minocycline and Memory-Disorders

Microglia play a critical role in many processes fundamental to learning and memory in health and are implicated in Alzheimer's pathogenesis. Minocycline, a centrally-penetrant tetracycline antibiotic, inhibits microglial activation and enhances long-term potentiation, synaptic plasticity, neurogenesis and hippocampal-dependent spatial memory in rodents, leading to clinical trials in human neurodegenerative diseases. However, the effects of minocycline on human memory have not previously been investigated. Utilising a double-blind, randomised crossover study design, we recruited 20 healthy male participants (mean 24.6 ± 5.0 years) who were each tested in two experimental sessions: once after 3 days of Minocycline 150 mg (twice daily), and once 3 days of placebo (identical administration). During each session, all completed an fMRI task designed to tap boundary- and landmark-based navigation (thought to rely on hippocampal and striatal learning mechanisms respectively). Given the rodent literature, we hypothesised that minocycline would selectively modulate hippocampal learning. In line with this, minocycline biased use of boundary- compared to landmark-based information (t

Topics: Hippocampus; Humans; Male; Memory Disorders; Minocycline; Neurogenesis; Spatial Memory

Alzheimer's disease (AD), as an advanced neurodegenerative disease, is characterized by the everlasting impairment of memory, which is determined by hyperphosphorylation of intracellular Tau protein and accumulation of beta-amyloid (Aβ) in the extracellular space. Minocycline is an antioxidant with neuroprotective effects that can freely cross the blood-brain barrier (BBB). This study investigated the effect of minocycline on the changes in learning and memory functions, activities of blood serum antioxidant enzymes, neuronal loss, and the number of Aβ plaques after AD induced by Aβ in male rats. Healthy adult male Wistar rats (200-220g) were divided randomly into 11 groups (n = 10). The rats received minocycline (50 and 100 mg/kg/day; per os (P.O.)) before, after, and before/after AD induction for 30 days. At the end of the treatment course, behavioral performance was measured by standardized behavioral paradigms. Subsequently, brain samples and blood serum were collected for histological and biochemical analysis. The results indicated that Aβ injection impaired learning and memory performances in the Morris water maze test, reduced exploratory/locomotor activities in the open field test, and enhanced anxiety-like behavior in the elevated plus maze. The behavioral deficits were accompanied by hippocampal oxidative stress (decreased glutathione (GSH) peroxidase enzyme activity and increased malondialdehyde (MDA) levels in the brain (hippocampus) tissue), increased number of Aβ plaques, and neuronal loss in the hippocampus evidenced by Thioflavin S and H&E staining, respectively. Minocycline improved anxiety-like behavior, recovered Aβ-induced learning and memory deficits, increased GSH and decreased MDA levels, and prevented neuronal loss and the accumulation of Aβ plaques. Our results demonstrated that minocycline has neuroprotective effects and can reduce memory dysfunction, which are due to its antioxidant and anti-apoptotic effects.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Disease Models, Animal; Hippocampus; Male; Maze Learning; Memory Disorders; Minocycline; Neurodegenerative Diseases; Neuroprotective Agents; Rats; Rats, Wistar

Binge drinking during adolescence impairs learning and memory on the long term, and many studies suggest a role of neuroinflammation. However, whether neuroinflammation occurs after the very first exposures to alcohol remains unclear, while initial alcohol exposure impairs learning for several days in male rats.. To investigate the role of neuroinflammation in the effects of only two binge-like episodes on learning and on neuronal plasticity in adolescent male rat hippocampus.. Animals received two ethanol i.p. injections (3 g/kg) 9 h apart. Forty-eight hours later, we recorded long-term depression (LTD) and potentiation (LTP) in CA1 area of hippocampus slices. In isolated CA1, we measured immunolabelings for microglial activation and Toll-like receptor 4 (TLR4) and mRNA levels for several cytokines.. Forty-eight hours after the two binges, rats performed worse than control rats in novel object recognition, LTD was reduced, LTP was increased, and excitatory neurotransmission was more sensitive to an antagonist of the GluN2B subunit of the NMDA receptor. Exposure to ethanol with minocycline or indomethacin, two anti-inflammatory drugs, or with a TLR4 antagonist, prevented all effects of ethanol. Immunolabelings at 48 h showed a reduction of neuronal TLR4 that was prevented by minocycline pretreatment, while microglial reactivity was undetected and inflammatory cytokines mRNA levels were unchanged.. Two binge-like ethanol exposures during adolescence in rat involved neuroinflammation leading to changes in TLR4 expression and in GluN2B functioning inducing disturbances in synaptic plasticity and cognitive deficits. Anti-inflammatory drugs are good candidates to prevent brain function and memory deficits induced by few binge-drinking episodes.

