minocycline and Brain-Injuries--Traumatic

Traumatic brain injury (TBI) results in both rapid and delayed brain damage. The speed, complexity, and persistence of TBI present large obstacles to drug development. Preclinical studies from multiple laboratories have tested the FDA-approved anti-microbial drug minocycline (MINO) to treat traumatic brain injury. At concentrations greater than needed for anti-microbial action, MINO readily inhibits microglial activation. MINO has additional pleotropic effects including anti-inflammatory, anti-oxidant, and anti-apoptotic activities. MINO inhibits multiple proteins that promote brain injury including metalloproteases, caspases, calpain, and polyADP-ribose-polymerase-1. At these elevated doses, MINO is well tolerated and enters the brain even when the blood-brain barrier is intact. Most preclinical studies with a first dose of MINO at less than 1 h after injury have shown improved multiple outcomes after TBI. Fewer studies with more delayed dosing have yielded similar results. A small number of clinical trials for TBI have established the safety of MINO and suggested some drug efficacy. Studies are also ongoing that either improve MINO pharmacology or combine MINO with other drugs to increase its therapeutic efficacy against TBI. This review builds upon a previous, recent review by some of the authors (Lawless and Bergold, Neural Regen Res 17:2589-92, 2022). The present review includes the additional preclinical studies examining the efficacy of minocycline in preclinical TBI models. This review also includes recommendations for a clinical trial to test MINO to treat TBI.

Topics: Antioxidants; Brain Injuries; Brain Injuries, Traumatic; Humans; Minocycline

Traumatic brain injury (TBI) causes substantial mortality and disability, but effective treatments are unavailable. An external force causes primary injury, which is followed by secondary injury that triggers chronic neurodegenerative diseases. Therefore, understanding the mechanisms underlying post-TBI secondary injury might provide insights into neurodegenerative diseases. The secondary injury is known to share some physiological features with neurodegenerative diseases. So far, many TBI models in mammals exist, but models in other species are required from the viewpoint of lifespan and animal welfare. In

Topics: Animals; Blood-Brain Barrier; Brain; Brain Injuries, Traumatic; Disease Models, Animal; Drosophila; Humans; Longevity; Minocycline; Neuroprotective Agents

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

Traumatic brain injury (TBI) is a public health concern with limited treatment options because it causes a cascade of side effects that are the leading cause of hospital death. Thioredoxin is an enzyme with neuroprotective properties such as antioxidant, antiapoptotic, immune response modulator, and neurogenic, among others; it has been considered a therapeutic target for treating many disorders.. The controlled cortical impact (CCI) model was used to assess the effect of recombinant human thioredoxin 1 (rhTrx1) (1 μg/2 μL, intracortical) on rats subjected to TBI at two different times of the light-dark cycle (01:00 and 13:00 h). We analyzed the food intake, body weight loss, motor coordination, pain perception, and histology in specific hippocampus (CA1, CA2, CA3, and Dental Gyrus) and striatum (caudate-putamen) areas.. Body weight loss, reduced food intake, spontaneous pain, motor impairment, and neuronal damage in specific hippocampus and striatum regions are more evident in rats subjected to TBI in the light phase than in the dark phase of the cycle and in groups that did not receive rhTrx1 or minocycline (as positive control). Three days after TBI, there is a recovery in body weight, food intake, motor impairment, and pain, which is more pronounced in the rats subjected to TBI at the dark phase of the cycle and those that received rhTrx1 or minocycline.. Knowing the time of day a TBI occurs in connection to the neuroprotective mechanisms of the immune response in diurnal variation and the usage of the Trx1 protein might have a beneficial therapeutic impact in promoting quick recovery after a TBI.

Topics: Animals; Brain Injuries, Traumatic; Disease Models, Animal; Hippocampus; Humans; Minocycline; Neuroprotective Agents; Rats; Thioredoxins; Weight Loss

