Perindopril and L‑arginine protect against arsenic trioxide-induced neurotoxicity via Keap1/Nrf2/HO‑1 activation and suppression of neuroinflammation and apoptosis.
📄 Abstract
Arsenic trioxide (ATO) remains vital in acute promyelocytic leukemia therapy, yet its clinical use is limited by cumulative organ toxicities, particularly neurotoxicity, which compromise tolerability and outcomes. Perindopril and L‑Arginine exert cytoprotective effects through antioxidant and anti‑inflammatory mechanisms. This study evaluated their neuroprotective efficacy against ATO‑induced neurotoxicity, emphasizing mechanistic pathways. Male rats were assigned to five groups: Control, ATO‑only (7.5 mg/kg, intraperitoneally, 14 days), Perindopril (2 mg/kg, orally), L‑Arginine (200 mg/kg, orally), and combined therapy. Interventions commenced seven days prior to the ATO challenge and continued for 21 days. Body weight was documented at baseline and endpoint; survival indices were monitored. Biochemical, histopathological, and molecular evaluations examined oxidative stress, inflammatory mediators, and apoptotic signaling. ATO exposure increased malondialdehyde (MDA) and nitric oxide derivatives (NOx), while reducing glutathione (GSH), superoxide dismutase (SOD), and catalase activities. It elevated tumor necrosis factor‑α (TNF‑α), interleukin‑1β (IL‑1β), and interleukin‑6 (IL‑6), while suppressing brain‑derived neurotrophic factor (BDNF) and nuclear factor erythroid 2‑related factor 2/heme oxygenase‑1 (Nrf2/HO‑1) signaling. Upregulation of Kelch‑like ECH‑associated protein 1/Nuclear factor kappa‑light‑chain‑enhancer of activated B cells (Keap1/NF‑κB), cleaved caspase‑3, and caspase‑3, alongside downregulation of B cell lymphoma‑2 (Bcl‑2), was evident. Histopathological lesions substantiated neurotoxicity. Perindopril and L‑Arginine markedly reversed these perturbations, reinstating molecular and structural homeostasis. Their combination afforded superior neuroprotection compared with monotherapies. Both agents mitigate ATO‑induced neurotoxicity through antioxidant, anti‑inflammatory, and anti‑apoptotic mechanisms, with their co‑administration surpassing individual efficacy. The Keap‑1/Nrf2/HO‑1 axis emerges as a critical therapeutic node, underscoring the translational potential of combined intervention.