minocycline and Cognition-Disorders

The concerted efforts of clinicians, scientists and caregivers of HIV-infected children have led to tremendous advances in our understanding of pediatric HIV/AIDS. Antiretroviral therapy (ART; formerly known as highly active antiretroviral therapy [HAART]) has significantly extended the longevity of HIV-infected children, but there are limitations to improvements in quality of life that may persist despite therapy. ART has remarkably reduced the incidence of neurologic deficits for the majority of infected children, but some patients do not experience these benefits and children living in poorer nations, who may not have access to antiretrovirals, are particularly at risk for developing neurologic deficits. This article reviews the neurologic symptoms of pediatric HIV infection that manifest as dopaminergic disruptions and explores potential future adjuvant therapies for HIV-related neurologic disorders in children.

Topics: AIDS Dementia Complex; Anti-Bacterial Agents; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Blood-Brain Barrier; Brain; Chemotherapy, Adjuvant; Child; Cognition Disorders; Dopamine; Humans; Minocycline

Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using 11C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, 11C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater 11C-PBR28 binding. Minocycline reduced 11C-PBR28 binding (mean Δwhite matter binding = -23.30%, 95% confidence interval -40.9 to -5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury.

Topics: Adult; Aged; Brain Injuries, Traumatic; Cognition Disorders; Cross-Sectional Studies; Female; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Magnetic Resonance Imaging; Male; Microglia; Middle Aged; Minocycline; Neurodegenerative Diseases; Neurofilament Proteins; Neuropsychological Tests; Positron-Emission Tomography; Pyrimidines; Statistics, Nonparametric; Young Adult

It is difficult to improve negative symptoms and cognitive impairments in schizophrenia. A previous pilot study has shown that minocycline, a semi-synthetic second-generation tetracycline, is effective in treating for negative and/or cognitive symptoms in schizophrenia.. The present study was designed to examine the efficacy and safety of minocycline for the treatment of negative symptoms and cognitive impairments in patients with schizophrenia.. Ninety-two patients with early stage schizophrenia treated with risperidone entered this 16-week, double blind, randomized, placebo-controlled clinical trial. Subjects were randomly assigned to receive minocycline (200mg per day) or the placebo. The primary outcome was evaluated using the Scale for the Assessment of Negative Symptoms (SANS). Secondary outcomes included the response rate of SANS, the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale (CGI), and cognitive tests.. Subjects receiving minocycline had greater improvements on SANS total scores and PANSS negative subscale scores (P<0.001) when compared with those receiving the placebo. Rates of treatment response (43.6%) in the minocycline group were significantly higher than those in the placebo group (10.0%) after 16weeks of treatment. There was no significant difference between the seven cognitive domains (P>0.05), except for the attention domain (P=0.044).. The addition of minocycline to atypical antipsychotic drugs in early schizophrenia had significant efficacy on negative symptoms but had a slight effect on the attention domains of patients with schizophrenia. It may be considered as a new adjunct treatment for negative symptoms of schizophrenia. Clinical trials.gov identifier: NCT01493622.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Cognition Disorders; Double-Blind Method; Female; Follow-Up Studies; Humans; Hyperkinesis; Male; Minocycline; Neuropsychological Tests; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Young Adult

Minocycline, a member of the tetracycline family, has a low risk of adverse effects and an ability to improve behavioral performance in humans with cognitive disruption. We performed a single-arm open-label trial in which 25 children diagnosed with Angelman syndrome (AS) were administered minocycline to assess the safety and tolerability of minocycline in this patient population and determine the drug's effect on the cognitive and behavioral manifestations of the disorder.. Participants, age 4-12 years old, were randomly selected from a pool of previously screened children for participation in this study. Each child received 3 milligrams of minocycline per kilogram of body weight per day for 8 weeks. Participants were assessed during 3 study visits: baseline, after 8-weeks of minocycline treatment and after an 8-week wash out period. The primary outcome measure was the Bayley Scales of Infant and Toddler Development 3rd Edition (BSID-III). Secondary outcome measures included the Clinical Global Impressions Scale (CGI), Vineland Adaptive Behavior Scales 2nd Edition (VABS-II), Preschool Language Scale 4th Edition (PLS-IV) and EEG scores. Observations were considered statistically significant if p < 0.05 using ANOVA and partial eta squared (η(2)) was calculated to show effect size. Multiple comparisons testing between time points were carried out using Dunnett's post hoc testing.. Significant improvement in the mean raw scores of the BSID-III subdomains communication and fine motor ability as well as the subdomains auditory comprehension and total language ability of the PLS-IV when baseline scores were compared to scores after the washout period. Further, improvements were observed in the receptive communication subdomain of the VABS-II after treatment with minocycline. Finally, mean scores of the BSID-III self-direction subdomain and CGI scale score were significantly improved both after minocycline treatment and after the wash out period.. The clinical and neuropsychological measures suggest minocycline was well tolerated and causes improvements in the adaptive behaviors of this sample of children with Angelman syndrome. While the optimal dosage and the effects of long-term use still need to be determined, these findings suggest further investigation into the effect minocycline has on patients with Angelman syndrome is warranted.. NCT01531582 - clinicaltrials.gov.

Topics: Angelman Syndrome; Anti-Bacterial Agents; Child; Child, Preschool; Cognition Disorders; Female; Humans; Male; Minocycline; Pilot Projects; Treatment Outcome

To evaluate the efficacy and safety of minocycline in the management of HIV-associated cognitive impairment.. We enrolled HIV-positive participants with a CD4 count of 250 to 500 cells/μL in a randomized, double-blind, placebo-controlled study. They received 100 mg of minocycline or matching placebo orally every 12 hours for 24 weeks. Cognitive function was measured using the Uganda neuropsychological test battery summary measure (U NP Sum) and the Memorial Sloan-Kettering (MSK) scale. The primary efficacy measure was the 24-week change in an average of 9 standardized U NP Sum z scores.. Seventy-three participants were enrolled. Of these, 90% were female, 49% were between the ages 30 and 39 years, and 74% had 6 or more years of education. One participant had MSK score of stage 1 (i.e., mild HIV dementia), and 72 participants had MSK stage 0.5 (i.e., equivocal or subclinical dementia) at the baseline evaluation. The minocycline effect on the 24-week change of the U NP Sum compared with placebo was 0.03 (95% confidence interval -0.51, 0.46; p = 0.37).. Minocycline was safe and well tolerated in HIV-positive individuals. However, it did not improve HIV-associated cognitive impairment.. This study provides Class II evidence that 100 mg of minocycline given orally every 12 hours for 24 weeks had no significant effect compared with placebo in the improvement of cognitive function in antiretroviral therapy-naive, HIV-positive patients.