Traumatic brain injury (TBI) impacts millions worldwide and can cause lasting psychiatric symptoms. Chronic neuroinflammation is a characteristic of post-injury pathology and is also associated with psychiatric conditions such as ADHD and bipolar disorder. Therefore, the current study sought to determine whether TBI-induced impulsivity and inattention could be treated using minocycline, an antibiotic with anti-inflammatory properties. Rats were trained on the five-choice serial reaction time task (5CSRT), a measure of motor impulsivity and attention. After behavior was stable on the 5CSRT, rats received either a bilateral frontal TBI or sham procedure. Minocycline was given at either an early (1 h post-injury) or chronic (9 weeks post-injury) timepoint. Minocycline was delivered every 12 h for 5 days (45 mg/kg, i.p.). Behavioral testing on the 5CSRT began again after one week of recovery and continued for 12 more weeks, then rats were transcardially perfused. Impulsivity and inattention were both substantially increased following TBI. Minocycline had no therapeutic effects at either the early or late time points. TBI rats had increased lesion volume, but minocycline did not attenuate lesion size. Additionally, microglia count measured by IBA-1

Topics: Animals; Anti-Bacterial Agents; Attention Deficit Disorder with Hyperactivity; Brain Injuries, Traumatic; Impulsive Behavior; Inflammation Mediators; Male; Minocycline; Rats; Rats, Long-Evans; Reaction Time; Treatment Failure

Traumatic brain injury (TBI) is one of the main concerns worldwide as there is still no comprehensive therapeutic intervention. Astrocytic water channel aquaporin-4 (AQP-4) system is closely related to the brain edema, water transport at blood-brain barrier (BBB) and astrocyte function in the central nervous system (CNS). Minocycline, a broad-spectrum semisynthetic tetracycline antibiotic, has shown anti-inflammation, anti-apoptotic, vascular protection and neuroprotective effects on TBI models. Here, we tried to further explore the underlying mechanism of minocycline treatment for TBI, especially the relationship of minocycline and AQP4 during TBI treatment. In present study, we observed that minocycline efficaciously reduces the elevation of AQP4 in TBI mice. Furthermore, minocycline significantly reduced neuronal apoptosis, ameliorated brain edema and BBB disruption after TBI. In addition, the expressions of tight junction protein and astrocyte morphology alteration were optimized by minocycline administration. Similar results were found after treating with TGN-020 (an inhibitor of AQP4) in TBI mice. Moreover, these effects were reversed by cyanamide (CYA) treatment, which notably upregulated AQP4 expression level

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Aquaporin 4; Brain Edema; Brain Injuries, Traumatic; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Minocycline; Recovery of Function

Clinical trials of therapeutics for traumatic brain injury (TBI) demonstrating preclinical efficacy for TBI have failed to replicate these results in humans, in part due to the absence of clinically feasible therapeutic windows for administration. Minocycline, an inhibitor of microglial activation, has been shown to be neuroprotective when administered early after experimental TBI but detrimental when administered chronically to human TBI survivors. Rather than focusing on the rescue of primary injury with early administration of therapeutics which may not be clinically feasible, we hypothesized that minocycline administered at a clinically feasible time point (24 h after injury) would be neuroprotective in a model of TBI plus delayed hypoxemia. We first explored several different regimens of minocycline dosing with the initial dose 24 h after injury and 2 h prior to hypoxemia, utilizing short-term neuropathology to select the most promising candidate. We found that a short course of minocycline reduced acute microglial activation, monocyte infiltration and hippocampal neuronal loss at 1 week post injury. We then conducted a preclinical trial to assess the long-term efficacy of a short course of minocycline finding reductions in hippocampal neurodegeneration and synapse loss, preservation of white matter myelination, and improvements in fear memory performance at 6 months after injury. Timing in relation to injury and duration of minocycline treatment and its impact on neuroinflammatory response may be responsible for extensive neuroprotection observed in our studies.

Topics: Animals; Brain Injuries, Traumatic; Female; Hypoxia; Male; Memory; Mice; Minocycline; Neuroprotective Agents; Recovery of Function

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

Minocycline is a type of tetracycline antibiotic with broad-spectrum antibacterial activity that has been demonstrated to protect the brain against a series of central nervous system diseases. However, the precise mechanisms of these neuroprotective actions remain unknown. In the present study, we found that minocycline treatment significantly reduced HT22 cell apoptosis in a mechanical cell injury model. In addition, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining confirmed the neuroprotective effects of minocycline in vivo through the inhibition of apoptosis in a rat model of controlled cortical impact (CCI) brain injury. The western blotting analysis revealed that minocycline treatment significantly downregulated the pro-apoptotic proteins BAX and cleaved caspase-3 and upregulated the anti-apoptotic protein BCL-2. Furthermore, the beam-walking test showed that the administration of minocycline ameliorated traumatic brain injury (TBI)-induced deficits in motor function. Taken together, these findings suggested that minocycline attenuated neuronal apoptosis and improved motor function following TBI.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Brain Injuries, Traumatic; Male; Minocycline; Motor Activity; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley

