Amantadine Attenuates Secondary Oxidative and Inflammatory Injury by Modulating the HIF-1α/BNIP3L/HMGB1 Axis in Rat Model of Traumatic Brain Injury

TL;DR

Amantadine reduces brain injury damage in rats by targeting a specific molecular pathway linked to oxidative stress and inflammation.

Contribution

The study reveals a novel mechanistic link between amantadine treatment and suppression of HIF-1α/BNIP3L/HMGB1 signaling in traumatic brain injury.

Findings

Amantadine improved oxidative balance and reduced histopathological damage in TBI rats.

ATD treatment lowered inflammatory markers like TNF-α, CRP, and Caspase-3.

Gene expression of HIF-1α, BNIP3L, and HMGB1 was reduced in ATD-treated groups.

Abstract

Background and Objectives: Traumatic brain injury (TBI) triggers oxidative stress, mitochondrial dysfunction, and sterile inflammation. Amantadine (ATD), a weak NMDA receptor antagonist, has shown neuroprotective potential, but its mechanistic basis remains unclear. This study examined whether ATD treatment is associated with changes in molecular and histological markers related to the HIF-1α/BNIP3L/HMGB1-mediated hypoxia–mitophagy–inflammation response in a rat TBI model. Materials and Methods: Thirty-two Wistar rats were assigned to four groups: sham, trauma, trauma + ATD (1 day), and trauma + ATD (7 days). TBI was induced using the impact-acceleration model, and ATD (45 mg/kg, i.p.) was administered post-injury. Oxidative stress indices (TOS, TAS, OSI), histopathology, inflammatory/apoptotic markers (CRP, TNF-α, Caspase-3), and gene expression (HIF-1α, BNIP3L, HMGB1) were evaluated. Results: ATD improved oxidative balance and histopathological integrity while reducing TNF-α, CRP, and Caspase-3 immunoreactivity. qPCR analysis showed lower HIF-1α, BNIP3L, and HMGB1 expression in ATD-treated groups, which is consistent with attenuation of hypoxia-related, mitochondrial stress-associated, and damage-associated molecular pattern-associated signaling after injury. Conclusions: In this experimental model, amantadine ameliorated oxidative, inflammatory, and apoptotic markers and was associated with reduced expression of HIF-1α, BNIP3L, and HMGB1. These findings support a mechanistic correlation between ATD treatment and suppression of secondary injury signatures; however, causal pathway relationships and functional neurological outcomes were not assessed.

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