Topics: Activities of Daily Living; Adult; AIDS Dementia Complex; Anti-Bacterial Agents; Antiretroviral Therapy, Highly Active; Cognition Disorders; Depression; Double-Blind Method; Female; Humans; Hyperpigmentation; Male; Middle Aged; Minocycline; Neuropsychological Tests; Sample Size; Treatment Outcome; Uganda; Young Adult

The onset and early course of schizophrenia is associated with subtle loss of grey matter which may be responsible for the evolution and persistence of symptoms such as apathy, emotional blunting, and social withdrawal. Such 'negative' symptoms are unaffected by current antipsychotic therapies. There is evidence that the antibiotic minocycline has neuroprotective properties. We investigated whether the addition of minocycline to treatment as usual (TAU) for 1 year in early psychosis would reduce negative symptoms compared with placebo. In total, 144 participants within 5 years of first onset in Brazil and Pakistan were randomised to receive TAU plus placebo or minocycline. The primary outcome measures were the negative and positive syndrome ratings using the Positive and Negative Syndrome Scale. Some 94 patients completed the trial. The mean improvement in negative symptoms for the minocycline group was 9.2 and in the placebo group 4.7, an adjusted difference of 3.53 (s.e. 1.01) 95% CI: 1.55, 5.51; p < 0.001 in the intention-to-treat population. The effect was present in both countries. The addition of minocycline to TAU early in the course of schizophrenia predominantly improves negative symptoms. Whether this is mediated by neuroprotective, anti-inflammatory or others actions is under investigation.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Antipsychotic Agents; Brazil; Cognition Disorders; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Minocycline; Neuroprotective Agents; Neurotoxicity Syndromes; Pakistan; Patient Dropouts; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Young Adult

We conducted a study of minocycline to assess its safety, tolerability, and efficacy for the treatment of HIV-associated cognitive impairment.. HIV-1-infected individuals with progressive neurocognitive decline were enrolled in a double-blind, placebo-controlled study of minocycline. Participants were randomized to receive minocycline 100 mg or matching placebo orally every 12 hours. The primary efficacy measure was change in a neuropsychological test composite z score (NPZ-8) from baseline to week 24. Measures of safety included the frequency of adverse events and changes over time in laboratory tests. After 50% of participants completed the double-blind phase, an interim analysis of futility for the primary outcome measure was performed, and our Data and Safety Monitoring Board recommended early study termination.. A total of 107 HIV-1-infected individuals with cognitive impairment were enrolled. The minocycline group did not show improvement in the primary outcome measure (NPZ-8) (mean 24-week change = 0.12) compared to placebo (mean 24-week change = 0.17) (95% confidence interval = [-0.26, 0.39], p = 0.70). There were few severe adverse events or laboratory abnormalities in either treatment group.. Minocycline was safe and well-tolerated in individuals with HIV-associated cognitive impairment, but cognitive improvement was not observed. Classification of evidence. This interventional study provides Class II evidence for the safety, tolerability, and efficacy of minocycline for the treatment of HIV-associated cognitive impairment.

Topics: Adult; Cognition Disorders; Cohort Studies; Double-Blind Method; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Male; Middle Aged; Minocycline; Treatment Outcome

Minocycline is a caspase inhibitor, decreases inducible nitric oxide synthase (iNOS), and has been shown to delay disease progression in the mouse model R6/2 of Huntington's disease (HD). This safety and tolerability study included 30 patients with HD who were given minocycline over a 6-month period and underwent assessments every 2 months with laboratory studies, the Abnormal Involuntary Movements Scale, the Unified Huntington's Disease Rating Scale, and the Mini-Mental State Examination. Minocycline was well tolerated during this study period and no serious adverse events were noted.

Topics: Adult; Aged; Caspase Inhibitors; Cognition Disorders; Enzyme Inhibitors; Female; Humans; Huntington Disease; Male; Middle Aged; Minocycline; Neuropsychological Tests; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pilot Projects

Major depressive disorder (MDD) is a chronic, recurring, and potentially life-threatening illness, which affects over 300 million people worldwide. MDD affects not only the emotional and social domains but also cognition. However, the currently available treatments targeting cognitive deficits in MDD are limited. Minocycline, an antibiotic with anti-inflammatory properties recently identified as a potential antidepressant, has been shown to attenuate learning and memory deficits in animal models of cognitive impairment. Here, we explored whether minocycline recovers the deficits in cognition in a mouse model of depression. C57BL6/J adult male mice were exposed to two weeks of chronic unpredictable mild stress to induce a depressive-like phenotype. Immediately afterward, mice received either vehicle or minocycline for three weeks in standard housing conditions. We measured anhedonia as a depressive-like response, and place learning to assess cognitive abilities. We also recorded long-term potentiation (LTP) as an index of hippocampal functional plasticity and ran immunohistochemical assays to assess microglial proportion and morphology. After one week of treatment, cognitive performance in the place learning test was significantly improved by minocycline, as treated mice displayed a higher number of correct responses when learning novel spatial configurations. Accordingly, minocycline-treated mice displayed higher LTP compared to controls. However, after three weeks of treatment, no difference between treated and control animals was found for behavior, neural plasticity, and microglial properties, suggesting that minocycline has a fast but short effect on cognition, without lasting effects on microglia. These findings together support the usefulness of minocycline as a potential treatment for cognitive impairment associated with MDD.

Topics: Animals; Anti-Bacterial Agents; Cognition; Cognition Disorders; Depressive Disorder, Major; Hippocampus; Male; Mice; Minocycline

This study provides crucial information that could be helpful in the development of new or repurposing of existing therapies for the treatment of cognitive deficit in individuals with sickle cell disease (SCD). Its impact is in demonstrating for the first time that neuroinflammation and along with abnormal neuroplasticity are among the underlying mechanism of cognitive and behavioral deficits in SCD and that drugs such as minocycline which targets these pathophysiological mechanisms could be repurposed for the treatment of this life altering complication of SCD.

