Abstract
Our previous studies have shown that sulbactam can play a neuroprotection role in hippocampal neurons by upregulating the expression and function of glial glutamate transporter-1 (GLT-1) during ischemic insult. Here, using rat global cerebral ischemia model, we studied in vivo the role of p38 mitogen-activated protein kinases (MAPK) in the sulbactam-induced GLT-1 upregulation and neuroprotection against ischemia. The hippocampal CA1 field was selected as observing target. The expressions of phosphorylated-p38 MAPK and GLT-1 were assayed with western blot analysis and immunohistochemistry. The condition of delayed neuronal death (DND) was assayed with neuropathological evaluation under thionin staining. It was shown that administration of sulbactam protected CA1 hippocampal neurons against ischemic insult accompanied with significantly upregulation in the expressions of phosphorylated-p38 MAPK and GLT-1. The time course analysis showed that sulbactam activated p38 MAPK before the GLT-1 upregulation in either normal or global cerebral ischemic rats. Furthermore, inhibiting p38 MAPK activation by SB203580 blocked the GLT-1 upregulation and neuroprotection induced by sulbactam. The above results suggested that p38 MAPK, at least partly, participated in the sulbactam-induced brain tolerance to ischemia mediated by GLT-1 upregulation in rats.
Highlights
A variety of studies have shown that cerebral ischemia and hypoxia may cause a great deal of glutamate release to the synaptic gap during ischemic stimulation and the glutamate excitotoxicity is a considerable mechanism involved in ischemic neuronal damage[1,2]
The present study in vivo further confirmed the role of p38 mitogen-activated protein kinases (MAPK) activation in the above process using a rats’ global cerebral ischemia model, which might be valuable for the establishment of the conclusion that p38 MAPK activation participates in the sulbactam-induced neuronal protection against ischemic insult via glutamate transporter-1 (GLT-1) upregulation
Considering the side effects of ceftriaxone such as dysbacteriosis and bacterial resistance which limit its application as an anti-ischemic medication, we further studied and showed that sulbactam, an atypical β-lactam medication, could protect hippocampal neurons against ischemic insult mediated by modulating the expression and uptake ability of GLT-1 in rats global cerebral ischemia m odel[9]
Summary
A variety of studies have shown that cerebral ischemia and hypoxia may cause a great deal of glutamate release to the synaptic gap during ischemic stimulation and the glutamate excitotoxicity is a considerable mechanism involved in ischemic neuronal damage[1,2]. Rothstein et al have reported the role of ceftriaxone in promoting GLT-1 expression and enhancing its ability to clear the glutamate from synaptic gap, which was of great benefit to alleviate disorders associated with over-accumulation of glutamate such as ischemic neuronal damage[6,7,8]. Sulbactam is an atypical β-lactam antibacterial and structurally similar to ceftriaxone, but has minor antibacterial activity It might be potentially valuable for clinical application in prevent and therapy brain ischemic disease if sulbactam has anti-ischemic effect as well. We found in vitro study that activation of p38 MAPK mediated the sulbactam-induced GLT-1 upregulation and neuronal protection against ischemic insult[13]. We established the present study in vivo to further confirm the role of p38 MAPK activation in the sulbactam-induced GLT-1 upregulation and neuronal protection against ischemic insult using a rats’ global cerebral ischemia model
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