; Antiviral Agents; Central Nervous System; Cognitive Dysfunction; Disease Models, Animal; Drug Therapy, Combination; Humans; Macaca mulatta; Macrophages; Minocycline; Mitoguazone; Natalizumab; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; T-Lymphocytes; Viral Load; Virus Latency

Despite advances in understanding the pathophysiology of Alzheimer's disease (AD), its therapy remains largely symptomatic and supportive. Acetylcholinesterase inhibitors - the first-line drugs used today do not prevent and treat AD. So far, over 90 Phase 3 trials of AD have been unsuccessful with 99.0% failure rate. There is, therefore, an urgent need to find effective new therapies for AD. Owing to the multifactorial nature of AD pathogenesis, polypharmacy with drugs that target heterogeneous pathophysiological pathways, needs to be considered. Fortunately, several drugs used currently in clinical use as monotherapies can be exploited in AD. This article, therefore, presents a novel pharmacological treatment paradigm and recommends the use of valuable diseasemodifying approved drugs, viz. melatonin, minocycline, modafinil, and memantine (the "M" Drugs). Melatonin - a neuroprotector is an antioxidant and anti-inflammatory. Minocycline is also neuroprotective, it reduces neuroinflammation and CNS pathology and prevents cell death. Sleep deprivation leads to decreased hippocampal neurogenesis, increased amyloid beta generation, and causes memory dysfunction. Modafinil - a wake-promoting agent is approved for use in narcolepsy and obstructive sleep apnea. It improves global mental status, hippocampal neurogenesis, attention, and cognition. Memantine is an uncompetitive N-methyl-d-aspartic acid receptor antagonist and is approved for the management of moderate-to-severe AD. The paramount possible beneficial effects of the M-drugs may include significant memory and cognitive enhancement in aging, mild cognitive impairment, and AD. The M drugs-centric pharmacotherapy strategy is comprehensive and pragmatic and is meant to combat multiple pathological targets and ameliorate cognitive dysfunction/AD.

Topics: Alzheimer Disease; Animals; Benzhydryl Compounds; Cognitive Dysfunction; Humans; Melatonin; Memantine; Minocycline; Modafinil

There are no effective pharmacologic interventions for preventing postoperative cognitive dysfunction in daily practice. Since the antibiotic minocycline is known to suppress postoperative neuroinflammation, this study hypothesized and investigated whether minocycline might have a preventive effect on postoperative cognitive dysfunction after noncardiac surgery.. This study included patients aged more than 60 yr undergoing total knee arthroplasty under general anesthesia. They were randomly assigned to minocycline and placebo groups, to orally receive 100 mg of minocycline or placebo twice daily from the day before surgery until the seventh day after surgery. Cognitive function was evaluated before surgery, and 1 week and 3 months after surgery, using a battery of four cognitive function tests, including Visual Verbal Learning Test, Trail Making Test, Stroop Color and Word Test, and Letter-Digit Coding Task. Additionally, 30 healthy volunteers were subjected to the same tests as the patients to examine the learning effect of repeated tests. The occurrence of postoperative cognitive dysfunction was judged from the results of the neurocognitive test battery, with consideration of the learning effect. The secondary endpoints were the effects of minocycline on postoperative delirium and postoperative pain.. A total of 100 patients were randomized to the minocycline group, and 102 were randomized to the placebo group. The average age of patients was 75 yr. Evaluation showed no significant difference in the incidence of postoperative cognitive dysfunction between the minocycline and placebo groups at both 1 week (8 of 90 [8.9%] vs. 4 of 95 [4.2%]; odds ratio, 2.22 [95% CI, 0.64 to 7.65]; P = 0.240) and 3 months (15.3 of 90 [17.0%] vs. 15.3 of 95 [16.1%]; odds ratio, 1.07 [95% CI, 0.49 to 2.32]; P = 0.889) postoperatively. Missing data 3 months after surgery were corrected by the multiple imputation method. There were no differences between the two groups in postoperative delirium and postoperative pain.. Minocycline is likely to have no preventive effect on postoperative cognitive dysfunction.

Topics: Aged; Arthroplasty, Replacement, Knee; Cognitive Dysfunction; Double-Blind Method; Emergence Delirium; Humans; Minocycline; Pain, Postoperative; Postoperative Cognitive Complications

Cognitive deficits of schizophrenia are predictors of poor function, but antipsychotic medication has limited efficacy for cognitive deficits. These deficits in learning and memory may result from activity of pro-inflammatory cytokines, which microglia produce. The microglia inhibitor minocycline might arrest this cytokine damage to the hippocampus and reverse the cognitive deficits of schizophrenia.. A double-blind, placebo-controlled study involved 75 patients with schizophrenia who randomly received low dose (100 mg/day) or high dose minocycline (200 mg/day) or placebo added to risperidone. MATRICS Consensus Cognitive Battery (MCCB) was used to assess the cognitive functioning, and serum levels of Interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) were assessed.. Minocycline. Minocycline adjunctive treatment was effective in improving cognitive deficits of patients with schizophrenia. The beneficial effect of minocycline may be related to reducing pro-inflammatory cytokines through microglia inhibition.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Antipsychotic Agents; Cognitive Dysfunction; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Male; Microglia; Middle Aged; Minocycline; Risperidone; Schizophrenia; Treatment Outcome; Tumor Necrosis Factor-alpha; Young Adult