Topics: Aging; Anemia, Sickle Cell; Animals; Behavior, Animal; Brain; Cognition Disorders; Dendritic Spines; Inflammation; Male; Mice; Minocycline; Neurogenesis; Neuronal Plasticity

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

Bile duct ligation (BDL) model is used to study hepatic encephalopathy accompanied by cognitive impairment. We employed the proteomic analysis approach to evaluate cognition-related proteins in the prefrontal cortex of young BDL rats and analyzed the effect of minocycline on these proteins and spatial memory.. BDL was induced in young rats at postnatal day 17. Minocycline as a slow-release pellet was implanted into the peritoneum. Morris water maze test and two-dimensional liquid chromatography-tandem mass spectrometry were used to evaluate spatial memory and prefrontal cortex protein expression, respectively. We used 2D/LC-MS/MS to analyze for affected proteins in the prefrontal cortex of young BDL rats. Results were verified with Western blotting, immunohistochemistry, and quantitative real-time PCR. The effect of minocycline in BDL rats was assessed.. BDL induced spatial deficits, while minocycline rescued it. Collapsin response mediator protein 2 (CRMP2) and manganese-dependent superoxide dismutase (MnSOD) were upregulated and nucleoside diphosphate kinase B (NME2) was downregulated in young BDL rats. BDL rats exhibited decreased levels of brain-derived neurotrophic factor (BDNF) mRNA as compared with those by the control. However, minocycline treatment restored CRMP2 and NME2 protein expression, BDNF mRNA level, and MnSOD activity to control levels.. We demonstrated that BDL altered the expression of CRMP2, NME2, MnSOD, and BDNF in the prefrontal cortex of young BDL rats. However, minocycline treatment restored the expression of the affected mediators that are implicated in cognition.

Topics: Animals; Bile Ducts; Blotting, Western; Brain-Derived Neurotrophic Factor; Chromatography, Liquid; Cognition Disorders; Delayed-Action Preparations; Disease Models, Animal; Hepatic Encephalopathy; Intercellular Signaling Peptides and Proteins; Male; Maze Learning; Minocycline; Nerve Tissue Proteins; NM23 Nucleoside Diphosphate Kinases; Prefrontal Cortex; Proteomics; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Spatial Memory; Superoxide Dismutase; Tandem Mass Spectrometry

The role of glial cells, especially microglia and astrocytes, in neuroinflammation and cognition has been studied intensively. Lipopolysaccharide (LPS), a commonly used inducer of neuroinflammation, can cause cognitive impairment. Minocycline is known to possess potent neuroprotective activity, but its effect on LPS-induced cognitive impairment is unknown.. This study aims to investigate the effects of minocycline on LPS-induced cognitive impairment and glial cell activation in mice.. Behavioral tests were conducted for cognitive function, immunohistochemistry for microglial and astrocyte response, and quantitative PCR for mRNA expression of proinflammatory cytokines.. Minocycline significantly reversed the decreased spontaneous alternation induced by intrahippocampal administration of LPS in the Y-maze task. In the Morris water maze place navigation test, minocycline decreased the escape latency and distance traveled compared to LPS-treated mice. In the probe test, minocycline-treated mice spent more time in the target quadrant and crossed the platform area more frequently than animals in the LPS-treated group. Minocycline produced a significant decrease in the number of Iba-1- and GFAP-positive hippocampal cells compared to the LPS-treated group. Minocycline-treated mice had significantly reduced hippocampal TNF-α and IL-1β mRNA levels compared with LPS-treated animals. Minocycline caused a significant increase in hippocampal BDNF expression compared to the LPS-treated group.. Minocycline can attenuate LPS-induced cognitive impairments in mice. This effect may be associated with its action to suppress the activation of microglia and astrocytes and to normalize BDNF expression. Since neuroinflammatory processes and cognitive impairments are implicated in neurodegenerative disorders, minocycline may be a promising candidate for treating such diseases.

Topics: Animals; Calcium-Binding Proteins; Cognition Disorders; Cytokines; Glial Fibrillary Acidic Protein; Hippocampus; Interleukin-1beta; Lipopolysaccharides; Macrophages; Male; Maze Learning; Mice; Mice, Inbred C57BL; Microfilament Proteins; Microinjections; Minocycline; Neuroglia; Neuroprotective Agents; RNA, Messenger; Tumor Necrosis Factor-alpha

Elevated microglial/macrophage-associated biomarkers in the cerebrospinal fluid of infant victims of abusive head trauma (AHT) suggest that these cells play a role in the pathophysiology of the injury. In a model of AHT in 11-day-old rats, 3 impacts (24 hours apart) resulted in spatial learning and memory deficits and increased brain microglial/macrophage reactivity, traumatic axonal injury, neuronal degeneration, and cortical and white-matter atrophy. The antibiotic minocycline has been effective in decreasing injury-induced microglial/macrophage activation while simultaneously attenuating cellular and functional deficits in models of neonatal hypoxic ischemia, but the potential for this compound to rescue deficits after impact-based trauma to the immature brain remains unexplored. Acute minocycline administration in this model of AHT decreased microglial/macrophage reactivity in the corpus callosum of brain-injured animals at 3 days postinjury, but this effect was lost by 7 days postinjury. Additionally, minocycline treatment had no effect on traumatic axonal injury, neurodegeneration, tissue atrophy, or spatial learning deficits. Interestingly, minocycline-treated animals demonstrated exacerbated injury-induced spatial memory deficits. These results contrast with previous findings in other models of brain injury and suggest that minocycline is ineffective in reducing microglial/macrophage activation and ameliorating injury-induced deficits following repetitive neonatal traumatic brain injury.

Topics: Amyloid beta-Protein Precursor; Animals; Animals, Newborn; Anti-Bacterial Agents; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Brain; Brain Injuries; Calcium-Binding Proteins; Cognition Disorders; Disease Models, Animal; Female; Fluoresceins; Macrophages; Male; Microfilament Proteins; Microglia; Minocycline; Rats; Rats, Sprague-Dawley; Spatial Learning; Time Factors

