fgfr1 Adenosine is a kind of

Adenosine is a kind of widely distributed endogenous nucleoside. Adenosine receptor includes three types: A1, A2 and A3. Cumulative animal studies have proved the neuroprotective effect of adenosine in ischemia-reperfusion injury. For example, blockade of A1 adenosine receptor by DPCPX, a selective A1 adenosine receptor antagonist enhanced ischemia-evoked cerebral neuronal injury in gerbil cerebral ischemic model or cultured fgfr1 cortical neurons of rats (Phillis, 1995, Zhong et al., 2015). The neuroprotection of adenosine is also presented in brain ischemic tolerance induced by sublethal ischemia or hypoxia, isoflurane and so on (Hiraide et al., 2001, Hu et al., 2012, Liu et al., 2006, Perez-Pinzon and Born, 1999). Particularly, it has been reported that activation of adenosine A1R or A3R could protects cardiomyocytes from hypoxia via phosphorylation of p38 MAPK (Leshem-Lev et al., 2010). In anoxic neuronally enriched primary cultures from turtle brain, the selective adenosine A1R agonist CCPA increased the expression of p-ERK, whereas DPCPX decreases p-ERK expression (Nayak et al., 2011). These reports suggested the correlation between activations of adenosine receptors and p38 MAPK and ERK in the adenosine-induced protection against ischemia. Based on the above results, the present study therefore was aimed to investigate the role of adenosine in up-regulation of p38 MAPK and ERK during limb ischemic conditioning-induced brain ischemic tolerance.
Results
Discussion Remote ischemic preconditioning (RIPC) has been tested in many animal studies. For example, pretreatment with transient limb, small intestine, or kidney ischemia could reduce experimental myocardial ischemia/reperfusion injury induced by severe ischemic insult (Gho et al., 1996, Kharbanda et al., 2002, Takaoka et al., 1999). At the same time, RIPC trials have taken place in humans for cardiac diseases. In 2010, Zhou et al. reported that RIPC was induced twice (24 h and 1 h preoperatively) on the left upper arm using a blood pressure cuff, which attenuated heart and lung injury after an open heart operation in infants (Zhou et al., 2010). There are a growing volume of literatures that have demonstrated the powerful effect of ischemic preconditioning as an endogenous neuroprotective mechanism against the effects of cerebral ischemia both in animal models and in early clinical studies (Gonzalez et al., 2013, Koch et al., 2011, Meng et al., 2012). The mechanisms of RIPC are involved in various factors, such as oxygenic free radical, adenosine, bradykinin, calcitonin gene-related peptide and so on. These factors can trigger several related intracellular protective signal pathways after entering the blood and reacting to corresponding receptors (Dong et al., 2010, Kageyama et al., 2015, Montero et al., 2014, Yang et al., 2014). The present study was used 4-vessel occlusion brain ischemia model combined with multiple methods to observe whether the protective effect of LIP on brain is involved in adenosine pathway. In previous studies, we have proved that the expression of p38 MAPK and ERK up-regulated in hippocampal CA1 region of rats during the induction of brain ischemic tolerance induced by LIP. So, another interest of the study is to observe the effect of adenosine on the up-regulation of p38 MAPK and ERK in brain ischemic tolerance by LIP. Many researchers have demonstrated the protective role of p38 MAPK and ERK of ischemic preconditioning. For example, cerebral ischemic preconditioning reduced DND in the gerbil CA1 hippocampus induced by ischemic insult, and pretreatment with SB 203580 (an inhibitor of p38 MAPK) blocked the induction of the ischemic tolerance (Nishimura et al., 2003). In 2014, Kovalska et al. indicated p-ERK took part in complex cascades triggered by ischemic preconditioning in the selectively vulnerable hippocampal region in the model of a 4-vessels occlusion of rats (Kovalska et al., 2014). These results about protection of p38 MAPK and ERK are consistent with our previous studies (Jin et al., 2006, Sun et al., 2006, Sun et al., 2010, Zhang et al., 2017). In fact, the role of p38 MAPK and ERK in brain ischemia is controversial. Excessive activation of p38 MAPK is responsible for ischemic injury (Ozawa et al., 1999), and moderate activation of p38 MAPK plays the neuroprotective role (Nishimura et al., 2003). About the two opposing roles of the ERK suffered from brain ischemia, many studies showed that activation of ERK might facilitate neuronal death (Alessandrini et al., 1999), or played a protective role (Hu et al., 2000).