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The IC87201 (a PSD95/nNOS Inhibitor) Attenuates Post- Stroke Injuries

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Abstract

N-methyl-D-aspartate receptor-dependent excitotoxicity is one of the most important mechanisms underlying stroke injury and the resulting neuronal death. In the present study, in order to reduce post-stroke brain injury and improve behavioral performance, a new molecule named IC87201, which acts as an inhibitor of PSD95/nNOS interaction in the intracellular signaling pathway of NMDA receptors, was administered. Using the middle cerebral artery occlusion (MCAO) technique, 24 adult male rats were subjected to one hour of cerebral ischemia. Animals were randomly divided into sham, MCAO, MCAO + DXM, and MCAO + IC87201 groups, and in the last two groups, intraperitoneal injection of dextromethorphan hydrobromide monohydrate (DXM), as an NMDA antagonist, and IC87201 was performed after ischemia. Neurobehavioral scores were evaluated for seven days, and on the last two days, the rats’ memory performance was appraised using the passive avoidance test. On seventh day, the brain tissue was properly prepared for stereological analysis. Stereological studies of the hippocampus CA1 and CA3 regions revealed that changes in the total and infarcted volumes, total number of neurons, non-neurons, and dead neurons are the consequences of cerebral ischemia. Also, following cerebral ischemia, neurobehavioral and memory function impairments which were assessed by modified neurological severity scores (mNSS) and passive avoidance test, were observed. The aforementioned impairments were recovered after administration of IC87201 significantly and more potently than DXM. Based on our findings, IC87201 successfully attenuated post-ischemia damages. Therefore, this molecule can be considered as a new therapeutic approach in future research.

Highlights

  • • Ischemic stroke severely destroys hippocampus neurons and causes memory impairment.

  • • IC87201 improved hippocampal histological injury following brain ischemia.

  • • IC87201 improved memory impairment resulting from brain ischemia.

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Data Availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Funding

This work was supported by a grant from the Shiraz University, Shiraz, Iran (Grant number: SU9531466), which was extracted from Maryam Mohammadian’s Ph.D. thesis.

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Authors and Affiliations

  1. Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran

    Maryam Mohammadian & Aminollah Bahaoddini

  2. Histomorphometry and Stereology Research Center, Department of Anatomical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran

    Mohammad Reza Namavar

Authors
  1. Maryam Mohammadian
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  2. Aminollah Bahaoddini
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  3. Mohammad Reza Namavar
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Contributions

MM: Designing the study, performing laboratory work, graphical design, data collection, and writing the manuscript draft. AB: Supervising laboratory works, conceptualization, methodology, and data analysis. MRN: Conceptualization, methodology editing, and revising the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Aminollah Bahaoddini or Mohammad Reza Namavar.

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Ethical Approval

All procedures were performed based on the National Institutes of Health?s Guidelines for Care and Use of Laboratory Animals and Animal Research: Reporting in Vivo Experiments (ARRIVE) and approved by the local Ethical Committee of Shiraz University (SU-9531466).

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The authors declare no competing interests.

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Mohammadian, M., Bahaoddini, A. & Namavar, M.R. The IC87201 (a PSD95/nNOS Inhibitor) Attenuates Post- Stroke Injuries. Neurochem Res (2024). https://doi.org/10.1007/s11064-024-04140-w

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  • DOI: https://doi.org/10.1007/s11064-024-04140-w

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