Topics: Animals; Anti-Inflammatory Agents; Binge Drinking; Cytokines; Ethanol; Hippocampus; Male; Memory Disorders; Minocycline; Neuronal Plasticity; Rats; RNA, Messenger; Toll-Like Receptor 4

Lead (Pb) and manganese (Mn) are common neurotoxins. However, individuals are subject to co-exposures in real life, and it is therefore important to study these metals in combination. Weaning Sprague-Dawley rats were given ad libitum access to drinking water solutions containing Pb (100 mg/L), Mn (2.5 mg/mL) or a mixture, and each treatment had its own minocycline (50 mg/(kg•day)) supplement group. The results showed a significant difference in spatial memory and induction levels of hippocampal long-term potentiation (LTP) in all exposure groups when compared with controls. The combined-exposure group exhibited the most pronounced effect when compared with each of the single-metal exposure groups. Microglia displayed activation at day 3 after exposure alone or in combination, while astrocytes showed activation at day 5, accompanied by decreased expression levels of GLAST, GLT-1, and GS. Furthermore, the levels of glutamate in the synaptic cleft increased significantly. When microglial activation was inhibited by minocycline, the activation of astrocytes and the expression of GLAST, GLT-1, and GS were both reversed. In addition, upon minocycline treatment, hippocampal LTP impairment and cognitive injury were significantly alleviated in each of the exposure groups. These results suggest that combined exposure to Pb and Mn can cause greater effects on cognition and synaptic plasticity when compared to single-metal exposure groups. The reason may involve abnormal activation of microglia leading to excessive regulation of astrocytes, resulting in glutamate reuptake dysfunction in astrocytes and leading to perturbed cognition and synaptic plasticity.

Topics: Animals; Glutamates; Ions; Lead; Manganese; Memory Disorders; Minocycline; Rats; Rats, Sprague-Dawley

Multiple drugs to treat traumatic brain injury (TBI) have failed clinical trials. Most drugs lose efficacy as the time interval increases between injury and treatment onset. Insufficient therapeutic time window is a major reason underlying failure in clinical trials. Few drugs have been developed with therapeutic time windows sufficiently long enough to treat TBI because little is known about which brain functions can be targeted if therapy is delayed hours to days after injury. We identified multiple injury parameters that are improved by first initiating treatment with the drug combination minocycline (MINO) plus N-acetylcysteine (NAC) at 72 h after injury (MN72) in a mouse closed head injury (CHI) experimental TBI model. CHI produces spatial memory deficits resulting in impaired performance on Barnes maze, hippocampal neuronal loss, and bilateral damage to hippocampal neurons, dendrites, spines and synapses. MN72 treatment restores Barnes maze acquisition and retention, protects against hippocampal neuronal loss, limits damage to dendrites, spines and synapses, and accelerates recovery of microtubule associated protein 2 (MAP2) expression, a key protein in maintaining proper dendritic architecture and synapse density. These data show that in addition to the structural integrity of the dendritic arbor, spine and synapse density can be successfully targeted with drugs first dosed days after injury. Retention of substantial drug efficacy even when first dosed 72 h after injury makes MINO plus NAC a promising candidate to treat clinical TBI.

Topics: Acetylcysteine; Animals; Brain; Brain Injuries, Traumatic; Drug Administration Schedule; Drug Therapy, Combination; Free Radical Scavengers; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Minocycline; Neurodegenerative Diseases; Neuroprotective Agents; Spatial Memory

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

Toluene can be intentionally misused by adolescents to experience psychoactive effects. Toluene has a complex mechanism of action and broad behavioral effects, among which memory impairment is reported consistently. We have previously reported that repeated toluene inhalation (8000 ppm) increases layer 5 prelimbic pyramidal cells' excitability in the medial prefrontal cortex (mPFC) of adolescent rats. Toluene also produces reactive oxygen species (ROS), which activate glial cells. Here, we tested the hypothesis that the anti-inflammatory agent minocycline would decrease toluene's effects because it inhibits NF-κB (nuclear factor enhancer of the kappa light chains of activated B cells) and reduces pro-inflammatory cytokine and ROS production. Our results show that minocycline (50 mg/kg, ip, for 10 days) prevents the hyperexcitability of mPFC neurons observed after repeated 8000 ppm toluene exposure (30 min/day, 2×/day for 10 days). Minocycline prevents toluene-induced hyperexcitability by a mechanism that averts the loss of the slow calcium-dependent potassium current, and normalizes mPFC neurons' firing frequency. These effects are accompanied by significant decreased expression of astrocytes and activated microglia in the mPFC, reduced NLRP3 inflammasome activation and mRNA expression levels of the pro-inflammatory cytokine interleukin 1β (IL-1β), as well as increased mRNA expression of the anti-inflammatory cytokine transforming growth factor β (TGF-β). Minocycline also prevents toluene-induced memory impairment in adolescent rats in the passive avoidance task and the temporal order memory test in which the mPFC plays a central role. These results show that neuroinflammation produces several effects of repeated toluene administration at high concentrations, and minocycline can significantly prevent them.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Gene Expression; Inhalant Abuse; Interleukin-1beta; Male; Memory Disorders; Minocycline; Neurons; NLR Family, Pyrin Domain-Containing 3 Protein; Prefrontal Cortex; Rats; Rats, Wistar; Reactive Oxygen Species; Toluene; Transforming Growth Factor beta

