Retigabine Ameliorates Demyelination In The Hippocampus And Recues Behavioral Changes In Chronic Restraint Stress Mice

Part Ⅰ Hippocampal demyelination contributes to chronic restraint stress induced depression-like behavior in mice Objection: The relationship between hippocampal demyelination and depression is still unclear.In this study,we will focus on the role of hippocampal demyelination in the chronic restraint stress induced depression.Methods:Chronic restraint stress was used to induce depression-like behaviors.Adult healthy Kunming mice were restrained in plastic pipes six hours from ten o’clock to four o’clock per day for totally 21 d.After stressor cessation,the depression-like behaviors were evaluated with sucrose preference test,tail suspension test and forced swim test.The expression of myelin basic protein(MBP)and CNPase,a marker of mature oligodendrocytes and PDGFα,a marker of oligodendrocytes precursor cell in the hippocampus was examined by immunohistochemistry and western blot.Mice were bilaterally microinjected with 1% lysophosphatidylcholine(LPC)into hippocampus CA3 region to induce focal demyelination.Results:(1)Compared with the control mice,chronic restraint stressed mice showed significant decreased sucrose preference in the sucrose preference test and increased motionless-time both in the tail suspended test and the forced swam test.It’s suggested that chronic restraint stress can successfully induce depression-like behaviors in mice.(2)Compared with the control group,stressed mice showed significant decrease of MBP protein level but without any change of CNPase in the hippocampus.(3)Compared with the control mice,the MBP and CNPase protein levels were remarkably decreased in the CA3 region,but without any notable change in the CA1 and DG regions of the hippocampus in stressed mice.(4)Compared with the vehicle group,the expression of MBP in the hippocampus was notably decreased in LPCinjected mice,and the LPC-injected mice showed significant decreased sucrose preference,increased motionless-time both in the tail suspended test and the forced swam test.Conclusion: Our results indicated that demyelination of hippocampal CA3 region contributed to the chronic restraint stress induced depression-like behaviors.Part Ⅱ Retigabine ameliorates demyelination in the hippocampus and recues behavioral changes in chronic restraint stress mice Objection:This study will investigate the protective effects and mechanisms of Retigabine on chronic restraint stress induced depression-like behavior and cognitive impairment in mice.Methods: Chronic restraint stress was used to induce depressionlike behaviors.Retigabine(10mg/kg)or Normal Saline were administrated thirty minutes before the daily restraint,we recorded the body weight every other day.21 days later,the depression-like behaviors were evaluated with sucrose preference test,tail suspension test and forced swim test.Cognitive function was evaluated by MWM and NOR test.The levels of MBP,CNPase,PDGFα,p-Akt and p-GSK-3b was examined by immunohistochemistry and western blot.Mice were bilaterally microinjected with 1% LPC(1 μl)into hippocampal CA3 region to induce demyelination,and retigabine(10 mg/kg)or vehicle(N.S)was administrated at 9:00-10:00 pm from the day LPC was injected for 7 consecutive days.Results:(1)Retigabine did not affect the rate of body weight gain of chronic restraint stressed mice.Body weight gain of chronic restraint stress mice markably decreased,treated with retigabine did not affect the reduction of growth body weight.(2)Retigabine alleviated the depression-like behaviors induced by chronic restraint stress in mice.Compared with stressed mice,Mice treated with retigabine showed significant less anhedonia in sucrose preference and decreased immobility in forced swim test and tail suspension test.(3)Retigabine ameliorated chronic restraint stress induced memory impairment in mice.Retigabine treatment increased the time spent in target quadrant and total times of crossing the target quadrant.Compared with stressed mice,Retigabine treatment decreased the escape latencies on day 4,but no significant difference was shown.(4)Retigabine rescued demyelination in the hippocampal CA3 region.Compared with stressed mice,retigabine treatment increased the expression of MBP both in the whole hippocampus and CA3 area.Retigabine increased the number of oligodendrocytes in the hippocampal CA3 region.(5)Retigabine ameliorated hippocampal demyelination-induced depression-like behaviors.Compared with LPC injected mice,Retigabine treatment significantly increase the expression of MBP in the hippocampus,increase the sucrose preference and decrease the immobility in tail suspension test and forced swim test.(6)Retigabine treatment significantly increased the p-Akt and p-GSK-3β in the hippocampus of depression mice.Conclusion: Retigabine enhances myelination in the hippocampus and rescues depression-like behavior and cognitive impairment in chronic restraint stressed mice,partly through up-reglulation of the expression of p-Akt/p-GSK-3β.Our results revealed that promoting adult myelination is a potential strategy for reversing chronic stress induced behavioral changes.