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  • br Acknowledgments This work was


    Acknowledgments This work was funded by Project 31500647 supported by National Natural Science Foundation of China; the Scientific Research Project of Jiangsu Health Commission, China (H2018035); the Natural Science Foundation of Jiangsu Province, China (BK20161279, BK20161290); the Scientific Research Project of \"333 Project\" in Jiangsu Province, China (BRA2018224); the Natural Science Foundation of the Jiangsu Higher Education Institution, China (15KJA310003); the ‘Top Six Types of Talents’ Financial Assistance of Jiangsu Province Grant, China (2015-YY-009); the Nantong Science and Technology Project, China (MS12015093).
    Introduction Glutamate is the major excitatory neurotransmitter in central nervous system. Five kinds of excitatory amino-acid transporters (EAATs) have been found in rat brain, among which EAAT2, also named as glial glutamate transporter-1 (GLT-1), is the most important one to maintain extracellular glutamate concentration in normal level in integrin signaling pathway (Sims and Robinson, 1999; Danbolt, 2001; Tanaka, 2000). Compelling evidences have indicated that cerebral ischemia usually led to dysfunction of GLT-1 (Gong et al., 2014; Raghavendra Rao et al., 2000; Rossi et al., 2000). Our previous studies have shown that severe global brain ischemic insult led to decreased GLT-1 or GLT-1a expression, increased extracellular glutamate level and delayed neuronal death in hippocampal CA1 subfield (Hu et al., 2015; Liu et al., 2012; Zhang et al., 2007). Nevertheless, the molecular mechanism regulating GLT-1 during cerebral ischemic injury is not clear yet. The mitogen-activated protein kinase (MAPK) family plays a key role in many pathological processes to a variety of stimulus including ischemia. The MAPK family consists of extracellular signal-related kinases (ERK), Jun amino-terminal kinases (JNK) and p38 MAPK subfamilies (Chang and Karin, 2001). Activation of p38 MAPK in astrocytes and neurons has been observed after ischemia (Guan et al., 2016; Nito et al., 2012). Furthermore, inhibiting p38 MAPK activation protected neurons survival from cerebral ischemic insult (Barone et al., 2001; Zhang et al., 2014). Notably, recent studies have revealed that p38 MAPK takes part in regulating GLT-1 expression in some pathological processes, including surgical incision, formaldehyde-induced toxicity in cultured astrocytes (Reichl et al., 2016; Song et al., 2010). Taken together, it is reasonable to hypothesize that the mechanism of GLT-1 mediating cerebral ischemic injury may be regulated by p38 MAPK. There is no literature, until now, that concerned the relationship between GLT-1 and p38 MAPK during cerebral ischemic injury, although a few studies reported that up-regulation of GLT-1 via p38 MAPK signaling pathway participated in acquisition of neuroprotective effect induced by ischemic preconditionning, sulbactam and Buyang Huanwu Decoction (Qi et al., 2018; Yu et al., 2017; Zhang et al., 2017). Thus, it remains unclear whether p38 MAPK takes part in regulating GLT-1 during cerebral ischemic injury. So, the present study is carried out to clarify the mechanism of GLT-1 mediating cerebral ischemic injury via p38 MAPK signaling pathway.
    Materials and methods
    Discussion In the present study, it was observed that global brain ischemia for 8 min lead to obvious neuronal death in CA1 hippocampus in rats, which was consistent with our previous study (Hu et al., 2015; Liu et al., 2012). Then, we found that the ischemia decreased GLT-1 expression and increased p-p38 MAPK expression at 6 h and 2d time points in CA1 hippocampus. It is well known that astrocytic GLT-1 is responsible for the majority of glutamate uptake in central nervous system and is critical to the neuronal survival in brain after cerebral ischemia (Karki et al., 2015; Soni et al., 2014). GLT-1 mRNA and protein were decreased after brain ischemia, which attenuated the clearance of the excessive glutamate, and resulted in glutamate accumulation that led to neuronal death (Krzyżanowska et al., 2017; Ketheeswaranathan et al., 2011; Krzyzanowska et al., 2016). The affinity and uptake activity of GLT-1 to glutamate were enhanced by cerebral ischemic preconditioning, ceftriaxone treatment as well as histamine administration, which contributed to the neuroprotection against cerebral ischemic insult (Fang et al., 2014; Hu et al., 2015; Liu et al., 2011). On the other hand, some literatures have indicated that p38 MAPK was activated and responsible for modulating neuronal injury after global brain ischemia and middle cerebral artery occlusion (MCAO) in rats (Kovalska et al., 2012; Park et al., 2018; Roy Choudhury et al., 2014). For example, p38 MAPK activation promoted blood-brain barrier dysfunction after 90 min-MCAO in rats (Nito et al., 2008). Knockout and inhibition of p38 MAPK reduced astrocyte migration induced by ischemic stroke (Roy Choudhury et al., 2014). Combined with the present study, it may be thought that both p38 MAPK and GLT-1 played key roles in cerebral ischemic injury. An interesting study reported that amyloid-beta peptide reduced GLT-1 expression through p38 MAPK signaling pathway in cultured astrocytes (Matos et al., 2008). Our recent study showed that p38 MAPK up-regulated GLT-1 expression during the induction of brain ischemic tolerance induced by cerebral ischemic preconditioning in rats (Zhang et al., 2017). These findings suggested that there maybe exists close relationship between p38 MAPK and GLT-1 in cerebral ischemic injury. Thus, we presume that integrin signaling pathway the mechanism of GLT-1 down-regulation after cerebral ischemic insult may be related to the activation of p38 MAPK.