Minocycline as a member of the tetracycline family is a lipophilic broad-spectrum antibiotic, which can display some non-antibiotic properties such as antioxidant, antiapoptosis, neuroprotection and modulation of pharmacological traits of drugs of abuse (ie, reward, sensitization and/or analgesia). Thus, the aim of the present study was to investigate the effect of intracerebroventricular (ICV) injection of minocycline on morphine-induced memory impairment and motor function in male Wistar rats. The behavioural responses were measured by a passive avoidance test for evaluating memory, and in the open field for studying motor function. Furthermore, the expression of Phospho-cAMP response element-binding protein (P-CREB) and c-Fos were assessed using immunohistochemistry in the dorsal hippocampus and basolateral amygdala (BLA). Our results showed that morphine dose-dependently impairs memory consolidation, but not motor function. Maximum effect was achieved with morphine at dose of 5 mg/kg. Pretreatment with ICV injection of minocycline (50 μg/rat) prevented morphine-induced memory impairment, but there was no effect on motor function. The results of immunohistochemistry analysis demonstrated that morphine decreased expression of P-CREB positive cells compared to saline control group in the BLA, but not in the dorsal hippocampus. On the other hand, pretreatment of animals with ICV injection of minocycline increased the expression of P-CREB in both brain areas. Moreover, there was no significant change in the expression of c-Fos positive cells in above-mentioned regions. In summary, our results indicated that pretreatment with ICV injection of minocycline prevented morphine-induced memory impairment and increased P-CREB expression in the dorsal hippocampus and BLA, which may explain its memory improvement property.

Topics: Animals; Avoidance Learning; Basolateral Nuclear Complex; Cyclic AMP Response Element-Binding Protein; Gene Expression Regulation; Hippocampus; Injections; Male; Memory Disorders; Minocycline; Morphine; Phosphoproteins; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar

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

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common type of age-related dementia. Cognitive decline, beta-amyloid (Aβ) accumulation, neurofibrillary tangles, and neuroinflammation are the main pathophysiological characteristics of AD. Minocycline is a tetracycline derivative with anti-inflammatory properties that has a neuroprotective effect. The aim of this study was to evaluate the effect of minocycline on memory, neurotrophins and neuroinflammation in an animal model of AD induced by the administration of Aβ (1-42) oligomer. Male BALB/c mice were treated with minocycline (50mg/kg) via the oral route for a total of 17days, 24h after intracerebroventricular administration of Aβ (1-42) oligomer. At the end of this period, was performed the radial maze test, and 24h after the last minocycline administration, serum was collected and the cortex and hippocampus were dissected for biochemical analysis. The administration of minocycline reversed the memory impairment caused by Aβ (1-42). In the hippocampus, minocycline reversed the increases in the levels of interleukin (IL-1β), Tumor Necrosis Factor- alpha (TNF-α) and, IL-10 caused by Aβ (1-42). In the cortex, AD-like model increase the levels of IL-1β, TNF-α and, IL-4. Minocycline treatment reversed this. In the serum, Aβ (1-42) increased the levels of IL-1β and IL-4, and minocycline was able to reverse this action, but not to reverse the decrease of IL-10 levels. Minocycline also reversed the increase in the levels of Brain-derived neurotrophic factor (BDNF) in the hippocampus caused by Aβ (1-42), and reduced Nerve Growth Factor (NGF) increases in the total cortex. Therefore, our results indicate that minocycline causes improvements in the spatial memory, and cytokine levels were correlated with this effect in the brain it. Besides this, minocycline reduced BDNF and NGF levels, highlighting the promising effects of minocycline in treating AD-like dementia.

