Comparative neuroprotective efficacy of pharmacological agents in contusion traumatic brain injury in rats

Introduction. Traumatic brain injury (TBI) remains a leading cause of mortality and disability among young and working-age individuals. Key mechanisms of secondary brain damage include glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, and dysregulation of matrix metalloproteinases. The comparative efficacy of neuroprotective agents with different mechanisms of action in TBI requires investigation due to the insufficient coverage of this problem.

Aim: To conduct a comparative experimental evaluation of the neuroprotective effects of memantine, choline alfoscerate, citicoline, and ethylmethylhydroxypyridine succinate in a rat model of contusion traumatic brain injury based on parameters of oxidative stress, neuroinflammation, excitotoxicity, MMP-2 activity, and energy metabolism.

Material and Methods. The study was performed on 60 male Wistar rats divided into 6 groups of 10 animals each: sham-operated (SO), negative control (NC), as well as groups receiving memantine, choline alfoscerate, citicoline, or EMHPS (ethylmethylhydroxypyridine succinate). Contusion traumatic brain injury (cTBI) was induced under anesthesia by dropping a 50 g weight from a height of 2 cm. The compounds were administered orally from days 2 to 8 post-injury. Brain homogenates and mitochondrial fractions were analyzed for TNFα, glutamate, MMP-2, MitoH₂O₂, as well as aerobic and anaerobic metabolism.

Results. cTBI caused an increase in TNFα by 261.8% (p < 0.05), MitoH₂O₂ by 92.3%, glutamate by 73.2%, MMP-2 by 81.8%, and anaerobic metabolism by 146.7%, as well as a decrease in aerobic metabolism by 56.1% (p < 0.05). The most pronounced restoration of cognitive function (Y-maze) was provided by EMHPS (+103% relative to NC, p < 0.05), which also maximally reduced MitoH₂O₂ (by 42.3%) and glutamate (by 26%), and increased aerobic metabolism (by 50%). Memantine reduced glutamate levels (by 31.3%; p < 0.05) and MMP-2 (by 25.6%; p < 0.05), but had no effect on TNFα or MitoH₂O₂ (p > 0.05). Choline alfoscerate and citicoline showed partial but divergent effects.

Conclusion. Ethylmethylhydroxypyridine succinate (EMHPS) demonstrated the most balanced neuroprotective effect in cTBI, making it promising for further preclinical and clinical studies. Investigation of combination therapy and longer observation periods is warranted.

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