Levetiracetam Prevents Perforin Mediated Neuronal Injury Induced by Acute Cerebral Ischemia Reperfusion

Abstract

The purpose of this study is to explore the neuroprotection mechanism of levetiracetam (LEV) with acute focal cerebral ischemia-reperfusion (I/P) mouse. The cerebral artery I/P animal model was prepared with a middle artery cerebral occlusion method. For drug intervention, mice were intraperitoneally injected with LEV with a dose of either 15 or 150 mg/kg. Neuronal injury was evaluated by measuring the infarct area, apoptosis ratio, and observation of blood-brain barrier ultrastructure with transmission electron microscope. CD8(+) antibody and perforin antibody were used to make cross-reference screen through flow cytometry to determine a perforin-positive rate in CD8(+) T lymphocytes (PFN + %). Injection of LEV can reduce infarct area, apoptosis ratio, and blood-brain barrier damage 24 h later after acute I/P in WT mice. In vitro, perforin can lower hippocampal neuron viability. In vivo, removing perforin can relieve neuronal injury. High dose injection of LEV (150 mg/kg) can inhibit perforin secreting from CD8(+)T lymphocytes. In addition, LEV can still protect neurons with perforin knockout mice. Therefore, our results suggested that LEV may contribute to neuron protection after cerebral ischemia reperfusion. The possible mechanism may be related with perforin release. However, we cannot roll out other mechanisms.

Comparison between the effect of human Wharton’s jelly–derived mesenchymal stem cells and levetiracetam on brain infarcts in rats

“…23 Our results showed that MCAO caused an increase in the infarct size as compared with the sham group, the histopathological examination revealed edema, increase in the cellular permeability as well as infiltration of inflammatory cells. We found that LEV treatment caused significant decrease in infarction volume as reported by Cuomo et al 27 and Zhang et al 25 LEV improved memory and learning in the LEV-treated group compared with the I/R group. 24 The results of the current study also showed impairment in memory and learning function in the ischemic group as compared with the sham-operated group as reported earlier.…”

“…Global ischemia is produced by transient bilateral carotid artery stenosis, while focal ischemia is produced by transient MCAO. 25 F I G U R E 3 A, Photomicrograph of the cerebral cortex of control group showing evenly distributed variable sized neuronal cells surrounded by eosinophilic neurofibrillary material, which contains normal glial cells: astrocytes and oligodendrocytes (H&E ×400). 23 Our results showed that MCAO caused an increase in the infarct size as compared with the sham group, the histopathological examination revealed edema, increase in the cellular permeability as well as infiltration of inflammatory cells.…”

“…24 The results of the current study also showed impairment in memory and learning function in the ischemic group as compared with the sham-operated group as reported earlier. 25 Epilepsy and vascular brain injuries share a similar cascade of synaptic and intracellular events. An increased release of excitatory amino acids and a reduced neuronal inhibition occur in both brain ischemia and epileptic fits.…”

“…24 The results of the current study also showed impairment in memory and learning function in the ischemic group as compared with the sham-operated group as reported earlier. 25 F I G U R E 3 A, Photomicrograph of the cerebral cortex of control group showing evenly distributed variable sized neuronal cells surrounded by eosinophilic neurofibrillary material, which contains normal glial cells: astrocytes and oligodendrocytes (H&E ×400). B, Photomicrograph of ischemic cerebral cortex of I/R group showing necrosis, tissue loss, and gliosis with areas of widely separated neurofibers indicating edema and apoptotic neurons (H&E ×400).…”

Reduced perforin release from T cells as a mechanism underlying hypothermia‐mediated neuroprotection

“…[14][15][16] Pfn is a cytolytic protein that, on release, inserts itself into the plasma membrane of the target cell, forming a pore that leads to necrotic cell death because of loss of plasma membrane homeostasis with excessive uptakes of water and loss of intracellular contents. Recent studies showed the significant role of direct cytotoxicity through perforin (Pfn) in CD8 + T cell-mediated neuronal damage during ischemia.…”