Topics: Amyloid beta-Peptides; Animals; Brain; Brain-Derived Neurotrophic Factor; Cerebral Cortex; Hippocampus; Inflammation; Infusions, Intraventricular; Interleukin-10; Interleukin-1beta; Interleukin-4; Male; Maze Learning; Memory Disorders; Mice; Minocycline; Neuroprotective Agents; Peptide Fragments; 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

The role of microglia in the pathophysiology of injury to the developing brain has been extensively studied. In children under the age of 4 who have sustained a traumatic brain injury (TBI), markers of microglial/macrophage activation were increased in the cerebrospinal fluid and were associated with worse neurologic outcome. Minocycline is an antibiotic that decreases microglial/macrophage activation following hypoxic-ischemia in neonatal rodents and TBI in adult rodents thereby reducing neurodegeneration and behavioral deficits. In study 1, 11-day-old rats received an impact to the intact skull and were treated for 3days with minocycline. Immediately following termination of minocycline administration, microglial reactivity was reduced in the cortex and hippocampus (p<0.001) and was accompanied by an increase in the number of fluoro-Jade B profiles (p<0.001) suggestive of a reduced clearance of degenerating cells; however, this effect was not sustained at 7days post-injury. Although microglial reactivity was reduced in the white matter tracts (p<0.001), minocycline treatment did not reduce axonal injury or degeneration. In the thalamus, minocycline treatment did not affect microglial reactivity, axonal injury and degeneration, and neurodegeneration. Injury-induced spatial learning and memory deficits were also not affected by minocycline. In study 2, to test whether extended dosing of minocycline may be necessary to reduce the ongoing pathologic alterations, a separate group of animals received minocycline for 9days. Immediately following termination of treatment, microglial reactivity and neurodegeneration in all regions examined were exacerbated in minocycline-treated brain-injured animals compared to brain-injured animals that received vehicle (p<0.001), an effect that was only sustained in the cortex and hippocampus up to 15days post-injury (p<0.001). Whereas injury-induced spatial learning deficits remained unaffected by minocycline treatment, memory deficits appeared to be significantly worse (p<0.05). Sex had minimal effects on either injury-induced alterations or the efficacy of minocycline treatment. Collectively, these data demonstrate the differential effects of minocycline in the immature brain following impact trauma and suggest that minocycline may not be an effective therapeutic strategy for TBI in the immature brain.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Axons; Cerebellar Cortex; Female; Head Injuries, Closed; Hippocampus; Male; Memory Disorders; Microglia; Minocycline; Nerve Degeneration; Rats; Rats, Sprague-Dawley; Spatial Learning; Thalamus; White Matter

Cerebral ischemia leads to memory impairment that is associated with loss of hippocampal CA1 pyramidal neurons. Neuroinflammation and oxidative stress may be implicated in the pathogenesis of ischemia/reperfusion damage. Minocycline has anti-inflammatory and antioxidant properties. We investigated the neuroprotective effects of minocycline in rats subjected to cerebral ischemia/reperfusion injury. Thirty male rats were divided into three groups: control, sham, and minocycline-pretreated group. Minocycline (40 mg/kg) was injected intraperitoneally immediately before surgery, and then ischemia was induced by occlusion of common carotid arteries for 20 min. Seven days after reperfusion, the Morris water-maze task was used to evaluate memory. Nissl staining was also performed to analyze pyramidal cell damage. We measured the contents of malondialdehyde and proinflammatory cytokines in the hippocampus by the thiobarbituric acid method and enzyme-linked immunosorbent assay, respectively. Microglial activation was also investigated by Iba1 immunostaining. The results showed that pretreatment with minocycline prevented memory impairment induced by cerebral ischemia/reperfusion. Minocycline pretreatment also significantly attenuated ischemia-induced pyramidal cell death and microglial activation in the CA1 region and reduced the levels of malondialdehyde and proinflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of ischemic rats. Minocycline showed neuroprotective effects on cerebral ischemia-induced memory deficit probably through its anti-inflammatory and antioxidant activities.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Brain Ischemia; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Inflammation; Male; Maze Learning; Memory Disorders; Minocycline; Neuroprotective Agents; Oxidative Stress; Rats; Reperfusion Injury

