Chronic Lithium Antagonistic Mechanisms Of Ischemic Brain Injury

Ischemic stroke is a leading cause of death and disability worldwide In more than80% of cases, it results from a transient or permanent reduction in cere(?)ral blood flow,caused by occlusion of a cerebral artery by an embolus or loc(?)l thrombosis.Two-thirds of patients survive the initial event but are left with signifi(?)ant degrees ofsensorimotor, cognitive, or other impairment. So it is critical for active (?)revention andearly treatment. Increasing evidence have showed that neurogenesis is i(?)creased in thebrain after ischemia. Furthermore, lithium, a mood stabilizer, car facilitate theneurogenesis and protect the brain against ischemic injury. In the c(?)rent study, toformulate the role of lithium and the underlying mechanisms in ischem c rats inducedby four-vessel occlusion, we examined whether lithium improves he behavioraldisorder in ischemic rats and whether lithium regulates hippocampal n urogenesis byERK pathway. Formulating the role and mechanism of lithium acti(?)ns may havepotential clinical benefits for the treatment of stroke in combination with otherneuroprotective agents.1. Lithium improves the behavioral disorder in rats subjected to tr(?)nsient globalcerebral ischemiaPrevious study has indicated that chronic treatment with lithium protects brainagainst ischemic injury by reducing apoptotic death. To investigate whether lithiumimproves the behavioral disorder induced by transient global cerebra ischemia, weexamined the effects of lithium treatment on the performance of r(?)s in a set ofbehavioral tests, i.e. beam balance, elevated plus maze (EPM), open fi(?)ld and Morriswater maze. Our results showed that lithium attenuated the worse gene(?)l 'well-being'and the worse performance in beam balance, and hyperactivity in EPM and open field,including increased open arm entries, time spent in the open arms, s(?)ares crossed,rearing and grooming over 7 days after 15 min ischemia, which were induced byfour-vessel occlusion in Sprague-Dawley rats. Moreover, lithium improved theinjured spatial learning and memory ability in Morris water maze at post-ischemicdays 8 and 9. Histological analysis displayed that it decreased obvious(?) cell death in##原图像不清晰 hippocampal CA1 region. Our study further confirmed the protective role of lithiumin the ischemia-reperfusion injury and suggested that lithium might be a helpfultherapeutic approach to the treatment of stroke combining with other neuroprotectiveagents.2. Lithium regulates hippocampal neurogenesis by ERK pathway and facilitatesrecovery of spatial learning and memory in rats after transient global cerebralischemiaRecent studies have demonstrated that lithium has a neuroprotective effect againstbrain ischemia. Whether this effect is mediated by hippocampal neurogenesis remainsunknown. The ERK (extracellular signal-regulated kinase) pathway plays an essentialrole in regulating neurogenesis. The present study was undertaken to investigatewhether lithium regulates hippocampal neurogenesis by the ERK pathway andimproves spatial learning and memory deficits in rats after ischemia. Rats were dailyinjected with lithium (1mmol/kg) and two weeks later subjected to 15-minuteischemia induced by four-vessel occlusion method. 5-bromo-2'-deoxyuridine (Brdu;50mg/kg) was administrated twice daily at postischemic day 6, or for 3 days frompostischemic day 6 to 8. We found that lithium increased the ERK1/2 activation afterischemia by western blotting analysis. There was a significant increase inBrdu-positive cells in the hippocampal dentate gyrus after lithium treatment,compared with ischemia group at postischemic day 7 and 21. And importantly, thesurvival rate of Brdu-positive cells was elevated by lithium. Inhibition of the ERK1/2activation by U0126 diminished these effects of lithium. The percentages ofBrdu-positive cells that expressed a neuronal marker or an astrocytic marker were notsignificantly influenced by lithium. Moreover, lithium improved the impaired spatiallearning and memory ability in Morris water maze, and U0126 attenuated thebehavioral improvement by lithium. These results suggest that lithium up-regulatesthe generation and survival of new-born cells in the hippocampus by the ERKpathway and improves the behavioral disorder in rats after transient global cerebralischemia.