The oxidative stress-induced dysregulation of the cyclic AMP response element-binding protein- brain-derived neurotrophic factor (CREB-BDNF) cascade has been linked to cognitive impairment in several studies. This study aimed to investigate the effect of minocycline on the levels of oxidative stress markers, CREB, and BDNF in lipopolysaccharide (LPS)-induced cognitive impairment. Fifty adult male Sprague Dawley rats were divided randomly into five groups. Group 1 was an untreated control group. Groups 2, 3, 4 and 5 were treated concurrently with LPS (5 mg/kg, i.p) once on day 5 and normal saline (0.7 ml/rat, i.p) or minocycline (25 and 50 mg/kg, i.p) or memantine (10 mg/kg, i.p) once daily from day 1 until day 14, respectively. From day 15 to day 22 of the experiment, Morris Water Maze (MWM) was used to evaluate learning and reference memory in rats. The levels of protein carbonyl (PCO), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) were determined by enzyme-linked immunosorbent assay (ELISA). CREB and BDNF expression and density were measured by immunohistochemistry and western blot analysis, respectively. LPS administration significantly increased escape latency to the hidden platform with decreased travelled distance, swimming speed, target crossings and time spent in the target quadrant. Besides, the hippocampal tissue of LPS rats showed increased levels of PCO and MDA, decreased levels of CAT and SOD, and reduced expression and density of BDNF and CREB. Treatment with minocycline reversed these effects in a dose-dependent manner, comparable to the effects of memantine. Both doses of minocycline treatment protect against LPS-induced cognitive impairment by reducing oxidative stress and upregulating the CREB-BDNF signalling pathway in the rat hippocampus.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cognitive Dysfunction; Cyclic AMP Response Element-Binding Protein; Hippocampus; Lipopolysaccharides; Male; Maze Learning; Memantine; Minocycline; Oxidative Stress; Rats; Rats, Sprague-Dawley; Signal Transduction; Superoxide Dismutase

Elderly patients after surgery are prone to cognitive decline known as postoperative cognitive dysfunction (POCD). Several studies have shown that the microglial activation and the increase of complement protein expression in hippocampus induced by surgery may be related to the pathogenesis of POCD. The purpose of this study was to determine whether microglia and complement system were involved in cognitive dysfunction in aged mice.. The POCD model was established by exploratory laparotomy in 15-month-old male C57BL/6J mice and animal behavioral tests were performed to test hippocampal-dependent memory capacity. Minocycline was used to suppress the activation of microglia, and complement 3 receptor inhibitor was used to suppress the association between microglia and complement 3. Western blot and immunofluorescence were used to detect the microglial activation, complement protein, and synaptic protein expressions.. Operation induced hippocampal-dependent memory impairment (P < 0.01), which was accompanied by microglial activation (P < 0.01). There was also a significant reduction in inhibitory synaptic protein expression in the hippocampus of mice in the surgery group (P < 0.01). However, minocycline, a microglia inhibitor, rescued all the above changes. In addition, C3RI intervention inhibited the phagocytosis of inhibitory synapses by microglia (P < 0.05) and improved the cognitive function of mice (P < 0.01).. Microglia participate in postoperative cognitive dysfunction by mediating inhibitory synaptic loss through the complement pathway.

Topics: Animals; Cognitive Dysfunction; Hippocampus; Male; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Postoperative Cognitive Complications; Synapses

The potential of minocycline to protect against methylphenidate‑induced neurodegeneration has been extensively reported in the literature but the mechanism of action is still unknown. This study aims to determine the role of mitochondrial chain enzymes and redox homeostasis on the neuroprotective effects of minocycline in methylphenidate‑induced neurodegeneration. Wistar adult male rats were randomly assigned to the seven experimental groups: Group 1 received saline solution; Group 2 received methylphenidate (10 mg/kg, i.p.); Groups 3, 4, 5, and 6 received methylphenidate and minocycline for 21 days; Group 7 received minocycline alone. Cognition was evaluated with the Morris water maze test. Activity of the hippocampal mitochondrial quadruple complexes I, II, III and IV, mitochondrial membrane potential, adenosine triphosphate (ATP) levels, total antioxidant capacity, and reactive oxygen species were determined. Treatment with minocycline inhibited methylphenidate‑induced cognitive dysfunction. Minocycline treatment increased mitochondrial quadruple complex activities, mitochondrial membrane potential, total antioxidant capacity, and ATP levels in the dentate gyrus and cornu ammonis‑1 (CA1) areas of the hippocampus. Minocycline is likely to confer neuroprotection against methylphenidate‑induced neurodegeneration and cognition impairment by regulating mitochondrial activity and oxidative stress.

