Edaravone provides neuroprotection against chronic heat stress-induced behavioral dysfunction through adaptive proteomic remodeling.

Heat stress is an increasing global health concern associated with high mortality and multi-organ dysfunction. The brain is particularly vulnerable to heat stress, which can lead 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. 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 exposure and edaravone 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 LC-MS/MS with a nanoElute-QTOF-MS system. Heat stress impaired memory retention and increased anxiety-like behavior, while evidence for depressive-like behavior was modest. Proteomic analysis revealed region-specific alterations, with the hippocampus showing the largest number of significantly altered proteins, while the cortex showed the strongest multivariate separation between groups. 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. These findings suggest that edaravone attenuates heat stress-induced brain dysfunction by promoting adaptive proteomic remodeling rather than complete restoration.