The aim of the present study was to investigate the effects of minocycline on cognitive functions in neonatal rat after hypoxia exposure and the underlying mechanism. A model of hypoxic brain damage (HBD) was developed by exposing postnatal 1 day (P1) rats to systemic hypoxia. The rats were intraperitoneally injected with normal saline (Hy group) or minocycline (Hy + M group) 2 h after hypoxia exposure. Some other P1 rats that were not subjected to systemic hypoxia were used as normal control (NG group). The Y-maze test was used to evaluate learning and memory ability on postnatal day 30. Inflammatory mediators (Iba-1, IL-1β, TNF-α and TGF-β1), glutamate transporters (EAAT1 and EAAT2), total Tau and phosphorylated Tau (phosphorylation sites: Tyr18, Thr205, Thr231, Ser396 and Ser404) protein expressions in the hippocampus were detected by Western blot 7 d after hypoxic exposure. The results showed that hypoxia induced learning and memory impairments of the neonatal rats, and minocycline administration could reverse the effects of hypoxia. The protein expression levels of Iba-1, IL-1β, TNF-α, EAAT2 and Tau phosphorylated at T231 were increased, but the total Tau expression was decreased in the hippocampus of the rats from Hy group 7 d after hypoxia exposure. In the hypoxia-treated rats, minocycline down-regulated Iba-1, IL-1β, TNF-α and EAAT2 protein expressions significantly, but did not affect total Tau and phosphorylated Tau protein expressions. Our results suggest that minocycline can prevent cognitive deficits of rats with hypoxia exposure, and the underlying mechanism may involve the inhibition of neuroinflammation and dysfunctional glutamate transporters but not the regulation of the Tau hyperphosphorylation.

Topics: Amino Acid Transport System X-AG; Animals; Animals, Newborn; Cognition; Cognition Disorders; Disease Models, Animal; Glutamates; Hippocampus; Hypoxia; Inflammation; Learning; Memory; Memory Disorders; Minocycline; Phosphorylation; Rats; tau Proteins; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Alzheimer's disease (AD), a common neurodegenerative disorder, recognized to be a major cause of dementia. The aim of the present study was to investigate the neuroprotective mechanisms of clove oil in intracerebroventricular (icv)-colchicine induced cognitive dysfunction in rats.. Single bilateral icv-colchicine (15μg/5μl) was administered, followed by drug treatment with clove oil (0.05ml/kg and 0.1ml/kg, ip), minocycline (25 and 50mg/kg, ip) and their combinations for a period of 21 days. Various neurobehavioral parameters followed by biochemical, acetylcholinesterase (AChE) level and mitochondrial respiratory enzyme complexes (I-IV) were assessed.. Colchicine icv administration significantly impaired cognitive performance in Morris water maze (MWM) causes oxidative stress, raised AChE level, caused neuroinflammation and mitochondrial dysfunction as compared to sham treatment. Treatment with clove oil (0.05ml/kg and 0.1ml/kg) and minocycline (25 and 50mg/kg) alone significantly improved cognitive performance as evidenced by reduced transfer latency and increased time spent in target quadrant (TSTQ) in MWM task, reduced AChE activity, oxidative damage (reduced lipid peroxidation levels, nitrite level and restored glutathione levels) and restored mitochondrial respiratory enzyme complex (I-IV) activities as compared to icv-colchicine treatment. Further, combinations of clove oil (0.1ml/kg) with minocycline (50mg/kg) significantly modulate the neuroprotective effect of clove oil as compared to their effect alone.. The present study highlights that the major neuroprotective effect of clove oil due to its mitochondrial restoring and anti-oxidant properties along with a microglial inhibitory mechanism.

Topics: Acetylcholinesterase; Animals; Brain; Clove Oil; Cognition Disorders; Colchicine; Drug Synergism; Electron Transport Complex IV; Infusions, Intraventricular; Male; Minocycline; Mitochondria; NADH Dehydrogenase; Neuroprotective Agents; Oxidative Stress; Rats; Succinate Dehydrogenase; Tetrazolium Salts; Thiazoles

Minocycline is purported to have neuroprotective properties in experimental models of some human neurologic diseases, and has therefore been identified as a putative neuroprotectant for chemotherapy-induced cognitive impairment (CICI) in breast cancer patients. However, because its mechanism of action is believed to be mediated through anti-inflammatory, anti-apoptotic, and anti-oxidant pathways, co-administration of minocycline with chemotherapeutic agents has the potential to reduce the efficacy of anticancer drugs. The objective of this study is to evaluate the effect of minocycline on the activity of the AC chemotherapeutic regimen (Adriamycin [doxorubicin], Cytoxan [cyclophosphamide]) in in vitro and in vivo models of triple-negative breast cancer (TNBC). Clonogenic and methylthiazol tetrazolium (MTT) assays were used to assess survival and viability in two TNBC cell lines treated with increasing concentrations of AC in the presence or absence of minocycline. Biomarkers of apoptosis, cell stress, and DNA damage were evaluated by western blot. The in vivo effects of AC and minocycline, each alone and in combination, were assessed in a xenograft model of TNBC in female athymic nude mice by weekly tumor volume measurement, body and organ weight measurement, and histopathology. Apoptosis and proliferation were characterized by immunohistochemistry in the xenografts tumors. Brains from tumor-bearing mice were evaluated for microglial activation, glial scars, and the proportion of neural progenitor cells. Data from these in vitro and in vivo studies demonstrate that minocycline does not diminish the cytotoxic and tumor-suppressive effects of this chemotherapeutic drug combination in TNBC cells. Moreover, minocycline appeared to prevent the reduction in doublecortin-positive neural progenitor cells observed in AC-treated mice. We posit that minocycline may be useful clinically for its reported neuroprotective activity in breast cancer patients receiving AC without loss of chemotherapeutic efficacy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Survival; Cognition Disorders; Cyclophosphamide; DNA Damage; Doxorubicin; Female; Humans; Immunohistochemistry; Mice; Mice, Nude; Minocycline; Neuroprotective Agents; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Chronic stress is considered to be a major risk factor in the development of psychopathological syndromes in humans. Cognitive impairments and long-term potentiation (LTP) impairments are increasingly recognized as major components of depression, anxiety disorders and other stress-related chronic psychological illnesses. It seems timely to systematically study the potentially underlying neurobiological mechanisms of altered cognitive and synaptic plasticity in the course of chronic stress. In the present study, a rat model of chronic unpredictable stress (CUS) induced a cognitive impairment in spatial memory in the Morris water maze (MWM) test and a hippocampal LTP impairment. CUS also induced hippocampal microglial activation and attenuated phosphorylation of glutamate receptor 1 (GluR1 or GluA1). Moreover, chronic treatment with the selective microglial activation blocker, minocycline (120 mg/kg per day), beginning 3 d before CUS treatment and continuing through the behavioral testing period, prevented the CUS-induced impairments of spatial memory and LTP induction. Additional studies showed that minocycline-induced inhibition of microglia activation was associated with increased phosphorylation of GluR1. These results suggest that hippocampal microglial activation modulates the level of GluR1 phosphorylation and might play a causal role in CUS-induced cognitive and LTP disturbances.

