minocycline and Carotid-Stenosis

Chronic cerebral hypoperfusion is a key mechanism associated with white matter disruption in cerebral vascular disease and dementia. In a mouse model relevant to studying cerebral vascular disease, we have previously shown that cerebral hypoperfusion disrupts axon-glial integrity and the distribution of key paranodal and internodal proteins in subcortical myelinated axons. This disruption of myelinated axons is accompanied by increased microglia and cognitive decline. The aim of the present study was to investigate whether hypoperfusion impairs the functional integrity of white matter, its relation with axon-glial integrity and microglial number, and whether by targeting microglia these effects can be improved. We show that in response to increasing durations of hypoperfusion, the conduction velocity of myelinated fibres in the corpus callosum is progressively reduced and that paranodal and internodal axon-glial integrity is disrupted. The number of microglial cells increases in response to hypoperfusion and correlates with disrupted paranodal and internodal integrity and reduced conduction velocities. Further minocycline, a proposed anti-inflammatory and microglia inhibitor, restores white matter function related to a reduction in the number of microglia. The study suggests that microglial activation contributes to the structural and functional alterations of myelinated axons induced by cerebral hypoperfusion and that dampening microglia numbers/proliferation should be further investigated as potential therapeutic benefit in cerebral vascular disease.

Topics: Action Potentials; Animals; Anti-Inflammatory Agents; Arginase; Axons; Carotid Stenosis; Corpus Callosum; Cytokines; Disease Models, Animal; Gene Expression Regulation; Gliosis; Ki-67 Antigen; Male; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Myelin-Associated Glycoprotein; Nerve Fibers; White Matter

Although it has been well established that ischemic insults promote cell proliferation in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), the mechanisms by which this occurs remain unclear. The present study demonstrates that early-activated microglia in the hilus of the DG play an important role in ischemia-induced cell proliferation. Transient forebrain ischemia induced by 20min of bilateral common carotid artery occlusion (BCCAO) significantly increased cell proliferation in the SGZ of the DG beginning 4 days post-reperfusion. Moreover, BCCAO increased microglial activation in the hilus of the DG from 1 day post-reperfusion and in the CA1 layer from 4 days post-reperfusion. An injection of minocycline (10 or 100nmol in 0.5microl) into the DG immediately after reperfusion decreased microglial activation in the hilus of the DG 1 day post-reperfusion, but only a high dose of minocycline (100nmol) significantly decreased microglial activation in the CA1 layer. Both high and low doses of minocycline significantly decreased the number of BrdU-positive cells at 7 days post-reperfusion. These results suggest that early-activated microglia in the hilus of the DG take part in the cell proliferation induced by transient forebrain ischemia.

Topics: Animals; Carotid Artery, Common; Carotid Stenosis; Cell Proliferation; Ischemic Attack, Transient; Male; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Neurons; Prosencephalon; Stem Cells