Repeated social defeat (RSD) is a murine stressor that recapitulates key physiological, immunological, and behavioral alterations observed in humans exposed to chronic psychosocial stress. Psychosocial stress promotes prolonged behavioral adaptations that are associated with neuroinflammatory signaling and impaired neuroplasticity. Here, we show that RSD promoted hippocampal neuroinflammatory activation that was characterized by proinflammatory gene expression and by microglia activation and monocyte trafficking that was particularly pronounced within the caudal extent of the hippocampus. Because the hippocampus is a key area involved in neuroplasticity, behavior, and cognition, we hypothesize that stress-induced neuroinflammation impairs hippocampal neurogenesis and promotes cognitive and affective behavioral deficits. We show here that RSD caused transient impairments in spatial memory recall that resolved within 28 d. In assessment of neurogenesis, the number of proliferating neural progenitor cells (NPCs) and the number of young, developing neurons were not affected initially after RSD. Nonetheless, the neuronal differentiation of NPCs that proliferated during RSD was significantly impaired when examined 10 and 28 d later. In addition, social avoidance, a measure of depressive-like behavior associated with caudal hippocampal circuitry, persisted 28 d after RSD. Treatment with minocycline during RSD prevented both microglia activation and monocyte recruitment. Inhibition of this neuroinflammatory activation in turn prevented impairments in spatial memory after RSD but did not prevent deficits in neurogenesis nor did it prevent the persistence of social avoidance behavior. These findings show that neuroinflammatory activation after psychosocial stress impairs spatial memory performance independent of deficits in neurogenesis and social avoidance.. Repeated exposure to stress alters the homeostatic environment of the brain, giving rise to various cognitive and mood disorders that impair everyday functioning and overall quality of life. The brain, previously thought of as an immune-privileged organ, is now known to communicate extensively with the peripheral immune system. This brain-body communication plays a significant role in various stress-induced inflammatory conditions, also characterized by psychological impairments. Findings from this study implicate neuroimmune activation rather than impaired neurogenesis in stress-induced cognitive deficits. This idea opens up possibilities for novel immune interventions in the treatment of cognitive and mood disturbances, while also adding to the complexity surrounding the functional implications of adult neurogenesis.

Topics: Animals; Brain; Bromodeoxyuridine; Calcium-Binding Proteins; Cell Proliferation; Disease Models, Animal; Doublecortin Domain Proteins; Encephalitis; Hippocampus; Leukocyte Common Antigens; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Microfilament Proteins; Microtubule-Associated Proteins; Minocycline; Neural Stem Cells; Neuronal Plasticity; Neuropeptides; Social Behavior; Stress, Psychological

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

Dysfunction of learning and memory is widely found in many neurological diseases. Understanding how to preserve the normal function of learning and memory will be extremely beneficial for the treatment of these diseases. However, the possible protective effect of minocycline in memory impairment is unknown. We used the well-established D-galactose rat amnesia model and two behavioral tasks, the Morris water maze and the step-down task, for memory evaluation. Western blot and PCR were used to examine the protein and mRNA levels of Arc/Arg3.1. We report that minocycline supplementation ameliorates both the spatial and fear memory deficits caused by D-galactose. We also found that Arc/Arg3.1, c-fos, and brain-derived neurotrophic factor levels are decreased in the D-galactose animal model, and that minocycline reverses the protein and mRNA levels of Arc in the hippocampus, suggesting the potential role of Arc/Arg3.1 in minocycline's neuroprotective mechanism. Our study strongly suggests that minocycline can be used as a novel treatment for memory impairment in neurological diseases.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cytoskeletal Proteins; Disease Models, Animal; Galactose; Gene Expression Regulation; Humans; Male; Maze Learning; Memory Disorders; Minocycline; Nerve Tissue Proteins; Proto-Oncogene Proteins c-fos; Rats

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

Oculoleptomeningeal amyloidosis (OA) is a fatal and untreatable hereditary disease characterized by the accumulation of transthyretin (TTR) amyloid within the central nervous system. The mechanisms underlying the pathogenesis of OA, and in particular how amyloid triggers neuronal damage, are still unknown. Here, we show that amyloid fibrils formed by a mutant form of TTR, A25T, activate microglia, leading to the secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and nitric oxide. Further, we found that A25T amyloid fibrils induce the activation of Akt, culminating in the translocation of NFκB to the nucleus of microglia. While A25T fibrils were not directly toxic to neurons, the exposure of neuronal cultures to media conditioned by fibril-activated microglia caused synapse loss that culminated in extensive neuronal death via apoptosis. Finally, intracerebroventricular (i.c.v.) injection of A25T fibrils caused microgliosis, increased brain TNF-α and IL-6 levels and cognitive deficits in mice, which could be prevented by minocycline treatment. These results indicate that A25T fibrils act as pro-inflammatory agents in OA, activating microglia and causing neuronal damage.

