[Keap1-tat peptide attenuates oxidative stress damage in hippocampal CA1 region and learning and memory deficits following global cerebral ischemia].

OBJECTIVE: To design Keap1-tat peptide and explore its neuroprotective role on hipocampal CA1 neuron, as well as the effect on spacial learning and memory function following global cerebral ischemia. METHODS: Adult male Sprague Dawley (SD) rats were subjected to global cerebral ischemia (GCI) by four-vessel occlusion for 15 min and randomly divided into five groups: sham, sham+Keap1-tat, ischemia/reperfusion (I/R), Keap1-tat peptide- and vehicle-administrated groups. For Keap1-tat or vehicle groups, the rats were treated with Keap1-tat (30, 50, 100 µg in 5 µL 0.9% saline) or the same volume vehicle by intracerebroventricular injection (icv) 30 min prior to ischemia. Cresyl violet staining was used to observe the surviving neurons and 4-hydroxy-2-noneal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) immunostaining were used to detect the change of markers response to oxidative stress in hippocampal CA1 region. The spatial learning and memory function of the rats was evaluated using Morris water maze. RESULTS: Compared with sham group, the number of surviving neurons in ischemia-reperfusion and vehicle groups significantly decreased in the hippocampal CA1 region (P<0.05), while administration of Keap1-tat significantly decreased the damage following GCI (P<0.05), and the dose of 50 µg existed the most effective neuroprotective role. Furthermore, immunostaining intensity of 4-HNE and 8-OHdG, markers of oxidative stress damage attenuated by Keap1-tat peptide as compared with vehicle group in CA1 region. Of significant interest, the time of finding underwater platform in Keap1-tat group animals was significantly short, and after removing the platform, the probe time of Keap1-tat group animals in the original quadrant where the platform was significantly increased compared with that of vehicle and I/R group animals (P<0.05). CONCLUSION: Keap1-tat peptide can effectively attenuate neuronal damage in hippocampal CA1 region and improve learning and memory function, which might bedue to the attenuation of oxidative stress caused by GCI.

Hypersensitivity of the hippocampal CA3 region to stress-induced neurodegeneration and amyloidogenesis in a rat model of surgical menopause.

Females who enter menopause prematurely via bilateral ovariectomy (surgical menopause) have a significantly increased risk for cognitive decline and dementia. To help elucidate the mechanisms underlying this phenomenon, we used an animal model of surgical menopause, long-term (10-week) bilateral ovariectomy in female rats. Herein, we demonstrate that long-term oestrogen deprivation dramatically increases sensitivity of the normally resistant hippocampal CA3 region to ischaemic stress, an effect that was gender-specific, as it was not observed in long-term orchiectomized males. Furthermore, the enhanced damage to the CA3 region correlated with a worse cognitive outcome after ischaemic stress. Long-term ovariectomized rats also displayed a robust hyperinduction of Alzheimer's disease-related proteins in the CA3 region and a switch in amyloid precursor protein processing from non-amyloidogenic to amyloidogenic following ischaemic stress CA3 hypersensitivity also extended to an Alzheimer's disease-relevant insult, as the CA3 region of long-term ovariectomized rats was profoundly hypersensitive to the neurotoxic effects of amyloid-ß1-42, the most amyloidogenic form of the amyloid-ß peptide. Additional studies revealed that CA3 region hypersensitivity, Alzheimer's disease-related protein induction, and amyloidogenesis are mediated by a NADPH oxidase/superoxide/c-Jun N-terminal kinase/c-Jun signalling pathway, involving both transcriptional and post-translational mechanisms. In addition, while 17ß-oestradiol replacement at the end of the long-term oestrogen deprivation period could not prevent CA3 hypersensitivity and amyloidogenesis, if 17ß-oestradiol was initiated at the time of ovariectomy and maintained throughout the 10-week oestrogen deprivation period, it completely prevented these events, providing support for the 'critical window' hypothesis for oestrogen replacement therapy benefit. Collectively, these findings may help explain the increased risk of cognitive decline and dementia observed in women following surgical menopause, and they provide increased support that early 17ß-oestradiol replacement is critical in preventing the negative neural effects associated with bilateral ovariectomy.