There is currently no effective treatment for neurological impairment caused by traumatic brain injury (TBI). It has been reported that excessive iron production in the brain may be a key factor in neurological impairment. In the present study, we investigated the effects of minocycline, a semi-synthetic tetracycline antibiotic, against TBI-induced neurological impairment and explored its underlying mechanism. Neurological impairment was assessed by foot-fault test, cylinder test, wire hang test, and Morris water maze. Nissl staining was performed to evaluate cell viability in the brain. The iron concentrations in cerebrospinal fluid (CSF), serum, and brain tissues were examined. The Fe

Topics: Animals; Anti-Bacterial Agents; Brain; Brain Injuries, Traumatic; Cation Transport Proteins; Cerebral Cortex; Chelating Agents; Disease Models, Animal; Ferritins; Hippocampus; Iron; Male; Maze Learning; Minocycline; Nervous System Diseases; Rats; Rats, Sprague-Dawley; Receptors, Transferrin; Tetracycline

Epimedii Herba (EH) has been used in traditional Asian medicine to treat hemiplegia following stroke. Icariin, its major active component, is used as a quality-control marker and for its various pharmacological effects. We hypothesized that icariin would show protective effects following traumatic brain injury (TBI). The TBI mouse model was induced using a controlled cortical impact method. Body weight, brain damage, motor function, and cognitive function were evaluated. Synaptogenesis markers were analyzed to investigate potential mechanisms of action. The animals were divided into six groups: sham, control, minocycline-treated group, and icariin-treated (3, 10, and 30 mg/kg, p. o.) groups. The icariin 30 mg/kg-treated group regained body weight at 7 and 8 d post TBI. Icariin 30 mg/kg- and 10 mg/kg-treated groups showed enhanced sensory-motor function at 8 d post TBI in rotarod and balance beam tests. Icariin-treated groups showed increased recognition index in the novel object recognition test at all doses and increased spontaneous alternation in the Y-maze test at 30 mg/kg. Icariin upregulated brain-derived neurotrophic factor, synaptophysin and postsynaptic density protein 95 expressions. However, no protective effects against brain damage or neuronal death were observed. The current results provide a basis for using icariin following TBI and suggest that it could be a candidate for the development of therapeutic agents for functional recovery after TBI.

Topics: Animals; Brain Injuries, Traumatic; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Disks Large Homolog 4 Protein; Dose-Response Relationship, Drug; Flavonoids; Maze Learning; Mice; Minocycline; Motor Skills; Neuronal Plasticity; Neuroprotective Agents; Synaptophysin

Minocycline is a pleomorphic neuroprotective agent well studied in animal models of traumatic brain injury (TBI) and brain ischemia.. To test the hypothesis that administration of minocycline in moderate to severe TBI (Glasgow Coma Score 3-12). Fifteen patients were enrolled in a two-dose escalation study of minocycline to evaluate the safety of twice the recommended antibiotic dosage; tier 1 n = 7 at a loading dose of 800 mg followed by 200 mg twice a day (BID) for 7 days; tier 2 n = 8 at a loading dose of 800 mg followed by 400 mg BID for 7 days.. The mean initial GCS was 5.6 for Tier 1 patients and 5.4 for Tier 2. The Disability Rating Scale (DRS) had a trend towards improvement with the higher dose 12.5 SD ± 7.7 (N = 5) for Tier 1 at 4 weeks and 8.5 SD ± 9.9 at week 12 (N = 5), whereas for Tier 2 it was 9.7 ± 6.9 (N = 6) for week 4 and 6.0 SD ± 6.1 (N = 7) for week 12 (p = .251 repeated measures ANOVA). Liver function tests increased but resolved after the first week and there were no infections.. Minocycline was safe for moderate to severe TBI at a dose twice that as recommended for treatment of infection. The higher dose did trend towards an improved outcome.