Topics: Animals; Antioxidants; Cognition; Cognitive Dysfunction; Hippocampus; Male; Methylphenidate; Minocycline; Mitochondria; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar

Neuroinflammation in Alzheimer's disease (AD) can occur due to excessive activation of microglia in response to the accumulation of amyloid-β peptide (Aβ). Previously, we demonstrated an increased expression of this peptide in the locus coeruleus (LC) in a sporadic model for AD (streptozotocin, STZ; 2 mg/kg, ICV). We hypothesized that the STZ-AD model exhibits neuroinflammation, and treatment with an inhibitor of microglia (minocycline) can reverse the cognitive, respiratory, sleep, and molecular disorders of this model.. To evaluate the effect of minocycline treatment in STZ model disorders.. We treated control and STZ-treated rats for five days with minocycline (30 mg/kg, IP) and evaluated cognitive performance, chemoreflex response to hypercapnia and hypoxia, and total sleep time. Additionally, quantification of Aβ, microglia analyses, and relative expression of cytokines in the LC were performed.. Minocycline treatment improved learning and memory, which was concomitant with a decrease in microglial cell density and re-establishment of morphological changes induced by STZ in the LC region. Minocycline did not reverse the STZ-induced increase in CO2 sensitivity during wakefulness. However, it restored the daytime sleep-wake cycle in STZ-treated animals to the same levels as those observed in control animals. In the LC, levels of A and expression of Il10, Il1b, and Mcp1 mRNA remained unaffected by minocycline, but we found a strong trend of minocycline effect on Tnf- α.. Our findings suggest that minocycline effectively reduces microglial recruitment and the inflammatory morphological profile in the LC, while it recovers cognitive performance and restores the sleep-wake pattern impaired by STZ.

Topics: Alzheimer Disease; Animals; Cognition; Cognitive Dysfunction; Disease Models, Animal; Maze Learning; Microglia; Minocycline; Neuroinflammatory Diseases; Rats; Sleep; Sleep Wake Disorders; Streptozocin

Post-traumatic stress disorder (PTSD)-associated cognitive dysfunction significantly disturbs patients' quality of life and will to live. However, its underlying mechanism is as yet unknown. Recent researches indicate that blood-brain barrier (BBB) breakdown is responsible for early cognitive dysfunction. Microglia might participate in remodeling of BBB-associated tight junction and regulating BBB integrity. Nevertheless, it is unclear whether microglia activation and BBB injury involve in PTSD-associated cognitive dysfunction. Hence, we established an animal model of PTSD, single prolonged stress (SPS), and investigated permeability changes in the hippocampus and further explored the effects of microglia on BBB remodeling. The Y maze was used to assess the changes of cognitive function. The sodium fluorescein (NaFlu) assay and western blotting analysis were employed to detect BBB integrity changes. Minocycline was administered to inhibit microglial activation. Immunofluorescence stains were used to assess the activation states in microglia. The results showed that SPS-exposed rats exhibited poorer cognitive performance, higher passage of NaFlu, and lower expression of tight junction proteins (occludin and claudin 5) in the hippocampus on the day after SPS, but no difference on the 7th day. Inhibition of microglial activation by minocycline attenuated poor cognitive performance and BBB impairment including the extravasation of NaFlu and protein levels of the tight junction. Taken together, the present study indicates that BBB impairment may underlie the shared pathological basis of PTSD and cognitive dysfunction. Microglial activation may involve in BBB remodeling at the early stage of SPS.

Topics: Animals; Blood-Brain Barrier; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Humans; Microglia; Minocycline; Quality of Life; Rats; Stress Disorders, Post-Traumatic

The aim of this study was to evaluate the effect of minocycline preadministration on cognitive dysfunction, hippocampal inflammatory response, and hippocampal senile dementia-related proteins induced by propofol anesthesia in aged rats. Sixty male SD rats, aged 20 months and weighing 340-410 g, were randomly divided into three groups: normal saline (NC) group, propofol group (prop), and minocycline (M) group. Prop group rats were injected intraperitoneally with 100 mg/kg propofol. The rats in group M were injected intraperitoneally with 50 mg/kg minocycline 30 minutes before injection of 100 mg/kg propofol, and the rest were the same as prop group. The rats in NC group were received intraperitoneal injection of the same amount of normal saline. The results indicated that compared with group C, the expressions of GSK-3

Topics: Alzheimer Disease; Anesthesia; Animals; Cognitive Dysfunction; Glycogen Synthase Kinase 3 beta; Hippocampus; Humans; Interleukin-6; Male; Minocycline; NF-kappa B; Propofol; Rats; Rats, Sprague-Dawley; Saline Solution; Tumor Necrosis Factor-alpha