Topics: Amyloid; Amyloid Neuropathies, Familial; Animals; Brain; Cell Death; Cell Nucleus; Cells, Cultured; Culture Media, Conditioned; Disease Models, Animal; Endocytosis; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Inflammation Mediators; Interleukin-6; Memory Disorders; Memory, Short-Term; Mice; Microglia; Minocycline; Mutation; Neurons; NF-kappa B; Phosphorylation; Prealbumin; Protein Transport; Proto-Oncogene Proteins c-akt; 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

Our aim was to examine whether neonatal lipopolysaccharide (LPS) exposure is associated with changes in microglia and whether these alternations could influence later seizure-induced neurobehavioral outcomes. Male pups were first injected intraperitoneally with either LPS or saline on postnatal day 3 (P3) and postnatal day 5 (P5). Immunohistochemical analysis showed that LPS-treated animals exhibited increased microglia activation that persisted into adolescence. At P45, seizures were induced in rats by intraperitoneal injection of kainic acid (KA). Rats treated with LPS neonatally showed significantly greater proinflammatory responses and performed significantly worse in the Y-maze, Morris water maze, and inhibitory avoidance tasks after KA insult. Treatment with minocycline at the time of neonatal LPS exposure to block LPS-induced microglia alternation attenuated the exaggerated neuroinflammatory responses and alleviated memory impairment associated with the KA insult. Our findings suggest that neonatal immune activation can predispose the brain to exacerbated behavioral deficits following seizures in adulthood, possibly by priming microglia.

Topics: Analysis of Variance; Animals; Animals, Newborn; Avoidance Learning; Cytokines; Disease Models, Animal; Female; Hippocampus; Kainic Acid; Lipopolysaccharides; Male; Maze Learning; Memory Disorders; Minocycline; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures; Time Factors; Up-Regulation

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

Activation of the NF-κB pathway plays an important role in the pathophysiology of Alzheimer's disease (AD), and blocking NF-κB pathway activation has been shown to attenuate cognitive impairment. Diabetic metabolic disorder contributes to β-amyloid protein (Aβ) generation. The goal of this study was to determine the effect of minocycline on Aβ generation and the NF-κB pathway in the hippocampus of diabetic rats and to elucidate the neuroprotective mechanisms of minocycline for the treatment of diabetic metabolic disorder. The diabetic rat model was established using a high-fat diet and an intraperitoneal injection of streptozocin (STZ). Behavioral tests showed that the capacity of learning and memory was significantly lower in diabetic rats. The levels of NF-κB, COX-2, iNOS, IL-1β and TNF-α after the STZ injection were significantly increased in the hippocampus. Significant increases in Aβ, BACE1, NF-κB, COX-2, iNOS, IL-1β and TNF-α were found in diabetic rats. The levels of Aβ, NF-κB, COX-2, iNOS, IL-1β and TNF-α were significantly decreased after minocycline administration; however, minocycline had no effect on BACE1 expression. In sum, diabetes contributes to the activation of the NF-κB pathway and upregulates BACE1 and Aβ. Minocycline downregulates Aβ in the hippocampus by inhibiting NF-κB pathway activation.

Topics: Amyloid beta-Peptides; Animals; Behavior, Animal; Diabetes Mellitus, Experimental; Dietary Fats; Down-Regulation; Hippocampus; Learning Disabilities; Male; Memory Disorders; Minocycline; Neuroprotective Agents; NF-kappa B; Rats; Rats, Wistar; Streptozocin

Subarachnoid hemorrhage (SAH) results in significant long-lasting cognitive dysfunction. Therefore, evaluating acute and long-term outcomes after therapeutic intervention is important for clinical translation. The aim of this study was to use minocycline, a known neuroprotectant agent, to evaluate the long-term benefits in terms of neurobehavior and neuropathology after experimental SAH in rats, and to determine which neurobehavioral test would be effective for long-term evaluation. SAH was induced by endovascular perforation in adult male Sprague-Dawley rats (n=118). The animals were treated with intraperitoneal injection of minocycline (45 mg/kg or 135 mg/kg) or vehicle 1 h after SAH induction. In the short-term, animals were euthanized at 24 and 72 h for evaluation of neurobehavior, brain water content, and matrix metalloproteinase (MMP) activity. In the long-term, neurobehavior was evaluated at days 21-28 post-SAH, and histopathological analysis was done at day 28. High-dose but not low-dose minocycline reduced brain water content at 24 h, and therefore only the high-dose regimen was used for further evaluation, which reduced MMP-9 activity at 24 h. Further, high-dose minocycline improved spatial memory and attenuated neuronal loss in the hippocampus and cortex. The rotarod, T-maze, and water maze tests, but not the inclined plane test, detected neurobehavioral deficits in SAH rats at days 21-28. This study demonstrates that minocycline attenuates long-term functional and morphological outcomes after endovascular perforation-induced SAH. Long-term neurobehavioral assessments using the rotarod, T-maze, and water maze tests could be useful to evaluate the efficacy of therapeutic intervention after experimental SAH.

