Acute Administration of Edaravone Improves Cognitive Impairment in a Mouse Model of MPFC Ischemia: Crosstalk Between Necroptosis, Neuroinflammation, and Antioxidant Defense

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2024 Oct 24

PMID 39448519

Authors

Alireza Barati

Sadegh Moghimi

Kiana Taghavi Zanjani

Mojde Rohani

Mehri Sohrabi Hesar

Arian Arfaie

Mohadese Ghezelche Khamsiyan

Javad Mahmoudi

Saeed Sadigh-Eteghad

Affiliations

Soon will be listed here.

Abstract

Edaravone (Eda), a well-known free radical scavenger, has been reported as a possible therapeutic agent for ischemic stroke patients' recovery. This study aimed to investigate the effects of time-dependent treatment with Eda on medial prefrontal cortex (mPFC) ischemia. Mice were randomly allocated into six groups: control, sham, normal saline, Eda-I, Eda-II, and Eda-III. After induction of a photothrombotic ischemia in the mPFC region, Eda-I, Eda-II, and Eda-III groups received 3 mg/kg Eda intraperitoneally at the times of 0, 2, and 6 h post-surgery. After 1 day of recovery, the mice underwent behavioral tests (open field, novel object recognition, and T-maze). Next, necroptosis, NOD-like receptor protein 3 (NLRP3), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway-related protein levels were measured in the lesioned area using western blot analysis. For double confirmation, IL-1β and IL-18 were also assessed by immunofluorescence in the area. Further, histological evaluations were performed to measure tissue damage. The results showed that mPFC ischemia impaired recognition and spatial working memory without affecting locomotor activity, while immediate Eda administration improved cognitive impairments. Furthermore, acute Eda treatment reduced RIP1, RIP3, and MLKL levels, inhibited NLRP3 inflammasome proteins (NLRP3, ASC, and Cas1), decreased IL-1β and IL-18, upregulated Nrf2 and its targets (NQO-1 and HO-1), and diminished tissue damage. Our results highlighted the effects of acute administration of Eda post-stroke on improving cognitive impairments by suppressing necroptosis and NLRP3 inflammasome pathways and activating the Nrf2 antioxidant defense mechanism.

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