Topics: Adult; Aged; Brain Injuries; Brain Injuries, Traumatic; Dose-Response Relationship, Drug; Feasibility Studies; Female; Humans; Male; Middle Aged; Minocycline; Neuroprotective Agents; Treatment Outcome; Young Adult

Symptoms of many neurodegenerative diseases appear later in human life. However, young animal models for penetrating traumatic brain injury (pTBI) have been used to study neurodegenerative diseases and evaluate the efficacy of neuroprotective medicines. Possibly because of this discordance, effective neuroprotective drugs have still not been developed. For patients suffering from pTBI, aging is known to be a significant prognostic factor of mortality. In this study, we aimed to establish a model of aged pTBI animals using Drosophila melanogaster. We successfully generated aged pTBI flies as a new pTBI model showing increased neurodegeneration and higher mortality. To elucidate the mechanism of increased vulnerability in aged pTBI animals, we analyzed the GenBank-deposited transcriptome data of young and aged flies, demonstrating the importance of innate immunity genes for higher mortality in aged pTBI models. We found that in the context of pTBI, normal aging strongly activated the expression of antimicrobial peptide genes and upregulated the nuclear factor-κB gene in the immune deficiency pathway, but not the Toll pathway. Moreover, we found that minocycline increased the survival of young pTBI flies, but not aged pTBI flies. These results suggested that immune system activation under neurodegenerative conditions was involved in normal aging, thereby inhibiting the medicinal efficacy of neuroprotective drugs effective for young flies in aged flies.

Topics: Aging; Animals; Brain; Brain Injuries; Brain Injuries, Traumatic; Drosophila melanogaster; Drosophila Proteins; Immunity, Innate; Male; Minocycline; Models, Animal; Neurodegenerative Diseases; Neuroprotective Agents

Topics: Acetylcysteine; Animals; Anti-Inflammatory Agents; Antioxidants; Brain Injuries, Traumatic; Disease Models, Animal; Drug Synergism; Inflammation; Male; Minocycline; Oligodendroglia; Rats; Rats, Sprague-Dawley; Remyelination

In response to cell injury, the danger signal high mobility group box-1 (HMGB) is released, activating macrophages by binding pattern recognition receptors. We investigated the role of the anti-inflammatory drug minocycline in attenuating HMGB1 translocation, microglial activation, and neuronal injury in a rat model of pediatric traumatic brain injury (TBI). Post-natal day 17 Sprague-Dawley rats underwent moderate-severe controlled cortical impact (CCI). Animals were randomized to treatment with minocycline (90 mg/kg, intraperitoneally) or vehicle (saline) at 10 min and 20 h after injury. Shams received anesthesia and craniotomy. We analyzed HMGB1 translocation (protein fractionation and Western blotting), microglial activation (Iba-1 immunohistochemistry), neuronal death (Fluoro-Jade-B [FJB] immunofluorescence), and neuronal cell counts (unbiased stereology). Behavioral assessments included motor and Morris-water maze testing. Nuclear to cytosolic translocation of HMGB1 in the injured brain was attenuated in minocycline versus vehicle-treated rats at 24 h (p < 0.001). Treatment with minocycline reduced microglial activation in the ipsilateral cortex, hippocampus, and thalamus (p < 0.05 vs. vehicle, all regions); attenuated neurodegeneration (FJB-positive neurons) at seven days (p < 0.05 vs. vehicle); and increased thalamic neuronal survival at 14 days (naïve 22773 ± 1012 cells/mm

Topics: Animals; Anti-Inflammatory Agents; Brain Injuries, Traumatic; HMGB1 Protein; Male; Microglia; Minocycline; Nerve Degeneration; Rats; Rats, Sprague-Dawley; Thalamus