Topics: Animals; Cerebral Arteries; Endovascular Procedures; Injections, Intraperitoneal; Male; Memory Disorders; Minocycline; Random Allocation; Rats; Rats, Sprague-Dawley; Recovery of Function; Subarachnoid Hemorrhage

The proinflammatory cytokine interleukin-1β (IL-1β) is critical for normal hippocampus (HP)-dependent cognition, whereas high levels can disrupt memory and are implicated in neurodegeneration. However, the cellular source of IL-1β during learning has not been shown, and little is known about the risk factors leading to cytokine dysregulation within the HP. We have reported that neonatal bacterial infection in rats leads to marked HP-dependent memory deficits in adulthood. However, deficits are only observed if unmasked by a subsequent immune challenge [lipopolysaccharide (LPS)] around the time of learning. These data implicate a long-term change within the immune system that, upon activation with the "second hit," LPS, acutely impacts the neural processes underlying memory. Indeed, inhibiting brain IL-1β before the LPS challenge prevents memory impairment in neonatally infected (NI) rats. We aimed to determine the cellular source of IL-1β during normal learning and thereby lend insight into the mechanism by which this cytokine is enduringly altered by early-life infection. We show for the first time that CD11b(+) enriched cells are the source of IL-1β during normal HP-dependent learning. CD11b(+) cells from NI rats are functionally sensitized within the adult HP and produce exaggerated IL-1β ex vivo compared with controls. However, an exaggerated IL-1β response in vivo requires LPS before learning. Moreover, preventing microglial activation during learning prevents memory impairment in NI rats, even following an LPS challenge. Thus, early-life events can significantly modulate normal learning-dependent cytokine activity within the HP, via a specific, enduring impact on brain microglial function.

Topics: Acoustic Stimulation; Animals; Animals, Newborn; Anti-Bacterial Agents; Bacterial Infections; Brain; CD11b Antigen; Conditioning, Classical; Cues; CX3C Chemokine Receptor 1; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Exploratory Behavior; Fear; Female; Flow Cytometry; Gene Expression Regulation; Glial Fibrillary Acidic Protein; In Vitro Techniques; Interleukin-1beta; Lipopolysaccharides; Male; Memory Disorders; Microglia; Minocycline; Neural Inhibition; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Chemokine; RNA, Messenger

Cognitive deficits are a core feature of patients with schizophrenia and methamphetamine (METH) psychosis. We have recently found that repeated METH treatment (1 mg/kg, s.c.) in mice, which induces behavioral sensitization, impairs long-term recognition memory in a novel object recognition test (NORT) and that the impairment is ameliorated by clozapine, but not haloperidol. Recent studies indicate that minocycline, a second-generation tetracycline, has potent neuroprotective effects in various animal models of neurological diseases.. In the present study, we investigated the effect of minocycline on learning and memory in the NORT and behavioral sensitization in mice that had been administered METH for 7 days.. When minocycline (20-40 mg/kg) was administered intraperitoneally once a day for seven consecutive days to mice that had previously been treated with METH for 7 days, it ameliorated the METH-induced impairment of recognition memory in a dose-dependent manner, although the same treatment with minocycline had no effect on behavioral sensitization to METH. The administration of minocycline, together with METH, inhibited the development of METH-induced behavioral sensitization. The improvement in memory caused by minocycline was associated with an amelioration of the novelty-induced activation of extracellular signal-regulated kinase 1/2 in the prefrontal cortex of METH-treated mice.. These results suggest that minocycline is useful for the treatment of cognitive deficits in patients with METH psychosis or schizophrenia.

Topics: Animals; Behavior, Animal; Clozapine; Dose-Response Relationship, Drug; Exploratory Behavior; Haloperidol; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Memory Disorders; Methamphetamine; Mice; Mice, Inbred ICR; Minocycline; Mitogen-Activated Protein Kinase 3; Motor Activity; Neuroprotective Agents; Phosphorylation; Time Factors

