Background and Purpose— Evidence suggests that activated microglia are detrimental to the survival of new hippocampal neurons, whereas blocking inflammation has been shown to restore hippocampal neurogenesis after cranial irradiation and seizure. The aim of this current study is to determine the effect of minocycline on neurogenesis and functional recovery after cerebral focal ischemia. Methods— Four days after temporary middle cerebral artery occlusion, minocycline was administered intraperitoneally for 4 weeks. BrdU was given on days 4 to 7 after middle cerebral artery occlusion to track cell proliferation. The number of remaining new neurons and activated microglia were quantified in the dentate gyrus. Infarct volume was measured to assess the treatment effect of minocycline. Motor and cognitive functions were evaluated 6 weeks after middle cerebral artery occlusion. Results— Minocycline delivered 4 days after middle cerebral artery occlusion for 4 weeks did not result in reduction in infarct size but significantly decreased the number of activated microglia in the dentate gyrus. Minocycline also significantly increased the number of newborn neurons that coexpressing BrdU and NeuN without significantly affecting progenitor cell proliferation in the dentate gyrus. Lastly, minocycline significantly improved motor coordination on the rotor rod, reduced the preferential use of the unaffected limb during exploration, reduced the frequency of footfalls in the affected limb when traversing on a horizontal ladder, and improved spatial learning and memory in the water maze test. Conclusions— Minocycline reduces functional impairment caused by cerebral focal ischemia. The improved function is associated with enhanced neurogenesis and reduced microglia activation in the dentate gyrus and possibly improved neural environment after chronic treatment with minocycline.

Background: Traumatic brain injury (TBI) induces activation of microglia. Activated microglia can in turn increase secondary injury and impair recovery. This innate immune response requires hours to days to become fully manifest, thus providing a clinically relevant window of opportunity for therapeutic intervention. Microglial activation is regulated in part by poly(ADP-ribose) polymerase-1 (PARP-1). Inhibition of PARP-1 activity suppresses NF-kB-dependent gene transcription and thereby blocks several aspects of microglial activation. Here we evaluated the efficacy of a PARP inhibitor, INO-1001, in suppressing microglial activation after cortical impact in the rat. Methods: Rats were subjected to controlled cortical impact and subsequently treated with 10 mg/kg of INO-1001 (or vehicle alone) beginning 20 - 24 hours after the TBI. Brains were harvested at several time points for histological evaluation of inflammation and neuronal survival, using markers for microglial activation (morphology and CD11b expression), astrocyte activation (GFAP), and neuronal survival (NeuN). Rats were also evaluated at 8 weeks after TBI using measures of forelimb dexterity: the sticky tape test, cylinder test, and vermicelli test. Results: Peak microglial and astrocyte activation was observed 5 to 7 days after this injury. INO-1001 significantly reduced microglial activation in the peri-lesion cortex and ipsilateral hippocampus. No rebound inflammation was observed in rats that were treated with INO-1001 or vehicle for 12 days followed by 4 days without drug. The reduced inflammation was associated with increased neuronal survival in the peri-lesion cortex and improved performance on tests of forelimb dexterity conducted 8 weeks after TBI. Conclusions: Treatment with a PARP inhibitor for 12 days after TBI, with the first dose given as long as 20 hours after injury, can reduce inflammation and improve histological and functional outcomes.

Brain waves resonate from the generators of electrical current and propagate across brain regions with oscillation frequencies ranging from 0.05 to 500 Hz. The commonly observed oscillatory waves recorded by an electroencephalogram (EEG) in normal adult humans can be grouped into five main categories according to the frequency and amplitude, namely δ (1–4 Hz, 20–200 μV), θ (4–8 Hz, 10 μV), α (8–12 Hz, 20–200 μV), β (12–30 Hz, 5–10 μV), and γ (30–80 Hz, low amplitude). Emerging evidence from experimental and human studies suggests that groups of function and behavior seem to be specifically associated with the presence of each oscillation band, although the complex relationship between oscillation frequency and function, as well as the interaction between brain oscillations, are far from clear. Changes of brain oscillation patterns have long been implicated in the diseases of the central nervous system including ischemic stroke, in which the reduction of cerebral blood flow as well as the progression of tissue damage have direct spatiotemporal effects on the power of several oscillatory bands and their interactions. This review summarizes the current knowledge in behavior and function associated with each brain oscillation, and also in the specific changes in brain electrical activities that correspond to the molecular events and functional alterations observed after experimental and human stroke. We provide the basis of the generations of brain oscillations and potential cellular and molecular mechanisms underlying stroke-induced perturbation. We will also discuss the implications of using brain oscillation patterns as biomarkers for the prediction of stroke outcome and therapeutic efficacy.

The selective serotonin reuptake inhibitor fluoxetine induces hippocampal neurogenesis, stimulates maturation and synaptic plasticity of adult hippocampal neurons, and reduces motor/sensory and memory impairments in several CNS disorders. In the setting of traumatic brain injury (TBI), its effects on neuroplasticity and function have yet to be thoroughly investigated. Here we examined the efficacy of fluoxetine after a moderate to severe TBI, produced by a controlled cortical impact. Three days after TBI or sham surgery, mice were treated with fluoxetine (10 mg/kg/d) or vehicle for 4 weeks. To evaluate the effects of fluoxetine on neuroplasticity, hippocampal neurogenesis and epigenetic modification were studied. Stereologic analysis of the dentate gyrus revealed a significant increase in doublecortin-positive cells in brain-injured animals treated with fluoxetine relative to controls, a finding consistent with enhanced hippocampal neurogenesis. Epigenetic modifications, including an increase in histone 3 acetylation and induction of methyl-CpG-binding protein, a transcription factor involved in DNA methylation, were likewise seen by immunohistochemistry and quantitative Western immunoblots, respectively, in brain-injured animals treated with fluoxetine. To determine if fluoxetine improves neurological outcomes after TBI, gait function and spatial learning and memory were assessed by the CatWalk-assisted gait test and Barnes maze test, respectively. No differences in these parameters were seen between fluoxetine- and vehicle-treated animals. Thus while fluoxetine enhanced neuroplasticity in the hippocampus after TBI, its chronic administration did not restore locomotor function or ameliorate memory deficits.