Rat BM-MSCs secretome alone and in combination with stiripentol and ISRIB, ameliorated microglial activation and apoptosis in experimental stroke

Neha Dhir; Ashish Jain; Amit Raj Sharma; Sunil Sharma; Dhruv Mahendru; Ajay Patial; Deepti Malik; Ajay Prakash; Savita Verma Attri; Shalmoli Bhattacharyya; Bishan Das Radotra; Bikash Medhi

doi:10.1016/j.bbr.2023.114471

Rat BM-MSCs secretome alone and in combination with stiripentol and ISRIB, ameliorated microglial activation and apoptosis in experimental stroke

Behav Brain Res. 2023 Jul 9:449:114471. doi: 10.1016/j.bbr.2023.114471. Epub 2023 May 4.

Authors

Affiliations

¹ Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
² Department of Neurology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India.
³ Department of Pediatrics, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India.
⁴ Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India; Department of Biochemistry, All India Institute of Medical Sciences, Bilaspur, Himachal Pradesh, India.
⁵ Department of Biophysics, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India.
⁶ Department of Histopathology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India.
⁷ Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. Electronic address: drbikashus@yahoo.com.

PMID: 37146724
DOI: 10.1016/j.bbr.2023.114471

Abstract

Background: Stroke, a devastating neurological emergency, is the leading cause of worldwide mortality and functional disability. Combining novel neuroprotective drugs offers a way to improve the stroke intervention outcomes. In the present era, the combination therapy has been proposed as a plausible strategy to target multiple mechanisms and enhance the treatment efficacy to rescue stroke induced behavioral abnormalities and neuropathological damage. In the current study, we have investigated the neuroprotective effect of stiripentol (STP) and trans integrated stress response inhibitor (ISRIB) alone and in combination with rat bone marrow derived mesenchymal stem cells (BM-MSCs) secretome in an experimental model of stroke.

Materials & methods: Stroke was induced in male Wistar rats (n = 92) by temporary middle cerebral artery occlusion (MCAO). Three investigational agents were selected including STP (350 mg/kg; i.p.), trans ISRIB (2.5 mg/kg; i.p.) and rat BM-MSCs secretome (100 µg/kg; i.v). Treatment was administered at 3 hrs post MCAO, in four doses with a 12 hrs inter-dose interval. Post MCAO, neurological deficits, brain infarct, brain edema, BBB permeability, motor functional and memory deficits were assessed. Molecular parameters: oxidative stress, pro inflammatory cytokines, synaptic protein markers, apoptotic protein markers and histopathological damage were assessed.

Results: STP and trans ISRIB, alone and in combination with rat BM-MSCs secretome, significantly improved neurological, motor function and memory deficits along with significant reduction in pyknotic neurons in the brain of post MCAO rats. These results were correlating with significant reduction in pro-inflammatory cytokines, microglial activation and apoptotic markers in the brain of drug treated post MCAO rats.

Conclusion: STP and trans ISRIB, alone and in combination with rat BM-MSCs secretome, might be considered as potential neuroprotective agents in the acute ischemic stroke (AIS) management.

Keywords: Apoptosis; BM-MSCs; ISRIB; Microglial activation; Secretome; Stiripentol; Stroke.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Brain Ischemia* / drug therapy
Cytokines / metabolism
Disease Models, Animal
Infarction, Middle Cerebral Artery / metabolism
Ischemic Stroke* / drug therapy
Ischemic Stroke* / metabolism
Male
Mesenchymal Stem Cells* / metabolism
Microglia / metabolism
Rats
Rats, Wistar
Secretome
Stroke* / drug therapy
Stroke* / pathology

Substances

stiripentol
Cytokines