minocycline and Atrophy

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

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

The neuronal ceroid lipofuscinoses (NCLs; or Batten disease) are fatal inherited human neurodegenerative diseases affecting an estimated 1:12,500 live births worldwide. They are caused by mutations in at least 11 different genes. Currently, there are no effective treatments. Progress into understanding pathogenesis and possible therapies depends on studying animal models. The most studied animals are the CLN6 South Hampshire sheep, in which the course of neuropathology closely follows that in affected children. Neurodegeneration, a hallmark of the disease, has been linked to neuroinflammation and is consequent to it. Activation of astrocytes and microglia begins prenatally, starting from specific foci associated with the later development of progressive cortical atrophy and the development of clinical symptoms, including the occipital cortex and blindness. Both neurodegeneration and neuroinflammation generalize and become more severe with increasing age and increasing clinical severity. The purpose of this study was to determine if chronic administration of an anti-inflammatory drug, minocycline, from an early age would halt or reverse the development of disease.. Minocycline, a tetracycline family antibiotic with activity against neuroinflammation, was tested by chronic oral administration of 25 mg minocycline/kg/day to presymptomatic lambs affected with CLN6 NCL at 3 months of age to 14 months of age, when clinical symptoms are obvious, to determine if this would suppress neuroinflammation or disease progression.. Minocycline was absorbed without significant rumen biotransformation to maintain pharmacological concentrations of 1 μM in plasma and 400 nM in cerebrospinal fluid, but these did not result in inhibition of microglial activation or astrocytosis and did not change the neuronal loss or clinical course of the disease.. Oral administration is an effective route for drug delivery to the central nervous system in large animals, and model studies in these animals should precede highly speculative procedures in humans. Minocycline does not inhibit a critical step in the neuroinflammatory cascade in this form of Batten disease. Identification of the critical steps in the neuroinflammatory cascade in neurodegenerative diseases, and targeting of specific drugs to them, will greatly increase the likelihood of success.

Topics: Animals; Anti-Bacterial Agents; Atrophy; Brain; Chromatography, High Pressure Liquid; Disease Progression; Female; Glial Fibrillary Acidic Protein; Growth; Image Processing, Computer-Assisted; Inflammation; Liver Function Tests; Macrophage Activation; Male; Minocycline; Neurodegenerative Diseases; Neuroglia; Neuronal Ceroid-Lipofuscinoses; Sheep

Histoid leprosy is a rare but well-defined entity with specific clinical, histopathologic, and bacteriologic features. We present a case of histoid leprosy in an 84-year-old Egyptian male in view of the rarity of this condition. The patient presented with erythematous itchy discrete and coalescent papules that were distributed bilaterally and symmetrically on the front and back of the trunk. Before approaching us, he was initially misdiagnosed as a case of pityriasis rosea. There was no mucosal or facial affection and the patient's general examination was normal. Routine hematologic investigations, urine analysis, liver and renal function tests were all normal. Slit skin smear revealed acid-fast bacilli of BI - 6+ and MI - 50-60%. Histopathologic examination of hematoxylin and eosin-stained section revealed atrophic epidermis with flattened rete ridges and dermal infiltration by nodular granulomata formed of spindle shaped histiocytes with pyknotic nuclei oriented in a storiform pattern. Fite's stain for lepra bacilli showed plenty of acid fast bacilli. So, the diagnosis of histoid leprosy was made. Therefore, ROM therapy (rifampicin 600 mg, ofloxacin 400 mg, minocycline 200 mg) was started and followed by multi-drug therapy for 2 years.

Topics: Aged; Atrophy; Dermis; Epidermis; Humans; Leprostatic Agents; Leprosy; Male; Minocycline; Ofloxacin; Rifampin

Evidence suggests that microglia activation contributes to brain injury after intracerebral hemorrhage (ICH). The present study aimed to determine if minocycline, an inhibitor of microglia activation, can reduce brain edema, brain atrophy and neurological deficits after ICH.Male Sprague-Dawley rats received an infusion of 100-microL autologous whole blood into the right basal ganglia. Rats received minocycline or vehicle treatment. There were two sets of experiments in this study. In the first set of experiments, the effects of minocycline on ICH-induced brain edema were examined at day 3. In the second set, behavioral tests were performed at days 1, 3, 7, 14 and 28. Rats were killed at day 28 for brain atrophy measurement (caudate and lateral ventricle size).Minocycline reduced perihematomal brain edema in the ipsilateral basal ganglia (78.8 +/- 0.4 vs. 80.9 +/- 1.1% in the vehicle-treated group, p < 0.01). Minocycline also improved functional outcome. In addition, minocycline reduced brain tissue loss in the ipsilateral caudate (p < 0.01) and ventricular enlargement (p < 0.05).In conclusion, minocycline attenuates ICH-induced brain edema formation, neurological deficits and brain atrophy in rats suggesting an important role of microglia in ICH-related brain injury.

