Effects Of Delayed Administration Of Hyperforin On Neurogenesis And Functional Recovery Post Ischemic Stroke

Part?The effects of post-stroke social isolation-induced PSD and PSA on the neurogenesis and functional recovery and the role of TGF-?in this processObjective:To determine the roles of post-stroke social isolation-induced PSD and PSA in hippocampal neurogenesis and functional recovery and to determine whether the inhibition of TGF-?is involved in post-stroke social isolation-mediated PSD and PSA and the attenuation of hippocampal neurogenesis and memory function.Methods:Adult male C57BL/6J mice were subjected to 60 minutes of middle cerebral artery occlusion(MCAO)and subsequent reperfusion.Each male mouse was randomly allocated to housing groups in standard clear plastic cages(27?17?12.5 cm)either individually(socially isolated,SI)or with an ovariectomized female mouse(pair-housed,PH)immediately following ischemia for 14 continuous days.Some mice were treated intracerebroventricularly with recombinant TGF-?or sterile PBS every 24h for 7continuous days commencing at 7 days post-ischemia.Cell proliferation was assessed by treating mice twice with BrdU with an 8-hour interval between injections at 13 days post-ischemia;on the following day,the animals were humanely killed to analyze BrdU labeling of dividing cells.TGF-?level in the ischemic hippocampus was analyzed by immunofluorescence and western blotting at 14 days post-ischemia,and behavioral assays were performed at 14 days post-ischemia.Results:Behavioral assessments showed an increase in depression-type behavior and anxiety-type behavior in the post-stroke SI mice.The mRNA and protein expression levels of TGF-?in the ischemic hippocampi were significantly decreased in the post-stroke SI mice compared with those in the post-stroke PH mice at 14 days post-ischemia.The numbers of Ki67~+?PH3~+?BrdU~+?BrdU~+/DCX~+cells in the ischemic hippocampi were significantly decreased in the post-stroke SI mice compared with those in the post-stroke PH mice at 14 days post-ischemia.The post-stroke SI mice treated with recombinant TGF-?exhibited similar numbers of Ki67~+?PH3~+?BrdU~+and BrdU~+/DCX~+cells in the ischemic hippocampi as the post-stroke PH mice.Impaired memory-associated behaviors were significantly increased in post-stroke SI mice compared with post-stroke PH mice at14 days post-ischemia.Treatment with recombinant TGF-?to post-stroke SI mice significantly restored the reduced memory function in the post-stroke SI mice.Conclusion:Post-stroke social isolation-mediated PSD and PSA reduce hippocampal neurogenesis and impair memory function via TGF-?.Part ? The effect and mechanism of natural antidepressant hyperforin on hippocampal neurogenesis and functional recoveryObjective: To determine wether the delayed 7-day administration of hyperforin to post-stroke socially isolated mice during stroke recovery can promote hippocampal neurogenesis and restore memory function via the inhibition of PSD and PSA and to elucidate the role of TGF-? in this process.Methods: Adult male C57BL/6J mice were subjected to 60 minutes of middle cerebral artery occlusion(MCAO)and subsequent reperfusion.All the male mice were housed individually(socially isolated,SI).The post-stroke SI mice were treated intranasally with hyperforin or normal saline(NS)every 24 h for 7 continuous days commencing at 7 days post-ischemia.Some mice were treated intracerebroventricularly with TGF-?-neutralizing antibody or sterile PBS 30 min prior to the application of hyperforin.Cell proliferation was assessed by treating mice twice with Brd U with an 8-hour interval between injections at 13 days post-ischemia;on the following day,the animals were humanely killed to analyze Brd U labeling of dividing cells.TGF-? level in the ischemic hippocampus was analyzed by immunofluorescence and western blotting at 14 days post-ischemia,and behavioral assays were performed at 14 days post-ischemia.Results: Intranasal administration of hyperforin to the post-stroke SI mice significantly increased the m RNA and protein expression levels of TGF-? in the ischemic hippocampi compared with those in the NS-treated post-stroke SI mice at 14 days post-ischemia.Hyperforin significantly improved post-stroke social isolation-induced PSD and PSA at 14 days post-ischemia.Intranasal administration of hyperforin to the post-stroke SI mice led to a significant increase in the number of Brd U+ and Brd U+/Neu N+ cells in ischemic hippocampi compared with that in the NS-treated post-stroke SI mice at 14 days post-ischemia.Intranasal administration of hyperforin significantly improved impaired memory-associated behaviors in post-stroke SI mice.TGF-?-neutralizing antibody treatment reversed the efficacy of hyperforin.Conclusion: The intranasal administration of hyperforin during stroke recovery activates TGF-?,which inhibits PSD and PSA and ultimately improves reduced hippocampal neurogenesis and memory deficits in socially isolated mice.