Topics: Animals; Behavior, Animal; Chronic Disease; Cognition; Cognition Disorders; Cytokines; Disease Models, Animal; Hippocampus; In Vitro Techniques; Inflammation Mediators; Long-Term Potentiation; Male; Maze Learning; Microglia; Minocycline; Phosphorylation; Rats, Sprague-Dawley; Receptors, AMPA; Restraint, Physical; Spatial Learning; Stress, Psychological; Time Factors

Minocycline has been implicated in the treatment for multiple diseases in the nervous system for its neuroprotective properties. However, the mechanism by which minocycline benefits postoperative anesthesia-induced cognitive dysfunction is still unclear. In this study, we introduced minocycline to a rat model of anesthetic-induced learning and memory impairment, to investigate the effects of minocycline on neuroinflammation, beta amyloid (Aβ) deposition, and activation of nuclear factor κB (NF-κB) signaling pathway in the hippocampus. Aged rats were treated with sevoflurane to induce cognitive impairment with and without pre-administration of minocycline. The rats were then subjected to Morris water maze tests to evaluate their learning and memory performance. Subsequently, apoptosis in the hippocampal tissue was assessed with TUNEL assays. Furthermore, the levels of apoptosis-related proteins and pro-inflammatory cytokines, Aβ responses, and activation of the NF-κB signaling pathway in the hippocampus were examined by Western blot analysis. Our results revealed that minocycline effectively alleviated sevoflurane-induced cognitive impairment in aged rats. Minocycline reduced sevoflurane-induced neuronal apoptosis and inflammation, as well as suppressed sevoflurane-induced Aβ accumulation and activation of NF-κB signaling pathway in the hippocampus of aged rats. In conclusion, our findings indicate that minocycline is a potent agent to counteract sevoflurane-induced cognitive impairment and neurotoxicity in the nervous system of aged rats, which is likely to be mediated via NF-κB signaling pathway.

Topics: Aging; Amyloid beta-Peptides; Animals; Apoptosis; Cognition Disorders; Hippocampus; Inflammation; Learning; Male; Memory Disorders; Methyl Ethers; Minocycline; NF-kappa B; Rats, Sprague-Dawley; Sevoflurane; Signal Transduction

Despite the potential adverse effects of maternal sleep deprivation (MSD) on physiological and behavioral aspects of offspring, the mechanisms remain poorly understood. The present study was intended to investigate the roles of microglia on neurodevelopment and cognition in young offspring rats with prenatal sleep deprivation. Pregnant Wistar rats received 72 h sleep deprivation in the last trimester of gestation, and their prepuberty male offspring were given the intraperitoneal injection with or without minocycline. The results showed the number of Iba1(+) microglia increased, that of hippocampal neurogenesis decreased, and the hippocampus-dependent spatial learning and memory were impaired in MSD offspring. The classical microglial activation markers (M1 phenotype) IL-1β, IL-6, TNF-α, CD68 and iNOS were increased, while the alternative microglial activation markers (M2 phenotype) Arg1, Ym1, IL-4, IL-10 and CD206 were reduced in hippocampus of MSD offspring. After minocycline administration, the MSD offspring showed improvement in MWM behaviors and increase in BrdU(+)/DCX(+) cells. Minocycline reduced Iba1(+) cells, suppressed the production of pro-inflammatory molecules, and reversed the reduction of M2 microglial markers in the MSD prepuberty offspring. These results indicate that dysregulation in microglial pro- and anti-inflammatory activation is involved in MSD-induced inhibition of neurogenesis and impairment of spatial learning and memory.

Topics: Animals; Arginase; Biomarkers; Cognition Disorders; Doublecortin Protein; Female; Gene Expression Regulation; Hippocampus; Interleukin-6; Male; Maternal Exposure; Memory; Microglia; Minocycline; Neurogenesis; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Sleep Deprivation; Spatial Learning

Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion develops with progressive white matter and cognitive impairments, yet no effective therapy is available. We investigated the temporal effects of minocycline on an experimental SIVD exerted by right unilateral common carotid arteries occlusion (rUCCAO). Minocycline treated at the early stage (day 0-3), but not the late stage after rUCCAO (day 4-32) alleviated the white matter and cognitive impairments, and promoted remyelination. The actions of minocycline may not involve the inhibition of microglia activation, based on the effects after the application of a microglial activation inhibitor, macrophage migration inhibitory factor, and co-treatment with lipopolysaccharides. Furthermore, minocycline treatment at the early stage promoted the proliferation of oligodendrocyte progenitor cells (OPCs) in subventricular zone, increased OPC number and alleviated apoptosis of mature oligodendrocytes in white matter. In vitro, minocycline promoted OPC proliferation and increased the percentage of OPCs in S and G2/M phases. We provided direct evidence that early treatment is critical for minocycline to alleviate white matter and cognitive impairments after chronic cerebral hypoperfusion, which may be due to its robust effects on OPC proliferation and mature oligodendrocyte loss. So, early therapeutic time window may be crucial for its application in SIVD.

Topics: Animals; Carotid Artery Injuries; Cell Proliferation; Cells, Cultured; Cognition Disorders; Dementia, Vascular; Disease Models, Animal; G2 Phase; Intramolecular Oxidoreductases; Lipopolysaccharides; Macrophage Migration-Inhibitory Factors; Male; Maze Learning; Mice; Mice, Inbred C57BL; Microglia; Microscopy, Electron; Minocycline; Neuroprotective Agents; Oligodendroglia; Rats; Rats, Sprague-Dawley; S Phase; Stem Cells; White Matter

Astrocytes are proving to be critical for the development of cognitive functions. In addition, astrocytic activation contributes to cognitive impairment induced by chronic cerebral hypoperfusion. Minocycline has been shown to exhibit long-term neuroprotective effects in vascular cognitive impairment rat models through the inhibition of astrogliosis, and has demonstrated potential for the prevention and treatment of postoperative cognitive decline in elderly patients. This study aimed to examine the effect of minocycline on hippocampal astrocytes and long-term postoperative cognitive dysfunction in aged mice. Mice were intraperitoneally injected with 45 mg/kg minocycline once a day for 30 days after 70% hepatectomy. Hippocampus-dependent spatial memory ability was evaluated using the Morris water maze test. The expression levels of hippocampal glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 were evaluated by western blotting, and the hippocampal mRNA relative expression levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 were tested using real-time PCR. The Morris water maze test showed that escape latency and swim distance were significantly prolonged by the surgery, but the extent of impairment was mitigated by minocycline treatment. Hippocampal GFAP levels and mRNA levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 showed corresponding changes that were consistent with the variations in spatial memory. Minocycline was able to alleviate hepatectomy-related long-term spatial memory impairment in aged mice, and was associated with reduced levels of hippocampal GFAP and proinflammatory cytokines resulting from astrocytic activation.

