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. (Stroke. 2007;38:146-152.)

Increased neurogenesis after cerebral ischemia suggests that functional recovery after stroke may be attributed, in part, to neural regeneration. In this study, we investigated the role of neurogenesis in the behavioral performance of gerbils after cerebral global ischemia. We used ionizing radiation to decrease neural regeneration, and 2 weeks later cerebral global ischemia was induced by bilateral common carotid artery occlusion. One month after the occlusion, the animals were behaviorally tested. Irradiation alone reduced neurogenesis but did not change vascular or dendritic morphology at the time of behavioral testing. Neither did irradiation, ischemia, or combined treatment impair rotor-rod performance or alter open-field activity. Gerbils subjected to both irradiation and ischemia demonstrated impaired performance in the water-maze task, compared with those that received only ischemia, radiation, or no treatment. These impairments after cerebral global ischemia under conditions of reduced neurogenesis support a role for the production of new cells in mediating functional recovery.

Radiation therapy is a widely used treatment for brain tumors but it can cause delayed progressive cognitive decline and memory deficits. Previous studies suggested that this neurocognitive dysfunction might be linked to the impairment of hippocampal neurogenesis. However, little is known regarding how to reduce the cognitive impairment caused by radiation therapy. To investigate whether environmental enrichment (EE) promotes neurogenesis and cognitive function after irradiation, irradiated gerbils were housed in EE for 2 months and evaluated by neurobehavioral testing for learning and memory function, and immunohistochemical analysis for neurogenesis. Our results demonstrated that even relatively low doses (5-10 Gy) of irradiation could acutely abolish precursor cell proliferation in the dentate gyrus by more than 90%. This reduction in precursor proliferation was persistent and led to a significant decline in the granule cell population 9 months later. EE housing enhanced the number of newborn neurons and increased residual neurogenesis. EE also significantly increased the total number of immature neurons in the dentate gyrus. Furthermore, irradiated animals after EE housing showed a significant improvement in spatial learning and memory during the water-maze test and in rotorod motor learning over a 5-day training paradigm. In conclusion, EE has a positive impact on hippocampal neurogenesis and functional recovery in irradiated adult gerbils. Our data suggest that there is still a considerable amount of plasticity remaining in the hippocampal progenitor cells in adult animals after radiation injury, which can become a target of therapeutic intervention for radiation-induced cognitive dysfunction.