Topics: Analysis of Variance; Animals; Atrophy; Brain; Brain Edema; Caudate Nucleus; Cerebral Hemorrhage; Disease Models, Animal; Lateral Ventricles; Male; Minocycline; Nervous System Diseases; Neurologic Examination; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Time Factors

Abnormally decreased deep gray matter (GM) signal intensity on T2-weighted MRI (T2 hypointensity) is associated with brain atrophy and disability progression in patients with multiple sclerosis (MS) and is believed to represent excessive iron deposition. We investigated the time course of deep GM T2 hypointensity and its relationship with disability at 3T in 8 stable relapsing-remitting (RR) MS patients treated with minocycline over 3years. MRI and disability measurements were compared at baseline, 6, 12, 24, and 36months. Grand mean deep GM T2 hypointensity was negatively correlated with EDSS over time (r=-0.94, P=0.02). This correlation was strongest in the head of caudate (r=-0.95, P=0.01) and putamen (r=-0.89, P=0.04). Additionally, baseline grand mean deep GM T2 hypointensity appears to predict third year EDSS (r=-0.72, P=0.04). These results suggest that iron associated deep GM injury correlates with patient disability in stable RRMS. Measurements of deep GM T2 hypointensity at high field MRI may prove to be useful in monitoring individuals with MS. Further studies are required to confirm these results in a large sample and to determine if T2 hypointensity changes in clinically active MS patients.

Topics: Adult; Analysis of Variance; Anti-Bacterial Agents; Atrophy; Brain; Disability Evaluation; Disabled Persons; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Minocycline; Multiple Sclerosis, Relapsing-Remitting; Nerve Fibers, Unmyelinated; Pilot Projects; Severity of Illness Index; Statistics as Topic; Time Factors

Minocycline, a semisynthetic tetracycline antibiotic, has been reported to ameliorate brain injury and inhibit microglial activation after focal cerebral ischemia. However, the cerebroprotective mechanism of minocycline remains unclear. In the present study, we investigated that mechanism of minocycline in a murine model of 4-hour middle cerebral artery (MCA) occlusion.. One day after 4-hour MCA occlusion, minocycline was administered intraperitoneally for 14 days. Neurologic scores were measured 1, 7, and 14 days after cerebral ischemia. Motor coordination was evaluated at 14 days by the rota-rod test at 10 rpm. Activated microglia and high-mobility group box1 (HMGB1), a cytokine-like mediator, were also evaluated by immunostaining and Western blotting. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling immunostaining was carried out 14 days after cerebral ischemia.. Repeated treatment with minocycline (1, 5, and 10 mg/kg) for 14 days improved neurologic score, motor coordination on the rota-rod test, and survival in a dose-dependent manner. Minocycline decreased the expression of Iba1, a marker of activated microglia, as assessed by both immunostaining and Western blotting. Moreover, minocycline decreased the activation of microglia expressing HMGB1 within the brain and also decreased both brain and plasma HMGB1 levels. Additionally, minocycline significantly decreased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells and prevented ischemic brain atrophy 14 days after cerebral ischemia.. Our results suggest that minocycline inhibits activated microglia expressing HMGB1 and decreases neurologic impairment induced by cerebral ischemia. Minocycline will have a palliative action and open new therapeutic possibilities for treatment of postischemic injury via an HMGB1-inhibiting mechanism.

Topics: Animals; Apoptosis; Atrophy; Brain; Brain Ischemia; Dose-Response Relationship, Drug; Drug Administration Schedule; HMGB1 Protein; In Situ Nick-End Labeling; Infarction, Middle Cerebral Artery; Injections, Intraperitoneal; Male; Mice; Microglia; Minocycline; Nervous System Diseases; Neuroprotective Agents; Psychomotor Performance; Survival Analysis