Topics: Aging; Animals; Astrocytes; Cognition; Cognition Disorders; Disease Models, Animal; Glial Fibrillary Acidic Protein; Hepatectomy; Hippocampus; Interleukin-1beta; Interleukin-6; Male; Maze Learning; Mice; Minocycline; Neuroprotective Agents; Tumor Necrosis Factor-alpha

Postoperative cognitive dysfunction (POCD) is a clinical phenomenon characterized by cognitive deficits in patients after anesthesia and surgery, especially in geriatric surgical patients. Although it has been documented that isoflurane exposure impaired cognitive function in several aged animal models, there are few clinical interventions and treatments available to prevent this disorder. Minocycline has been well established to exert neuroprotective effects in various experimental animal models and neurodegenerative diseases. Therefore, we hypothesized that pretreatment with minocycline attenuates isoflurane-induced cognitive decline in aged rats. In the present study, twenty-month-old rats were administered minocycline or an equal volume of saline by intraperitoneal injection 12 h before exposure to isoflurane. Then the rats were exposed to 1.3% isoflurane for 4 h. Two weeks later, spatial learning and memory of the rats were examined using the Morris Water Maze. We found that pretreatment with minocycline mitigated isoflurane-induced cognitive deficits and suppressed the isoflurane-induced excessive release of IL-1β and caspase-3 in the hippocampal CA1 region at 4 h after isoflurane exposure, as well as the number of TUNEL-positive nuclei. In addition, minocycline treatment also prevented the changes of synaptic ultrastructure in the hippocampal CA1 region induced by isoflurane. In conclusion, pretreatment with minocycline attenuated isoflurane-induced cognitive impairment in aged rats.

Topics: Aging; Anesthesia; Animals; Apoptosis; Arterial Pressure; CA1 Region, Hippocampal; Caspase 3; Cognition Disorders; Heart Rate; Interleukin-1beta; Isoflurane; Male; Maze Learning; Minocycline; Rats; Rats, Sprague-Dawley; Synapses; Tumor Necrosis Factor-alpha

Traumatic brain injury (TBI) differs in severity from severe to mild. This study examined whether a combination of the drugs minocycline (MINO) plus N-acetylcysteine (NAC) produces behavioral and histological improvements in a mild version of the controlled cortical impact model of TBI (mCCI). Following mCCI, rats acquired an active place avoidance task by learning the location of a stationary shock zone on a rotating arena. Rats acquired this task with a training protocol using a 10-minute intertrial interval. Mildly injured rats had an apparent deficit in long-term memory since they did not acquire the task when the intertrial interval was increased to 24 h. Mildly injured rats also had an apparent deficit in set shifting since, after successfully learning one shock zone location they did not learn the location of a second shock zone. MINO plus NAC synergistically limited these behavioral deficits in long-term memory and set shifting. mCCI also produced neuroinflammation at the impact site and at distal white matter tracts including the corpus callosum. At the impact site, MINO plus NAC attenuated CD68-expressing phagocytic microglia without altering neutrophil infiltration or astrocyte activation. The drugs had no effect on astrocyte activation in the corpus callosum or hippocampus. In the corpus callosum, MINO plus NAC decreased CD68 expression yet increased overall microglial activation as measured by Iba-1. MINO plus NAC acted synergistically to increase Iba-1 expression since MINO alone suppressed expression and NAC alone had no effect. Despite the known anti-inflammatory actions of the individual drugs, MINO plus NAC appeared to modulate, rather than suppress neuroinflammation. This modulation of neuroinflammation may underlie the synergistic improvement in memory and set-shifting by the drug combination after mCCI.

Topics: Acetylcysteine; Animals; Avoidance Learning; Brain Injuries; Cognition Disorders; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Inflammation; Memory Disorders; Minocycline; Neuroprotective Agents; Rats; Rats, Sprague-Dawley

Postoperative cognitive dysfunction (POCD) is a severe neurological sequela that occurs in individuals who have undergone anesthesia and surgery, especially in the geriatric surgical population. Although it is known that isoflurane exposure impairs cognitive function in aged rodents, there are few clinical interventions for the prophylaxis and treatment of this disorder. Minocycline, a derivative of tetracycline, produces neuroprotection from several neurodegenerative diseases. Therefore, we set out to investigate the effects of minocycline pretreatment on isoflurane-induced cognitive impairment in aged rats. We found that pretreatment with minocycline remarkably alleviated isoflurane-induced cognitive dysfunction and inhibited the isoflurane-induced over expression of TNF-α, IL-1β, and IL-6, possibly by inhibiting the degradation of IκBα. In addition, minocycline downregulated the isoflurane-induced increase in the protein levels of cleaved caspase 3 and bax, and upregulated the bcl-2 protein level. These findings highlight the beneficial role of minocycline in preventing isoflurane-induced cognitive impairment and suggested that minocycline can be used as a clinical treatment to mitigate the cognitive impairment induced by isoflurane in elderly patients.

Topics: Aging; Anesthetics, Inhalation; Animals; bcl-2-Associated X Protein; Caspase 3; Cells, Cultured; Cognition Disorders; Cytokines; Disease Models, Animal; Embryo, Mammalian; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Isoflurane; Male; Maze Learning; Minocycline; Neurons; Pregnancy; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley

Comorbidity of cognitive and stress disorders is a common clinical sequel of traumatic brain injury (TBI) that is essentially determined by the site and severity of the insult, but also by the extent of the ensuing neuroinflammatory response. The present study sought to examine the late effects of closed-head TBI on memory function and anxiety in mice, in order to further examine the potential efficacy of an acute anti-inflammatory treatment with minocycline. The mouse model of closed-head injury by mechanical percussion was applied on anesthetized Swiss mice. The treatment protocol included three injections of minocycline (i.p.) at 5 min (90 mg/kg), 3 h and 9 h (45 mg/kg) post-TBI. The Novel Object Recognition Test as well as the Elevated Plus Maze (EPM) and Elevated Zero Maze (EZM) tasks were employed to assess post-TBI memory and anxiety respectively. Our results revealed a recognition memory deficit that was significant up to at least 13 weeks post-TBI. However, neither EPM nor EZM revealed any alteration in post-TBI anxiety levels albeit some mild disinhibition. Most importantly, minocycline was able to attenuate the memory impairment in an effective and lasting manner, highlighting its therapeutic potential in TBI.