Minocycline, a semisynthetic tetracycline-derived antibiotic, has various pharmacological effect such as anti-inflammatory, anti-oxidative stress, and anti-apoptotic effects. The current study investigated the involvement of neuro-inflammatory, oxidative stress, and cholinergic markers in neuroprotection by minocycline against scopolamine-induced brain damage.. Minocycline was administered (oral, 10, 15, and 30 mg/kg, daily) to groups of amnesic rats for 21 days. Passive avoidance memory and spatial learning and memory were assessed. Following that, oxidative stress, cholinergic function, and neuro-inflammation markers were evaluated in the brain tissue.. According to our biochemical data, treatment of the scopolamine-injured rats with minocycline decreased the levels of malondialdehyde and acetylcholinesterase (AChE) as well as mRNA expression of AChE and neuro-inflammation markers (tumor necrosis factor-α, interleukin (IL)-1β, IL-6). It also increased the total thiol levels and superoxide dismutase activity as well as mRNA expression of cholinergic receptor M1 (ChRM1). Moreover, minocycline modified distance and latencies in Morris water maze, prolonged latency to enter the black zone and light time while decreasing time spent and frequency of entries to darkness.. Taken together, the data indicate that treatment with minocycline improved memory dysfunction mediated possibly through restoring AChE and ChRM1 levels, oxidant/antioxidant balance, as well as inhibiting inflammatory responses.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cholinergic Agents; Cognitive Dysfunction; Inflammation; Maze Learning; Minocycline; Rats; RNA, Messenger; Scopolamine

Cognitive decline occurs frequently in Parkinson's disease (PD), which greatly decreases the quality of life of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by overactivated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using a rotenone-induced mouse PD model.. To evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by Morris water maze, objective recognition, and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation, and apoptosis were determined by immunohistochemistry and Western blot or immunofluorescence staining. The gene expression of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively.. Rotenone dose-dependently induced cognitive deficits in mice by showing decreased performance of rotenone-treated mice in the novel objective recognition, passive avoidance, and Morris water maze compared with that of vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, and Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. A time course experiment revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 and minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in mice treated with combined PLX3397 or minocycline and rotenonee compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis.. Taken together, our findings suggested that microglial activation contributes to cognitive impairments in a rotenone-induced mouse PD model via neuroinflammation, oxidative stress, and apoptosis, providing novel insight into the immunopathogensis of cognitive deficits in PD.

Topics: Aminopyridines; Animals; Cognitive Dysfunction; Insecticides; Male; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Parkinsonian Disorders; Pyrroles; Rotenone

Cognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal networks. This dysfunction emerges during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Here, we address this open question by combining in vivo electrophysiology, optogenetics, neuroanatomy, and behavioral assays during development in mice mimicking the dual genetic-environmental etiology of psychiatric disorders. We report that pyramidal neurons in superficial layers of the prefrontal cortex are key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing relate to sparser dendritic arborization and lower spine density. Administration of minocycline during the first postnatal week, potentially acting via microglial cells, rescues the neuronal deficits and restores pre-juvenile cognitive abilities. Elucidation of the cellular substrate of developmental miswiring causing later cognitive deficits opens new perspectives for identification of neurobiological targets amenable to therapies.

Topics: Animals; Animals, Newborn; Atrophy; Behavior, Animal; Beta Rhythm; Cognitive Dysfunction; Dendrites; Dendritic Spines; Female; Gamma Rhythm; Male; Mice; Microglia; Minocycline; Mutation; Nerve Tissue Proteins; Neural Pathways; Optogenetics; Poly I-C; Prefrontal Cortex; Pyramidal Cells

Neurodegeneration is one of the serious adverse effects of stimulant agents such as nicotine. Minocycline possess established neuroprotective properties. The role of CREB-BDNF signaling pathway in mediating the neuroprotective effects of minocycline against nicotine-induced neurodegeneration in rats was evaluated in current study.. Seventy adult male rats were divided randomly into seven groups. Group 1 and 2, received 0.7 ml/rat of normal saline (i.p) and nicotine (10 mg/kg, s.c) respectively. Groups 3, 4, 5 and 6, treated concurrently with nicotine (10 mg/kg) and minocycline (10, 20, 30 and 40 mg/kg, i.p, respectively) for 21 days. Group 7 received minocycline alone (40 mg/kg, i.p) for 21 days. From 17th to 21 st days of experiment, Morris water maze (MWM) was used to evaluate learning and spatial memory in rats treated in different groups. According to the critical role of hippocampus in cognitive behavior, hippocampal neurodegenerative parameters (oxidative stress and inflammatory biomarkers) and also cyclic AMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) levels were evaluated in isolated hippocampus in day 22 of experiment and after drug treatment. Also hippocampal cell density and tissue changes were evaluated by hematoxylin and eosin staining.. Nicotine administration impaired the learning and spatial memory in rats and simultaneous treatment with various doses of minocycline attenuated the nicotine-induced cognition disturbances. In addition, nicotine treatment increased lipid peroxidation and the levels of oxidized form of glutathione (GSSG), interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and Bax protein, while decreasing reduced form of glutathione (GSH), Bcl-2 protein, P-CREB and BDNF levels in the hippocampus of experimental animals. Nicotine also reduced the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) in the hippocampus. Minocycline attenuated nicotine-induced neurodegeneration and elevating CREB (both forms) and BDNF levels. Also minocycline treatment alone increases the cognitive activity and increased CREB (both forms) and BDNF levels and decreased oxidative stress, inflammation and apoptotic biomarkers. Minocycline at high doses cause inhibition of nicotine induced cell density and changes in both area of dentate gyrus (DG) and CA1 in hippocampus.. It can be concluded that minocycline, probably through activation of P-CREB/BDNF signaling pathway, confers neuroprotection against nicotine-induced neurodegeneration in rat hippocampus.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cognition; Cognitive Dysfunction; Cyclic AMP Response Element-Binding Protein; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Hippocampus; Lipid Peroxidation; Male; Minocycline; Neurodegenerative Diseases; Neuroprotection; Neuroprotective Agents; Nicotine; Oxidative Stress; Rats; Rats, Wistar; Signal Transduction; Superoxide Dismutase