Persistent inflammation, mediated in part by increases in cytokines, is a hallmark of traumatlc brain injury (TBI). Minocycline has been shown to inhibit post-TBI neuroinflammation in male rats and mice, but has not been tested in females. Here, we studied sex differences in thermal, stress, and inflammatory responses to TBI and minocycline. Female rats were ovariectomized under isoflurane anesthesia at 33-36 days of age. At 45-55 days of age, male and female rats were implanted intraperitoneally (i.p.) with calibrated transmitters for monitoring body temperature. Moderate cortical contusion injury (CCI) or sham surgery was performed when the rats attained 60-70 days of age. One hour after surgery, rats were injected i.p. with minocycline (50 mg/kg) or saline (0.3 mL); injections were repeated once daily for the next 3 days. At 28 days after CCI or sham surgery, 30 min restraint stress was initiated and blood samples were obtained by tail venipuncture before the onset of restraint and at 30, 60, and 90 min after stress onset. At 35 days after CCI or sham surgery, rats were decapitated and blood was collected for corticosterone (CORT) and cytokine analysis. The brains were removed and ipsilateral cortical tissue and hippocampus were dissected and subsequently assayed for interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Hyperthermia occurred during days 1-6 post-CCI in male rats, but only on the day of CCI in female rats, and minocycline prevented its occurrence in both sexes. Minocycline facilitated suppression of the CORT response to restraint stress in both sexes. In females, but not males, hippocampal IL-6 content increased post-CCI compared with sham-injured controls, whereas IL-1β content was augmented by minocycline. Hippocampal TNF-α was unaffected by CCI and minocycline. These results demonstrate sex differences in immediate thermal and long-lasting stress and cytokine responses to CCI, and only short-term protective effects of minocycline on hyperthermia.

Topics: Animals; Anti-Inflammatory Agents; Body Temperature; Brain Injuries, Traumatic; Cortisone; Cytokines; Female; Inflammation; Male; Minocycline; Rats; Rats, Sprague-Dawley; Sex Characteristics; Stress, Psychological

Alcohol use is a well characterized risk factor for traumatic brain injury (TBI); however, emerging clinical and experimental research suggests that TBI may also be an independent risk factor for the development of alcohol use disorders. In particular, TBIs incurred early in life predict the development of problem alcohol use and increase vulnerability to neuroinflammation as a consequence of alcohol use. Critically, the neuroinflammatory response to alcohol, mediated in large part by microglia, may also function as a driver of further alcohol use. Here, we tested the hypothesis that TBI increases alcohol consumption through microglia-mediated neuroinflammation. Mice were injured as juveniles and alcohol consumption and preference were assessed in a free-choice voluntary drinking paradigm in adolescence. TBI increased alcohol consumption; however, treatment with minocycline, an inhibitor of microglial activation, reduced alcohol intake in TBI mice to sham levels. Moreover, a single injection of ethanol (2 g/kg) significantly increased microglial activation in the nucleus accumbens and microglial expression of the proinflammatory cytokine IL-1β in TBI, but not sham or minocycline-treated, mice. Our data implicate TBI-induced microglial activation as a possible mechanism for the development of alcohol use disorders.

Topics: Alcohol Drinking; Animals; Brain Injuries, Traumatic; Ethanol; Interleukin-1beta; Male; Mice; Microglia; Minocycline; Nucleus Accumbens

The cognitive and behavioural deficits caused by traumatic brain injury (TBI) to the immature brain are more severe and persistent than TBI in the mature brain. Understanding this developmental sensitivity is critical as children under four years of age sustain TBI more frequently than any other age group. Microglia (MG), resident immune cells of the brain that mediate neuroinflammation, are activated following TBI in the immature brain. However, the type and temporal profile of this activation and the consequences of altering it are still largely unknown. In a mouse model of closed head weight drop paediatric brain trauma, we characterized i) the temporal course of total cortical neuroinflammation and the phenotype of ex vivo isolated CD11B-positive microglia/macrophage (MG/MΦ) using a battery of 32 markers, and ii) neuropathological outcome 1 and 5days post-injury. We also assessed the effects of targeting MG/MΦ activation directly, using minocycline a prototypical microglial activation antagonist, on these processes and outcome. TBI induced a moderate increase in both pro- and anti-inflammatory cytokines/chemokines in the ipsilateral hemisphere. Isolated cortical MG/MΦ expressed increased levels of markers of endogenous reparatory/regenerative and immunomodulatory phenotypes compared with shams. Blocking MG/MΦ activation with minocycline at the time of injury and 1 and 2days post-injury had only transient protective effects, reducing ventricular dilatation and cell death 1day post-injury but having no effect on injury severity at 5days. This study demonstrates that, unlike in adults, the role of MG/MΦ in injury mechanisms following TBI in the immature brain may not be negative. An improved understanding of MG/MΦ function in paediatric TBI could support translational efforts to design therapeutic interventions.

Topics: Animals; Brain; Brain Injuries; Brain Injuries, Traumatic; Chemokines; Cytokines; Disease Models, Animal; Macrophage Activation; Macrophages; Mice; Microglia; Minocycline