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Cerebrolysin reduces excitotoxicity by modulation of cell-death proteins in delayed hours of ischemic reperfusion injury

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Abstract

Recent preclinical and clinical reports suggest that cerebrolysin shows neuroprotective properties similar to endogenous neurotrophic factors in neurodegenerative disorders including ischemic stroke. However, little is known about its underlying antiexcitotoxic action. Adult male Wistar rats were intraperitoneally treated with cerebrolysin (0.15 or 0.30 mg/kg) or vehicle at 3, 6 and 12 h after ischemic reperfusion and were assessed 24 h after reperfusion in ischemic rats. We added cerebrolysin (2.5 or 5 mg/ml) or vehicle in primary cortical culture cells at 3, 6 and 12 h of post-glutamate exposure and performed cell viability assays at 24 h. Our in-vivo and in-vitro findings showed that cerebrolysin substantially reduced neuronal cell death in delayed hours of post ischemic- and glutamate-insult conditions respectively. Further, we have assessed the influence of NR-2 A/-2B receptor antagonism on neuroprotective action of cerebrolysin at 6 h in in-vivo as well as in-vitro conditions. Neuroprotective effect of cerebrolysin at 6 h of reperfusion was enhanced by pretreatment of NR2B antagonist RO25-6981.We found that cerebrolysin restrained upregulation of extrasynaptic NR2B responsible for triggering apoptotic pathways. Cerebrolysin reduced expression of important cell death proteins such as, JNK, PTEN, Calpain and Caspase-3 components. Importantly, we also found that cerebrolysin reduced SREBP1 expression, which gets activated only after 6 h of ischemia. These results demonstrate that cerebrolysin reduces excitotoxicity and protect neuronal cells in delayed hours of ischemic reperfusion injuries by decreasing cell death proteins.

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Data Availability

All data generated or analyzed during this study are included in this article.

Abbreviations

ANOVA:

Analysis of variance

JNK:

c-Jun N-terminal kinase

LDH:

Lactate dehydrogenase

MCAO:

Middle cerebral artery occlusion

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

NMDAR:

N-methyl-D-aspartate receptor

PTEN:

Phosphatase and tensin homolog

SREBP1:

Sterol regulatory element-binding protein 1

TTC:

2,3,5-triphenyltetrazolium chloride

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Funding

This study has been financially supported by Science and Engineering Research Board, Department of Science and Technology, Government of India. (EMR/2014/001015) 

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Contributions

AP and RRU designed the study. LPS, TG and VM performed experiments, analyzed and interpreted the data presented in this study. LPS and RRU prepared manuscript. BV performed the experiments and revised the manuscript.

Corresponding author

Correspondence to Rajesh R. Ugale.

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Ethical approval

All experimental procedures involving laboratory animals were approved by the Institutional Animal Ethical Committee (Approval letter no. IAEC/UDPS/2018/11, IAEC/UDPS/2018/13) and executed strictly according to the guidelines of Committee for the Purpose of Control and Supervision of Experiments on Animals, Government of India.

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All authors are willing to submit this manuscript in Metabolic Brain Disease.

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Authors declare that they have not any scientific or financial conflict of interest to any person or organization.

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Sarode, L.P., Ghatage, T., Mardhekar, V. et al. Cerebrolysin reduces excitotoxicity by modulation of cell-death proteins in delayed hours of ischemic reperfusion injury. Metab Brain Dis 38, 2401–2416 (2023). https://doi.org/10.1007/s11011-023-01240-4

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  • DOI: https://doi.org/10.1007/s11011-023-01240-4

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