The neuroprotection of cerebrolysin after spontaneous intracerebral hemorrhage through regulates necroptosis via Akt/ GSK3β signaling pathway.

Yunna Tao,Yeping Xu,Yan Wu,Liuyan Shen,Yuhai Wang,Youping Wu,Meng Shen,Xiaoyan Feng

doi:10.1590/acb361002

Yunna Tao, Yeping Xu + Show 6 more

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https://doi.org/10.1590/acb361002

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Abstract

ABSTRACTPurpose:Spontaneous intracerebral hemorrhage (ICH) is a major cause of death and disability with a huge economic burden worldwide. Cerebrolysin (CBL) has been previously used as a nootropic drug. Necroptosis is a programmed cell death mechanism that plays a vital role in neuronal cell death after ICH. However, the precise role of necroptosis in CBL neuroprotection following ICH has not been confirmed.Methods:In the present study, we aimed to investigate the neuroprotective effects and potential molecular mechanisms of CBL in ICH-induced early brain injury (EBI) by regulating neural necroptosis in the C57BL/6 mice model. Mortality, neurological score, brain water content, and neuronal death were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, Evans blue extravasation, Western blotting, and quantitative real-time polymerase chain reaction (PCR).Results:The results show that CBL treatment markedly increased the survival rate, neurological score, and neuron survival, and downregulated the protein expression of RIP1 and RIP3, which indicated that CBL-mediated inhibition of necroptosis, and ameliorated neuronal death after ICH. The neuroprotective capacity of CBL is partly dependent on the Akt/GSK3β signaling pathway.Conclusions:CBL improves neurological outcomes in mice and reduces neuronal death by protecting against neural necroptosis.

Highlights

Spontaneous intracerebral hemorrhage (ICH) has the highest mortality rate among stroke subtypes, accounts for 15 to 20% of all stroke types, and has an increased incidence in elderly patients[1,2,3,4]
The results show that CBL treatment markedly increased the survival rate, neurological score, and neuron survival, and downregulated the protein expression of RIP1 and RIP3, which indicated that CBL-mediated inhibition of necroptosis, and ameliorated neuronal death after ICH
Acute ICH due to a large intracranial hematoma is associated with high morbidity and mortality, as it can lead to primary brain injury through the destruction of brain tissue and the high intracranial pressure (ICP) that results from the large hematoma[5,6]

Summary

Introduction

Spontaneous intracerebral hemorrhage (ICH) has the highest mortality rate among stroke subtypes, accounts for 15 to 20% of all stroke types, and has an increased incidence in elderly patients[1,2,3,4]. Previous studies revealed that craniotomy for hematoma evacuation is an effective therapy for limiting primary brain damage and decreasing ICP after ICH, which is of substantial interest[5,7,8]. Increasing evidence shows that red blood cell debris, hemoglobin, its degradation products, and blood components trigger secondary brain injury following ICH and contributes to a series of damaging events, including neuroinflammation, brain edema, oxidative stress, bloodbrain barrier (BBB) damage, and neuron death[10,11,12,13,14,15]. An increasing number of studies have been conducted focusing on the mechanisms underlying ICHinduced secondary injury to search for better therapeutic targets for ICH. The possible mechanisms underlying early brain injury (EBI) include autophagy, apoptosis, direct neuronal death, and necroptosis[11,16,17]

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