Enhanced neuroprotective effects of remdesivir-loaded solid lipid nanoparticles in ethanol-induced neurodegenerative model: Role of TREM/PPARγ/NLRP3.

Chronic ethanol exposure is detrimental, leading to neurodegeneration through mechanisms such as oxidative stress, inflammation, and interference with neuronal signaling pathways. In this study, a solid lipid nanoparticle formulation of remdesivir (RDV-SLNs) was evaluated for its neuroprotective effects against ethanol-induced neurodegeneration as compared to RDV dispersion. Adult male albino mice were administered ethanol, and various behavioral paradigms were used to evaluate cognitive decline. Mice exposed to ethanol exhibited notable deficits in recognition, spatial learning, and working memory. However, these impairments were significantly restored following treatment with RDV-SLNs. Furthermore, our data demonstrated a significant interaction between triggering receptors expressed on myeloid cells 1 (TREM1) (pro-inflammatory) and triggering receptor expressed on myeloid cells 2 (TREM2) (neuroprotective) in ethanol neurotoxicity, wherein their dysregulation results in NLRP3 inflammasome overactivation. Additionally, the downregulation of peroxisome proliferator-activated receptor (PPARγ) intensified this inflammatory cascade, coupled to hyper-elevated malondialdehyde (MDA) and nitric oxide (NO) levels in the ethanol-intoxicated group. Moreover, treatment with RDV-SLNs or RDV alone restored PPARγ activity and antioxidant enzymes such as catalase (CAT), glutathione (GSH), and glutathione S-transferase (GST). This restoration of PPARγ, coupled to the TREM signaling pathway balanced by RDV-SLNs, alleviated ethanol-induced neurodegeneration. These findings highlight the dual role of RDV by protecting against ethanol-induced neurodegeneration both as a modulator of neuroinflammation/oxidative stress and a metabolic regulator.