Neuroprotective effects of zonisamide on cerebral ischemia injury via inhibition of neuronal apoptosis

Junna He,Yanzhao Xie,Weiliang He,Rong Chen,Yang Yang,Xiangjian Zhang,Yanxia Chen

doi:10.1590/1414-431x202010498

Abstract

It is known that neuronal apoptosis contributes to pathology of cerebral ischemia injury. Zonisamide (ZNS) has shown anti-apoptosis effects in recent studies. The present study investigated whether the anti-apoptotic effect can account for the neuroprotective action of ZNS on cerebral ischemia. Neuronal cells were maintained under oxygen-glucose deprivation conditions to simulate cerebral ischemia and treated with ZNS simultaneously. The apoptosis of the cells and expression of apoptosis-related proteins were investigated by flow cytometry and western blot analysis, respectively. A cerebral ischemia mouse model was created via middle cerebral artery occlusion, and the mice were treated with ZNS. Neurological deficit scores and infarct volumes of the cerebral ischemia mice were measured. The apoptosis status of the neuronal cells was evaluated by TUNEL staining. In vitro, the ZNS treatment inhibited both the apoptosis of the neuronal cells and apoptosis-related protein expression (caspase-3, caspase-8, and calpain-1) induced by the oxygen-glucose deprivation. The anti-apoptosis effect of ZNS could occur through the blocking of reactive oxygen species. Moreover, ZNS treatment significantly ameliorated neurological deficits and reduced infarct volumes in the cerebral ischemia mice model. In this study, ZNS exerted neuroprotective effects by inhibition of apoptosis in neuronal cells in cerebral ischemia. Therefore, ZNS might be a promising therapy for cerebral ischemia.

Highlights

Cerebrovascular accidents, including cerebral ischemia, are the second leading cause of death and the third leading cause of disability globally [1]
ZNS reduced the neurological deficit score and infarct size after cerebral ischemia Neurological deficit was investigated at 24 h after surgery
Our results showed that treatment with ZNS significantly improved the cerebral ischemia outcome, as lower neurological deficit scores (3.55 in middle cerebral artery occlusion (MCAO) vs 1.99 in ZNS) and lower infarct volumes (67.93% in MCAO vs 54.48% in ZNS) were recorded

Summary

Introduction

Cerebrovascular accidents (stroke), including cerebral ischemia, are the second leading cause of death and the third leading cause of disability globally [1]. Cerebral ischemia leads to irreversible pathological injury in the penumbra, such as energy failure, ionic homeostasis loss, excitotoxicity, increased oxidative stress, and cell apoptosis, resulting in neuronal necrosis [2]. Much progress has been made in the treatment of cerebral ischemia, such as antithrombotic therapy and neuroprotective therapy [3], efficient therapeutic strategies to minimize the damage to neurons and assist functional recovery are still lacking. Inhibition of apoptosis during cerebral ischemia may be an ideal option to salvage the neurons of the penumbra and ensure their survival. Anti-apoptosis treatment was shown to improve the prognosis of cerebral ischemia [6]

Methods

Results

Conclusion