Noisy environment often occurs in hospitals. We set out to determine whether noisy environment induces neuroinflammation and impairment of learning and memory and whether the effects of noise contribute to the development of neuroinflammation and impairment of learning and memory during the perioperative period. Seven-week old CD-1 male mice were exposed to noisy environment in the presence or absence of surgery (right carotid artery exposure). Noisy environment was 75 db, 6 h/day, for 3 days or 5 days. Minocycline (40 mg/kg), an antibiotic with anti-inflammatory property, was administered intraperitoneally 1 h before surgery or each episode of noise. The learning and memory of mice were assessed by Barnes maze and fear conditioning tests. Brain was harvested for the determination of interleukin (IL)-1β and IL-6 and for immunohistochemical staining. We found that noise induced learning and memory impairment. Noise also increased IL-1β, IL-6 and ionized calcium binding adapter molecule 1 (Iba-1) in the hippocampus. The combination of noisy environment and surgery induced dysfunction of additional domains of learning and memory and a higher expression of Iba-1 in the hippocampus. The effects of noisy environment or the combination of noisy environment and surgery were attenuated by minocycline. These findings suggest that noisy environment induces neuroinflammation and impairment of learning and memory. These effects may contribute to the development of neuroinflammation and dysfunction of learning and memory during the perioperative period. Neuroinflammation may be an underlying pathophysiological process for cognitive dysfunction induced by noise or the combination of noise and surgery. Minocycline may be effective in attenuating these noise-induced effects.

Topics: Acoustic Stimulation; Animals; Brain; Cognitive Dysfunction; Inflammation Mediators; Male; Maze Learning; Memory Disorders; Mice; Minocycline; Noise; Perioperative Care

Inflammatory pain is commonly associated with cognitive impairment. However, its molecular mechanisms are poorly understood. Thus, this study was conducted to investigate the molecular mechanisms of behavioral changes associated with inflammatory pain. Briefly, 36 Wistar rats were randomly divided into two main groups: CFA group treated with 100 μL of Complete Freunds' Adjuvant (CFA) and CFA + Minocycline group treated with 100 μL of CFA+40 mg/kg/day of minocycline). After that, each group was divided into three subgroups based on different time points of the study. The pain was induced using CFA and subsequent behavioral changes (i.e., hyperalgesia and learning and spatial memory) were analyzed by the Morris Water Maze (MWM) task and Radiant Heat. Then, the cellular and molecular changes were assessed using Western Blotting, Immunohistochemistry, and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) techniques. Results of the study indicated that CFA-induced pain impaired spatial learning and memory functions. Studying the cellular changes showed that persistent inflammatory pain increased the microglial activity in CA1 and Dentate Gyrus (DG) regions. Furthermore, an increase was observed in the percentage of TUNEL-positive cells. Also, pro-Brain-Derived Neurotrophic Factor (BDNF)/BDNF ratio, Caspase3, and Receptor-Interacting Protein kinase 3 (RIP3) levels increased in the rats' hippocampus following induction of persistent inflammatory pain. These changes were reversed following the cessation of pain as well as the injection of minocycline. Taking together, the results of the current study for the first time revealed that an increase in the microglia dependent proBDNF/BDNF ratio following persistent inflammatory pain leads to cell death of the CA1 and DG neurons that subsequently causes a cognitive deficit in the learning and spatial memory functions.

