| The mechanism of brain ischemic tolerance (BIT) induced by cerebral ischemic preconditioning (CIP) involves cascades of events including release of neurotransmitter, activation of receptors and gene expression. During the induction of BIT, some changes happen in the processes of signal triggering and transduction, gene duplication and transcription and protein synthesis and modification in cells. In the link of signal triggering, the role of adenosine underling the mechanism of BIT have drawn close attention of scholars. Recent researches of our lab showed that both the amount and the affinity of adenosine receptors increased during the induction of BIT, which enriched the studies on adenosine mechanism of BIT. However, the neuroprotection provided by the agonist of adenosine receptors acting as a pharmacological preconditioning in place of CIP was weaker than that provided by CIP, which suggested that there might be other mechanisms implicating in the induction of BIT. In recent years, the role of nitric oxide (NO) in the induction of hypoxic/ischemic tolerance has aroused the interests of researchers. Some in vitro studies showed that NO played an important role in the induction of neuronal hypoxic/ischemic (HI) tolerance induced by HI preconditioning. For example, a hypoxic insult could decrease the amplitude of evoked potentials of the hippocampal slices, while an anoxic preconditioning could prevent the decrease. The effect of CIP could be blocked by the nitric oxide synthase (NOS) inhibitor 7-NI. The results suggested that NO produced by the constitutive NOS (cNOS) might be involved in the protective effect ofhypoxic preconditioning. Recently, the effect of NO on the induction of oxygen-glucose deprivation (OGD) tolerance was systematically studied in cultured neurons. It was found that the OGD tolerance of the neurons was blocked by NOS inhibitor and was induced by NO donor as a preconditioning instead of OGD. It showed that the production of NO was both essential and sufficient condition for the induction of OGD tolerance. These results mentioned above provided a clue for studying the effect of NO on the induction of BIT in vivo. In the neonatal rat hypoxic preconditioning model, the administration of non-specific NOS inhibitor L-NNA could block completely the protective effect of the preconditioning on neurons, but the administration of neuronal NOS (nNOS)-specific inhibitor 7-NI and the inducible NOS (iNOS)-specific inhibitor aminoguanidine (AG) were not effective, which indicated that NO produced by the endothelial NOS isoform (eNOS) contributed to the protective effects. Comparing the expression of NADPH-diaphorase activity of CA1 pyramidal neurons of rats subjected to 3 min ischemia as well as 6 min ischemia with and without CIP before 3 d, it was found that the changes of the expression of NADPH-diaphorase activity in the 3 groups were basically similar, such as that an increase in the expression of NADPH-diaphorase activity was seen both in the damaged and non-damaged CA1 regions, and the time courses of increased expression of NADPH-diaphorase activity among the 3 groups were coincidence, which suggested that NO production might not be related certainly to neuronal damage. However, whether the increase of NO production contributes to the induction of BIT has remained to be clarified.The present study was undertaken to explore the role of NO in the induction of BIT in vivo and the possible signaling mechanism underling the involvement of NO in the induction of BIT. For the aim, the effects of NOS activity, NO production and NOS inhibitor L-NAME on the induction ofBIT and changes of phosphorylated-ERK1/2 (phospho-ERK1/2) expression induced by CIP as well as the effect of L-NAME on the changes were investigated in rat global cerebral ischemic model. 1. The effect of duration of ischemia and sex on the protective effect of CIP in rat global cerebral ischemic model The effects of 3 parameters, including the duration of CIP, interval between the CIP and the... |
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