Cerebral microvascular amyloid beta protein (Abeta) deposition and associated neuroinflammation is increasingly recognized as an important component leading to cognitive impairment in Alzheimer's disease and related cerebral amyloid angiopathy disorders. Transgenic mice expressing the vasculotropic Dutch/Iowa (E693Q/D694N) mutant human Abeta precursor protein in brain (Tg-SwDI) accumulate abundant cerebral microvascular fibrillar amyloid deposits and exhibit robust neuroinflammation. In the present study, we investigated the effect of the anti-inflammatory drug minocycline on Abeta accumulation, neuroinflammation, and behavioral deficits in Tg-SwDI mice. Twelve-month-old mice were treated with saline or minocycline by intraperitoneal injection every other day for a total of 4 weeks. During the final week of treatment, the mice were tested for impaired learning and memory. Brains were then harvested for biochemical and immunohistochemical analysis. Minocycline treatment did not alter the cerebral deposition of Abeta or the restriction of fibrillar amyloid to the cerebral microvasculature. Similarly, minocycline-treated Tg-SwDI mice exhibited no change in the levels of total Abeta, the ratios of Abeta40 and Abeta42, or the amounts of soluble, insoluble, or oligomeric Abeta compared with the saline-treated control Tg-SwDI mice. In contrast, the numbers of activated microglia and levels of interleukin-6 were significantly reduced in minocycline-treated Tg-SwDI mice compared with saline-treated Tg-SwDI mice. In addition, there was a significant improvement in behavioral performance of the minocycline-treated Tg-SwDI mice. These finding suggest that anti-inflammatory treatment targeted for cerebral microvascular amyloid-induced microglial activation can improve cognitive deficits without altering the accumulation and distribution of Abeta.

Topics: Animals; Cerebral Amyloid Angiopathy; Disease Models, Animal; Humans; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Minocycline

It is well established that inflammatory changes contribute to brain ageing, and an increased concentration of proinflammatory cytokine, interleukin-1beta (IL-1beta), has been reported in the aged brain associated with a deficit in long-term potentiation (LTP) in rat hippocampus. The precise age at which changes are initiated is unclear. In this study, we investigate parallel changes in markers of inflammation and LTP in 3-, 9- and 15-month-old rats. We report evidence of increased hippocampal concentrations of the proinflammatory cytokines IL-1alpha, IL-18 and interferon-gamma (IFNgamma), which are accompanied by deficits in LTP in the older rats. We also show an increase in expression of markers of microglial activation, CD86, CD40 and intercellular adhesion molecules (ICAM). Associated with these changes, we observed a significant impairment of hippocampal LTP in the same rats. The importance of microglial activation in the attenuation of long-term potentiation (LTP) was demonstrated using an inhibitor of microglial activation, minocycline; partial restoration of LTP in 15-month-old rats was observed following administration of minocycline. We propose that signs of neuroinflammation are observed in middle age and that these changes, which are characterized by microglial activation, may be triggered by IL-18.

Topics: Aging; Animals; Anti-Inflammatory Agents; B7-2 Antigen; Biomarkers; CD40 Antigens; Cytokines; Dentate Gyrus; Encephalitis; Gliosis; Hippocampus; Intercellular Adhesion Molecule-1; Interferon-gamma; Interleukin-18; Interleukin-1alpha; Long-Term Potentiation; Male; Memory Disorders; Microglia; Minocycline; Rats; Rats, Wistar

Two prominent characteristics of Alzheimer's disease are basal forebrain cholinergic degeneration and neuroinflammation characterized by glial activation and the release of pro-inflammatory cytokines. Mu p75- saporin (SAP) is a novel immunotoxin that mimics the selective loss of basal forebrain cholinergic neurons and induces cognitive impairment in mice. We report that cholinergic cell loss in the medial septal nucleus and ventral diagonal band after i.c.v. injection of mu p75-SAP is accompanied by simultaneous activation of microglia and astrocytes in the basal forebrain region as well as significant memory loss. Consistent with a role of glial cells in the pathology of Alzheimer's disease, minocycline, a second-generation tetracycline with known anti-inflammatory and neuroprotective properties, attenuated mu p75-SAP-induced cholinergic cell loss, glial activation and transcription of downstream pro-inflammatory mediators. In addition to neuroprotection, minocycline treatment mitigated the cognitive impairment that appears to be a functional consequence of mu p75-SAP lesioning. The current study demonstrates that glial-related inflammation plays a significant role in the selective neurotoxicity of mu p75-SAP, and suggests that minocycline may provide a viable therapeutic option for degenerating cholinergic systems.

Topics: Alzheimer Disease; Animals; Astrocytes; Cholinergic Fibers; Disease Models, Animal; Gene Expression; Immunohistochemistry; Immunotoxins; Injections, Intraventricular; Interleukin-1; Macrophage Activation; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Microglia; Minocycline; N-Glycosyl Hydrolases; Nerve Degeneration; Neuroprotective Agents; Plant Proteins; Prosencephalon; Reverse Transcriptase Polymerase Chain Reaction; Ribosome Inactivating Proteins, Type 1; Saporins; Tumor Necrosis Factor-alpha