Topics: Animals; Anti-Bacterial Agents; Behavior, Animal; Brain-Derived Neurotrophic Factor; CA1 Region, Hippocampal; Cell Death; Cognitive Dysfunction; Dentate Gyrus; Freund's Adjuvant; Inflammation; Male; Microglia; Minocycline; Nociceptive Pain; Rats; Rats, Wistar; Spatial Memory

Early life stress exerts detrimental effects on cognitive function, but the mechanism by which this occurs is unknown. The NLRP3 inflammasome-mediated inflammatory response has emerged as a prominent contributor to cognitive impairment induced by chronic stress. In the present study, we showed that 8-week chronic social isolation (SI) led to cognitive impairment in mice, remarkably increasing expression of the hippocampal NLRP3 inflammasome. Furthermore, the 8-week SI procedure significantly increased the levels of hippocampal IL-1β and IL-18 without significant alteration of the level of serum IL-1β, suggesting a central mechanism for IL-1β-related CNS inflammation. Moreover, inflammatory microglial and expression of AMPAR were reduced in the hippocampus of SI mice. Minocycline is an antibiotic that limits microglia responses, and previous study also showed that minocycline could prevent stress-induced pro-inflammatory cytokine expression in the brain. Our experiment found that minocycline improved cognitive behavior in SI mice. Minocycline also prevented expression of the hippocampal NLRP3 inflammasome, indicating that microglia might be the primary contributor to SI-induced hippocampal NLRP3 inflammasome activation. Furthermore, alterations in SI mice were also restored by chronic treatment with the NLRP3 inhibitor MCC950. These results indicate that the microglia-derived NLRP3 inflammasome may be primarily involved in the inflammatory response to social isolation and that specific NLRP3 inflammasome inhibition using MCC950 may represent a promising therapeutic approach for early stress induced cognitive impairment.

Topics: Animals; Anti-Bacterial Agents; Behavior, Animal; Cognition; Cognitive Dysfunction; Corticosterone; Furans; Hippocampus; Indenes; Inflammasomes; Inflammation; Interleukin-18; Interleukin-1beta; Interleukin-6; Male; Mice; Microglia; Minocycline; NLR Family, Pyrin Domain-Containing 3 Protein; Open Field Test; Receptors, AMPA; Recognition, Psychology; Social Isolation; Social Perception; Stress, Psychological; Sulfonamides

Interleukin (IL)-33 is expressed in a healthy brain and plays a pivotal role in several neuropathologies, as protective or contributing to the development of cerebral diseases associated with cognitive impairments. However, the role of IL-33 in the brain is poorly understood, raising the question of its involvement in immunoregulatory mechanisms.. We administered recombinant IL-33 (rmIL-33) by intra-hippocampal injection to C57BL/6 J (WT) and IL-1αβ deficient mice. Chronic minocycline administration was performed and cognitive functions were examined trough spatial habituation test. Hippocampal inflammatory responses were investigated by RT-qPCR. The microglia activation was assessed using immunohistological staining and fluorescence-activated cell sorting (FACS).. We showed that IL-33 administration in mice led to a spatial memory performance defect associated with an increase of inflammatory markers in the hippocampus while minocycline administration limited the inflammatory response. Quantitative assessment of glial cell activation in situ demonstrated an increase of proximal intersections per radius in each part of the hippocampus. Moreover, rmIL-33 significantly promoted the outgrowth of microglial processes. Fluorescence-activated cell sorting analysis on isolated microglia, revealed overexpression of IL-1β, 48 h post-rmIL-33 administration. This microglial reactivity was closely related to the onset of cognitive disturbance. Finally, we demonstrated that IL-1αβ deficient mice were resistant to cognitive disorders after intra-hippocampal IL-33 injection.. Thus, hippocampal IL-33 induced an inflammatory state, including IL-1β overexpression by microglia cells, being causative of the cognitive impairment. These results highlight the pathological role for IL-33 in the central nervous system, independently of a specific neuropathological model.

Topics: Animals; Cognitive Dysfunction; Hippocampus; Inflammation; Interleukin-33; Mice; Mice, Knockout; Microglia; Minocycline; Spatial Memory

Antipsychotic medication is the primary treatment for schizophrenia, which is effective on ameliorating positive symptoms and can reduce the risk of recurrence, but it has limited efficacy for negative symptoms and cognitive dysfunction. The negative symptoms and cognitive dysfunction seriously affects the life quality and social function for the patients with schizophrenia. Currently, there is plenty evidence that antipsychotic drugs combined with adjuvant therapy drugs can effectively improve the negative symptoms and cognitive dysfunction. These drugs include anti-oxidants, nicotinic acetylcholine receptors and neuro-inflammatory drugs (anti-inflammatory drugs, minocycline), which show potential clinical effects.. 抗精神病药物是治疗精神分裂症的主要方法，可有效缓解阳性症状和减少复发风险，但对阴性症状和认知功能障碍的临床疗效有限，而阴性症状和认知功能障碍严重影响精神分裂症患者的社会功能和生活质量。目前有较多的研究支持抗精神病药物联合辅助治疗药物可有效改善阴性症状和认知功能障碍。其中，作用于氧化应激、烟碱能乙酰胆碱受体和神经炎症的药物(抗炎药、米诺环素)有潜在的临床疗效。.

