ABSTRACT: Background: Heat stress is an increasing global health concern associated with high mortality and multi-organ dysfunction. The brain is particularly vulnerable, leading to behavioral impairments. At the molecular level, heat stress disrupts proteins involved in synaptic communication, mitochondrial function, and cellular homeostasis. Current treatments are mainly symptomatic, highlighting the need for targeted neuroprotective strategies. Edaravone, a potent free-radical scavenger with anti-inflammatory properties, has demonstrated neuroprotective effects in various neurological conditions. This study aimed to evaluate the neuroprotective effects of edaravone against heat stress–induced behavioral dysfunction and to investigate the underlying molecular mechanisms using proteomic analysis. Methodology: Male Wistar rats (n = 54) were assigned to four groups: control, heat stress (HS), edaravone (Edv), and heat stress plus edaravone (HS+Edv). Heat stress and treatment were administered for 12 weeks. Behavioral assessments, including radial arm water maze (RAWM), open field test (OFT), elevated plus maze (EPM), and tail suspension test (TST), were conducted. Proteomic analysis of the cortex, hippocampus, and cerebellum was performed using UHPLC–QTOF-MS. Result: Heat stress induced significant impairments in memory, learning, anxiety-like, and depressive-like behaviors. Proteomic analysis revealed region-specific alterations, with the cerebral cortex showing the most pronounced changes, particularly in pathways related to mitochondrial function, oxidative stress, synaptic signaling, and protein quality control. The HS+Edv group showed partial normalization of behavioral outcomes and modulation of key proteomic pathways, including improved mitochondrial function, reduced oxidative stress, and preservation of synaptic and cytoskeletal integrity. Conclusion: Edaravone attenuates heat stress–induced brain dysfunction by promoting adaptive proteomic remodeling rather than complete restoration.
Ruba Zenati 
