| ROLE OF BKc2 CHANNEL IN THE DELAYED NEURONAL DEATHOF RAT HIPPOCAMPAL CAl PYRAMIDAL NEURONS AFTERFOREBRAIN ISCHEMIA AND ITS MECHANISMM.S Student: Huang HaoMentor:Prof. Gao Tian-MingABSTRACT1.Neuroprotection of potassium channel blockers on delayed neuronal death after transient forebrain ischemia in hippocampal CAl pyramidal neuronsPyramidal neurons in the CAl field of the hippocampus occur delayed neuronal death after transient forebrain ischemia. Glutamate excitotoxicity has been suggested as a potential mediator of postischemic cell injury. However, neuronal hyperactivity as predicted by excitotoxic hypothesis is not evident in CAl region after ischemia. Both in vitro and in vivo intracellular recording studies have demonstrated that the spontaneous firing rate and neuronal excitability of CAl neurons progressively decrease following reperfusion. It has been speculated that increased potassium currents may be responsible for the reduced neuronal excitability after ischemia. Indeed, recent studies reported an enhancement in activities of potassium channels in CAl pyramidal neurons of rat hippocampus after transient forebrain ischemia. Moreover, it has been shown recently that the enhancement of outward potassium current mediates apoptotic cell death in cultured cortical neurons, and that the apoptotic cell death induced by serum deprivation could be inhibited by potassium channel blocker TEA.Therefore, we hypothesized that an enhanced potassium current contributes to the pathogenesis of delayed neuronal death in hippocampal CAl region after transient forebrain ischemia. To address this question, we evaluated the effect of potassium channel blockers TEA, 4-AP, CHTX, givenby lateral ventriculap on the neuronal damage in hippocampal CAl fieldfollowing transient forebrain ischemia in rats. The results are as fOllowing:In the postischemic TEA treated-rats, the neuronal injury inhippocampal CAl region was significantly less than that of the controls.Except those treated with low dose of TEA, about 30-40% neurons in CAlfield survived from ischemic insult, and the average neuronal density was 99t 9.3 and 78t8.7 in 250 mmol/5 pl and 500 mmol/5 pl TEA-treated group,respectively. Compared with the ACSF-treated ischemic controls, thesetwo TEA-treated groups showed a significant neuroprotective effect (P<0.0l ).In contrast to postischemic administration, TEA at a dose of 250 mmol/5 pl. infused before ischemia and 4-AP given 30 min fOllowing reperfusionexerted no obvious neuroprotection(P>0.05).After ischemia, the activities in BKc. charmel increase significantly.The open probability (Po) of BKc. channel from CAl pyramidal neurons 6hafter ischemia and control neurons is 0.395 i0.086 and 0.268 t0.075,respectively. Moreover, CHTX, a specific blocker of BKc. channel, given 30min following ischemia, also showed significant neuroprotection(P<0.05).The survived average neuronal density in CAl hippocampal region was 84 18 in 5 mmol/ 5 pl CHTX-treated group.The present study shows an enhancement in activities of BKc. chanl1elin postischemic CAl neurons and a neuroprotective effect of potassiumchannel blockers TEA and CHTX on ischemia-induced CAl neuronaldamage in rats, suggesting that the over-activities of BKc, channel maycontribute to the delayed neuronal death in hippocampus afier transientforebrail1 ischel11ia2. The inhibitory effect of TEA on BKc, current in CAl neurons al1dchanges in sensitivitY of BKc. channel to TEA after ischemia.As a classic pharmacological tool, TEA is widely used to study thepharmacological properties and structure of some voltage-gated potassiumchannels. Previous studies l1ave shown m1 e11l1ancement in activity of BKc:,channel in CAl neurons after transient forebrain ischemia. TO understand6whether the pharmacological properties and structure of BK~a is changed after ischemia, the inhibitory effects of TEA on BK~a current in control and ischemic neurons were compared. The result...
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