Topics: Anti-Inflammatory Agents; Antipsychotic Agents; Cognitive Dysfunction; Humans; Minocycline; Schizophrenia

There is evidence that hyperammonia and inflammation play crucial roles in hepatic encephalopathy. This study intends to determine neuroprotective effects of minocycline (MINO) and ibuprofen (IBU), and also set out to assess whether inhibition of inflammation is enough to achieve optimal improvement of hepatic encephalopathy symptoms. The hepatic encephalopathy was induced by bile-duct ligation (BDL), and the animals received first dose of MINO and/or IBU 15 days later and then every day until the 28 day. The rats were divided into the 6 groups of control, sham, BDL + V and BDL + IBU, BDL + MINO and BDL + MINO + IBU, which each group had 3 sub-groups for evaluations of blood-brain barrier (BBB), memory performance, synaptic-plasticity and apoptosis. The long-term potentiation (LTP) and short-term potentiation were evaluated by field potential recording. The memory performance, apoptosis and BBB integrity were assessed via passive avoidance, Western-blotting of caspase-3 and Evans-blue dye extravasation, respectively. The MINO, IBU or their co-treatment in the BDL rats did not improve liver dysfunction. The BDL increased hippocampal apoptosis and BBB disruption, which were fully recovered by all three pharmacological interventions. The MINO treatment alone or combined with IBU had similar neuroprotective effects on the BDL-induced disturbances of hippocampal basal synaptic transmission, LTP and memory performance, whereas they were not ameliorated by the single IBU therapy. Therefore, it seems likely that inhibition of inflammation is not able to improve functionally impaired memory and LTP in the hepatic encephalopathy, and they may be recovered by the direct neuroprotective effects of the MINO.

Topics: Animals; Bile Ducts; Blood-Brain Barrier; Cognition; Cognitive Dysfunction; Disease Models, Animal; Hepatic Encephalopathy; Ibuprofen; Inflammation; Ligation; Long-Term Potentiation; Male; Memory Disorders; Minocycline; Neuroprotection; Rats; Rats, Sprague-Dawley; Recovery of Function

Minocycline a tetracycline antibiotic is known for anti-inflammatory and neuroprotective actions. Here we determine the therapeutic potential of minocycline against type 2 diabetes associated cognitive decline in rats.. High fat diet (HFD) and low dose streptozotocin (STZ; 25 mg/kg) were used to induce diabetes in Sprague-Dawley rats. Fasting blood glucose and haemoglobin (Hb) A1c were measured in these animals. Cognitive parameters were measured using passive avoidance and elevated plus maze test. Hippocampal Acetylcholine esterase (AchE), reduced glutathione (GSH), cytokines, chemokine levels were measured and histopathological evaluations were conducted. The diabetic animals were then given minocycline (50 mg/kg; 15 days) and the above parameters were reassessed. MTT and Lactate dehydrogenase (LDH) assays were conducted on neuronal cells in the presence of glucose with or without minocycline treatment.. We induced diabetes using HFD and STZ in these animals. Animals showed high fasting blood glucose levels (>245 mg/dl) and HbA1c compared to control animals. Diabetes significantly lowered step down latency and increased transfer latency. Diabetic animals showed significantly higher AchE, Tumor necrosis factor (TNF)-α, Interleukin (IL)-1β and Monocyte chemoattractant protein (MCP)-1 and lower GSH levels and reduced both CA1 and CA3 neuronal density compared to controls. Minocycline treatment partially reversed the above neurobehavioral and biochemical changes and improved hippocampal neuronal density in diabetic animals. Cell line studies showed glucosemediated neuronal death, which was considerably reversed upon minocycline treatment.. Minocycline, primarily by its anti-inflammatory and antioxidant actions prevented hippocampal neuronal loss thus partially reversing the diabetes-associated cognitive decline in rats.

Topics: Animals; Anti-Inflammatory Agents; Avoidance Learning; Cell Survival; Cognitive Dysfunction; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hippocampus; Male; Maze Learning; Minocycline; Neurons; Neuroprotective Agents; Rats, Sprague-Dawley; Streptozocin

Increasing evidence shows that the developmental perturbation of immune activity can lead to long-lasting neurodevelopmental and behavioral abnormalities. In our previous study, we found that deficiencies of microglia and TNFα in the medial prefrontal cortex (mPFC) were involved in the impairment of cognitive flexibility induced by adolescent social stress in adult mice. It remains unclear how and when immune changes occur following adolescent stress exposure and whether it is possible to prevent the delayed occurrence of cognitive impairment through early immune intervention. Firstly, the present study investigated the time courses of microglia and TNFα changes in the mPFC following adolescent social stress. The results showed that compared to the controls, stress-exposed animals showed parallel variations in the protein expression of ionized calcium-binding adaptor molecule 1 (Iba1), a biomarker specific to microglia, and TNFα in the mPFC, with a transient increase during stress exposure, then a gradual decrease after the end of stress, leading to a significantly decreased level in adulthood. We further investigated the preventive effect of chronic treatment with the immune inhibitor minocycline during stress exposure on the cognitive and molecular alterations induced by adolescent social stress. The results showed that minocycline prevented the delayed cognitive deficit and the decreased immune changes in the mPFC of previously stressed adult mice. These results suggest that the transient upregulation of microglia and TNFα in the mPFC induced by adolescent social stress may participate in the development of cognitive flexibility deficit and that immunomodulation may act as a potential target for the early prevention of cognitive deficits in psychiatric disorders.

