Chronic Treatment With Minocycline Preserves Adult New Neurons and Reduces Functional Impairment After Focal Cerebral Ischemia

Abstract

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.)

A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke

“…Also, it is likely that other cortical systems and distinct molecular signals within these systems play a role in the larger context of behavioral recovery after stroke. These molecular systems may include myelin inhibitors (NogoA), cytokines, and inducers of specific serine/ threonine kinases (35,48,49). Pharmacological targets for poststroke neural repair will result from further identification of the axonal sprouting control points in the adult, as well as the development of delivery systems to modulate these control points in a specific and local manner.…”

Microglia and Monocyte-Derived Macrophages in Stroke

“…These cells display proinflammatory properties with elevated levels of reactive oxygen species and TNF, supporting their role in poststroke inflammation. Rats treated with minocycline for 4 weeks after middle cerebral artery occlusion had reduced microglial activation with improved neurogenesis and neurological function [57,58]. Additionally, indomethacin, an antiinflammatory agent that inhibits microglia activation, enhances neurogenesis in focal brain ischemia [59].…”

Fluoxetine Increases Hippocampal Neurogenesis and Induces Epigenetic Factors But Does Not Improve Functional Recovery after Traumatic Brain Injury

“…For unbiased stereological estimation of cell numbers (Stereo Investigator, MicroBrightField; MBF Bioscience, Williston, VT) in the dentate gyrus (DG) and striatum, every sixth coronal section spanning the entire region was used. To achieve a coefficient of error (CE) of less than 0.10, counting frames of 15Â15Â20 mm were used in a 40Â40 mm matrix (for estimating DCX-and MBD1-expressing cells), that were randomly superimposed onto the region of interest by the program as previously described (Liu et al, 2007;Matsumori et al, 2006).…”