Topics: Animals; Anti-Inflammatory Agents; Anxiety; Brain Injuries; Cognition Disorders; Male; Mice; Minocycline

Activated microglia with macrophage-like functions invade and surround β-amyloid (Aβ) plaques in Alzheimer's disease (AD), possibly contributing to the turnover of Aβ, but they can also secrete proinflammatory factors that may be involved in the pathogenesis of AD. Microglia are known to modulate adult hippocampal neurogenesis.. To determine the role of microglia on neurogenesis in brains with Aβ pathology, we inhibited microglial activation with the tetracycline derivative minocycline in doubly transgenic mice expressing mutant human amyloid precursor protein (APP) and mutant human presenilin-1 (PS1).. Minocycline increased the survival of new dentate granule cells in APP/PS1 mice indicated by more BrdU+/NeuN+ cells as compared to vehicle-treated transgenic littermates, accompanied by improved behavioral performance in a hippocampus-dependent learning task. Both brain levels of Aβ and Aβ-related morphological deficits in the new neurons labeled with GFP-expressing retrovirus were unaffected in minocycline-treated mice.. These results suggest a role for microglia in Aβ-related functional deficits and in suppressing the survival of new neurons, and show that modulation of microglial function with minocycline can protect hippocampal neurogenesis in the presence of Aβ pathology.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents; Cognition Disorders; Disease Models, Animal; Female; Hippocampus; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Minocycline; Mutation; Neurogenesis; Presenilin-1

We investigated the effects of minocycline, a microglia suppressant, on olfactory bulbectomized (OBX) rats, a model of cognitive and behavioral impairments arising from neurodegenerative processes. Previously, we demonstrated that the major OBX-induced behavioral and cognitive impairments develop between day 3 and 7 following bulbectomy. Here we show that the onset of these cognitive changes parallel in time with signs of microglia activation (increased mRNA levels of IL-1β and CD68) in hippocampus. Next, rats were treated with minocycline (50mg/kg, i.p.) once daily for 4 weeks. OBX surgery was done at day 3 of drug treatment. Animals were tested in a battery of behavioral assays: open field, passive avoidance (fear learning and memory-acquired prior to OBX) and T-maze (spatial memory, conducted post bulbectomy). Minocycline normalized OBX-induced hyperactivity in the open field. Minocycline failed to prevent fear memory loss, but protected the OBX rats against hippocampal-dependent spatial memory deficit. Our findings suggest that treatment with minocycline may be effective in the early phase of a neurodegenerative disease.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Avoidance Learning; Behavior, Animal; Cognition; Cognition Disorders; Disease Models, Animal; Fear; Hippocampus; Injections, Intraperitoneal; Interleukin-1beta; Male; Memory; Memory Disorders; Microglia; Minocycline; Neuropsychological Tests; Nootropic Agents; Olfactory Bulb; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Up-Regulation

Postoperative cognitive dysfunction (POCD) is reported to occur frequently after all types especially cardiac surgery in elderly patients. It can be short-term or long-term and some cases even develop into Alzheimer's disease (AD). Although multi-risk factors associated with POCD have been identified, the etiology and pathophysiological mechanisms of this surgical complication remain elusive. Therefore, developing strategies for preventing or treating POCD is still challenging. However, increasing evidence suggests that central and systemic inflammation triggered by surgery likely plays a fundamental role in POCD developing and progression. Minocycline, a tetracycline derivative with anti-inflammatory properties, has been shown to be effective in treating neuroinflammatory related conditions or neurodegenerative diseases such as AD, Parkinson's disease, Huntington's disease. Considering that inflammation may be a potential factor of POCD and minocycline is effective in improving cognitive dysfunction induced by inflammation, we hypothesize that minocycline may be useful to treat/prevent the POCD development after surgery in elderly patients.

Topics: Aged; Anti-Bacterial Agents; Anti-Inflammatory Agents; Brain Diseases; Cognition Disorders; Humans; Inflammation; Minocycline; Models, Theoretical; Neurodegenerative Diseases; Postoperative Complications; Sepsis; Tetracycline; Treatment Outcome

To study the neuroprotective mechanism of minocycline against vascular cognitive impairment after cerebral ischemia.. The rat model with vascular cognitive impairment was established by permanent bilateral common carotid artery occlusion (BCCAO). The observing time-points were determined at 4, 8 and 16 weeks after BCCAO. Animals were randomly divided into sham-operated group (n = 6), model group (subdivided into 3 groups: 4 weeks after BCCAO, n = 6; 8 weeks after BCCAO, n = 6; and 16 weeks after BCCAO, n = 6), and minocycline group (subdivided into 3 groups: 4 weeks after BCCAO, n = 6; 8 weeks after BCCAO, n = 6; and 16 weeks after BCCAO, n = 6). Minocycline was administered by douche via stomach after BCCAO until sacrifice. Glial fibrillary acidic protein (GFAP) was examined by Western blotting and immunohistochemistry. Levels of cyclooxygenase-2 (COX-2) and nuclear factor-kappaB (NF-kappaB) were measured by immunohistochemistry. IL-1beta and TNF-alpha levels were tested with ELISA method.. Levels of GFAP, COX-2, NF-kappaB, IL-1beta and TNF-alpha were all up-regulated after permanent BCCAO, which could be significantly inhibited by minocycline.. Minocycline could ameliorate the inflammation and oxidative stress in the hippocampus of the vascular cognitive impairment rat model.