Topics: Age Factors; Animals; Cognition; Cognition Disorders; Cognitive Dysfunction; Male; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Prefrontal Cortex; Stress, Psychological; Tumor Necrosis Factor-alpha

Objective Postoperative cognitive dysfunction (POCD) is common after surgery in elderly patients and is associated with high morbidity. The molecular mechanisms responsible for POCD are unknown. Minocycline, an inhibitor of microglial activation, may be useful in treating and preventing POCD. We explored whether minocycline can inhibit microglial activation and prevent POCD in aged rats as a surgery model. Methods Rats aged 18 to 20 months were randomly allocated to the following groups: naïve, abdominal surgery alone, or minocycline injection before abdominal surgery. Hippocampal cytokine mRNA levels were measured at 3 hours, 1 day, 3 days, and 7 days after surgery, and microglial activation was measured at 3 hours and 7 days after surgery. Memory was assessed using the Morris water maze test. Results Surgery resulted in severe cognitive impairment in aged rats and induced a significant neuroinflammatory response and microglial activation. The use of minocycline can prevent microglial activation after surgery, but delayed microglial activation may occur. The use of minocycline may further impair memory after surgery. Conclusion Minocycline can restrain microglial activation and restrict the inflammatory response in the hippocampus early after surgery, but it may induce delayed microglial activation and cannot prevent POCD in aged rats.

Topics: Aging; Animals; Cognitive Dysfunction; Dose-Response Relationship, Drug; Hippocampus; Interleukin-1beta; Memory, Short-Term; Microglia; Minocycline; Postoperative Complications; Rats, Sprague-Dawley; RNA, Messenger; Tumor Necrosis Factor-alpha

Memory deficit is the most visible symptom of cerebral ischemia that is associated with loss of pyramidal cells in CA1 region of the hippocampus. Oxidative stress and inflammation may be involved in the pathogenesis of ischemia/reperfusion (I/R) damage. Minocycline, a semi-synthetic tetracycline derived antibiotic, has anti-inflammatory and antioxidant properties. We evaluated the neuroprotective effect of minocycline on memory deficit induced by cerebral I/R in rat. I/R was induced by occlusion of common carotid arteries for 20min. Minocycline (40mg/kg, i.p.) was administered once daily for 7days after I/R. Learning and memory were assessed using the Morris water maze test. Nissl staining was used to evaluate the viability of CA1 pyramidal cells. The effects of minocycline on the microglial activation was also investigated by Iba1 (Ionized calcium binding adapter molecule 1) immunostaining. The content of malondialdehyde (MDA) and pro-inflammatory cytokines (IL-1β and TNF-α) in the hippocampus were measured by thiobarbituric acid reaction substances method and ELISA, respectively. Minocycline reduced the increase in escape latency time and in swimming path length induced by cerebral I/R. Furthermore, the ischemia-induced reduction in time spent in the target quadrant during the probe trial was increased by treatment with minocycline. Histopathological results indicated that minocycline prevented pyramidal cells death and microglial activation induced by I/R. Minocycline also reduced the levels of MDA and pro-inflammatory cytokines in the hippocampus in rats subjected to I/R. Minocycline has neuroprotective effects on memory deficit induced by cerebral I/R in rat, probably via its anti-inflammatory and antioxidant properties.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Brain Ischemia; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Inflammation; Ischemic Attack, Transient; Learning; Male; Memory; Memory Disorders; Minocycline; Neuroprotective Agents; Oxidants; Oxidative Stress; Pyramidal Cells; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury; Tumor Necrosis Factor-alpha

Although it is known that isoflurane exposure or surgery leads to post-operative cognitive dysfunction in aged rodents, there are few clinical interventions and treatments available to prevent this disorder. Minocycline (MINO) produces neuroprotection from several neurodegenerative diseases and various experimental animal models. Therefore, we set out to investigate the effects of MINO pre-treatment on isoflurane or surgery induced cognitive impairment in aged mice by assessing the hippocampal-dependent spatial memory performance using the Morris water maze task. Hippocampal tissues were isolated from mice and evaluated by Western blot analysis, immunofluorescence procedures and protein array system. Our results elucidate that MINO down-regulated the isoflurane-induced and surgery-induced enhancement in the protein levels of pro-inflammatory cytokine tumour necrosis factor alpha, interleukin (IL)-1β, interferon-γ and microglia marker Iba-1, and up-regulated protein levels of the anti-inflammatory cytokine IL-4 and IL-10. These findings suggest that pre-treatment with MINO attenuated isoflurane or surgery induced cognitive impairment by inhibiting the overactivation of microglia in aged mice.

Topics: Aging; Animals; Anti-Inflammatory Agents; Appendectomy; Calcium-Binding Proteins; Cell Count; Cognitive Dysfunction; Cytokines; Hippocampus; Inflammation Mediators; Interleukin-1beta; Isoflurane; Mice; Microfilament Proteins; Microglia; Minocycline; Spatial Memory; Up-Regulation