Neuroprotective Effects of Remdesivir in ICV-STZ Induced Alzheimer-Like Pathology: Potential Involvement of ACE2-Associated Signaling.

Abstract

Alzheimer's disease involves interacting metabolic, oxidative, and inflammatory disturbances, with accumulating evidence implicating dysregulation of the brain renin-angiotensin system in disease-related pathology. This study investigated the neuroprotective effects of remdesivir against intracerebroventricular streptozotocin (ICV-STZ)-induced Alzheimer-like pathology and examined the potential involvement of ACE1/ACE2-associated signaling. Following ICV-STZ administration on Days 1 and 3, remdesivir treatment was initiated on Day 4 and continued once daily through Day 31. Remdesivir was evaluated using molecular docking, molecular dynamics simulation, behavioral testing, cholinesterase inhibition assays, biochemical analyses, ELISA, immunohistochemistry, qRT-PCR, Western blotting, and histopathology. ICV-STZ induced memory-related and affective-like behavioral impairments, altered exploratory activity, reduced ACE2 expression, increased ACE1 expression, oxidative stress, NLRP3/NF-κB-associated neuroinflammation, amyloid/tau-related alterations, and neuronal degeneration. Remdesivir dose-dependently improved behavioral and biochemical outcomes, increased ACE2 expression, reduced ACE1 expression, and attenuated neuroinflammation, oxidative injury, and neurodegeneration, with the most pronounced effects observed at 30 mg/kg. Pharmacological modulation with DX600 and diminazene aceturate altered the protective effects of remdesivir, providing supportive but not definitive evidence for the involvement of ACE2-associated signaling. However, ACE2 enzymatic activity and downstream Ang-(1-7)/Mas receptor signaling were not directly assessed. Remdesivir also inhibited AChE and BChE, with IC50 values of 237.4 μM and 535.7 μM, respectively. These findings demonstrate that early remdesivir intervention attenuates the development of ICV-STZ-induced Alzheimer-like pathology and suggest that modulation of the ACE1/ACE2 expression balance may be associated with its antioxidant, anti-inflammatory, and neuroprotective effects.

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