Topics: Animals; Astrocytes; Carotid Artery Diseases; Carotid Artery, Common; Cognition Disorders; Cyclooxygenase 2; Disease Models, Animal; Female; Glial Fibrillary Acidic Protein; Hippocampus; Interleukin-1beta; Minocycline; Neuroprotective Agents; NF-kappa B; Random Allocation; Rats; Rats, Wistar; Time Factors; Tumor Necrosis Factor-alpha

Minocycline and valproic acid are potential adjuvant therapies for the treatment of human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine whether minocycline alone or in combination with valproic acid affected atazanavir plasma concentrations. Twelve adult HIV-infected subjects whose regimen included atazanavir (300 mg)-ritonavir (100 mg) daily for at least 4 weeks were enrolled. Each subject received atazanavir-ritonavir on day 1, atazanavir-ritonavir plus 100 mg minocycline twice daily on days 2 to 15, and atazanavir-ritonavir plus 100 mg minocycline twice daily and 250 mg valproic acid twice daily on days 16 to 30 with meals. The subjects had 11 plasma samples drawn over a dosing interval on days 1, 15, and 30. The coadministration of minocycline and valproic acid with atazanavir-ritonavir was well tolerated in all 12 subjects (six male; mean [+/- standard deviation] age was 43.1 [8.2] years). The geometric mean ratios (GMRs; 95% confidence interval [CI]) for the atazanavir area under the concentration-time curve from 0 to 24 h at steady state (AUC(0-24)), the plasma concentration 24 h after the dose (C(min)), and the maximum concentration during the dosing interval (C(max)) with and without minocycline were 0.67 (0.50 to 0.90), 0.50 (0.28 to 0.89), and 0.75 (0.58 to 0.95), respectively. Similar decreases in atazanavir exposure were seen after the addition of valproic acid. The GMRs (95% CI) for atazanavir AUC(0-24), C(min), and C(max) with and without minocycline plus valproic acid were 0.68 (0.43 to 1.06), 0.50 (0.24 to 1.06), and 0.66 (0.41 to 1.06), respectively. Coadministration of neither minocycline nor minocycline plus valproic acid appeared to influence the plasma concentrations of ritonavir (P > 0.2). Minocycline coadministration resulted in decreased atazanavir exposure, and there was no evidence that the addition of valproic acid mediated this effect.

Topics: Adult; Anticonvulsants; Atazanavir Sulfate; Cognition Disorders; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Minocycline; Oligopeptides; Pyridines; Ritonavir; Valproic Acid

Nitric oxide (NO) was speculated to play an important role in the pathophysiology of cerebral ischemia. Minocycline, a tetracycline derivative, reduced inflammation and protected against cerebral ischemia. To study the neuroprotection mechanism of minocycline for vascular dementia, the influences of minocycline on expressions of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) were observed in the brains of Wistar rats.. The vascular dementia rat model was established by permanent bilateral common carotid arteries occlusion (BCCAO). Wistar rats were divideded into 3 groups randomly: sham-operation group (S group), vascular dementia model group (M group), and minocycline treatment group (MT group). The behaviour was tested with Morris water maze and open-field task. Expressions of iNOS and eNOS were measured by immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). The optical density value was measured by imaging analysis. Percentage of positive cells with iNOS and eNOS expression was analyzed with optical microscope.. Minocycline attenuated cognitive impairment. Inducible NOS was significantly down-regulated in MT group, compared with that in M group (P < 0.01), while eNOS was significantly up-regulated, compared with that in M group (P < 0.01). The expressions of iNOS and eNOS in M and MT groups were higher than those in S group (P < 0.01).. Minocycline can down-regulate the expression of iNOS and up-regulate the expression of eNOS in vascular dementia, which restrains apoptosis and oxidative stress to protect neural function.

Topics: Animals; Behavior, Animal; Carotid Artery Diseases; Carotid Artery, Common; Cognition Disorders; Disease Models, Animal; Exploratory Behavior; Female; Hippocampus; Maze Learning; Minocycline; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Rats; Rats, Wistar; Reaction Time; Time Factors

The N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP)-induced cognitive deficits have been used as an animal model for schizophrenia. This study was undertaken to determine whether the antibiotic drug minocycline could improve PCP-induced cognitive deficits in mice.. Saline (10 ml/kg/day, s.c., once daily on day 1-5, 8-12) or PCP (10 mg/kg/day, s.c., once daily on day 1-5, 8-12) were administered to mice for 10 days. Subsequently, vehicle (10 ml/kg/day, i.p.) or minocycline (4.0 or 40 mg/kg/day, i.p.) was injected for 14 consecutive days. One day after the final injection, a novel object recognition test was performed.. PCP-induced cognitive deficits in mice were significantly improved by subsequent subchronic (14 days) administration of minocycline (40 mg/kg), but not minocycline (4.0 mg/kg).. This study suggests that minocycline could be a potential therapeutic drug for cognitive deficits in schizophrenic patients.

Topics: Animals; Anti-Bacterial Agents; Behavior, Animal; Cognition Disorders; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Exploratory Behavior; Humans; Injections, Subcutaneous; Male; Mice; Mice, Inbred ICR; Minocycline; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Schizophrenic Psychology

Minocycline is a semi-synthetic tetracycline antibiotic that effectively crosses the blood-brain barrier. Minocycline has been reported to have significant neuroprotective effects in models of cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. In this study, we demonstrate that minocycline has neuroprotective effects in in vitro and in vivo Alzheimer's disease models. Minocycline was found to attenuate the increases in the phosphorylation of double-stranded RNA-dependent serine/threonine protein kinase, eukaryotic translation initiation factor-2 alpha and caspase 12 activation induced by amyloid beta peptide1-42 treatment in NGF-differentiated PC 12 cells. In addition, increases in the phosphorylation of eukaryotic translation initiation factor-2 alpha were attenuated by administration of minocycline in Tg2576 mice, which harbor mutated human APP695 gene including the Swedish double mutation and amyloid beta peptide(1-42)-infused rats. We found that minocycline administration attenuated deficits in learning and memory in amyloid beta peptide(1-42)-infused rats. Increased phosphorylated state of eukaryotic translation initiation factor-2 alpha is observed in Alzheimer's disease patients' brains and may result in impairment of cognitive functions in Alzheimer's disease patients by decreasing the efficacy of de novo protein synthesis required for synaptic plasticity. On the basis of these results, minocycline may prove to be a good candidate as an effective therapeutic agent for Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Avoidance Learning; Brain; Case-Control Studies; Cell Death; Cognition Disorders; Disease Models, Animal; Humans; Male; Maze Learning; Mice; Mice, Transgenic; Minocycline; Nerve Growth Factor; Neurons; Neuroprotective Agents; PC12 Cells; Peptide Fragments; Rats; Rats, Wistar; Transfection

Topics: Anti-Bacterial Agents; Cognition Disorders; Exons; Humans; Huntington Disease; Minocycline; Movement Disorders; Neuropsychological Tests