Salidroside Alleviates Methamphetamine-Induced Cognitive Impairment by Targeting the AKT Pathway to Reduce Neuronal Apoptosis and Neuroinflammation

Methamphetamine (METH) abuse causes cognitive impairment via neuronal apoptosis, inflammation, and oxidative stress. Salidroside (Sal), a natural compound with anti-apoptotic and anti-inflammatory properties, may offer neuroprotection. This study evaluated the effects of Sal on METH-induced cognitive impairment and the underlying mechanisms. C57BL/6 mice were divided into control, METH, and METH + Sal groups. Behavioral tests (Novel Object Recognition and Y-maze) assessed cognitive function. Neuronal apoptosis and microglial activation were examined by TUNEL staining and Iba-1 immunofluorescence. Western blotting detected cleaved-caspase 3, cleaved-PARP, IL-6, IL-1β, and components of the Nrf2-HO-1, NF-κB, and AKT pathways. Oxidative stress markers (total antioxidant capacity [T-AOC], superoxide dismutase [SOD], and malondialdehyde [MDA]) were measured using an enzyme-linked immunosorbent assay (ELISA). Network pharmacology and protein-protein interaction (PPI) analysis identified AKT as a key Sal target, which was validated using the AKT inhibitor, MK-2206. Sal significantly improved cognitive performance, reduced neuronal apoptosis, suppressed microglial activation, and alleviated oxidative stress. Mechanistically, Sal activated the AKT pathway, which mediated the neuroprotective effects. These results suggest that Sal mitigates METH-induced cognitive dysfunction by targeting AKT to inhibit apoptosis, inflammation, and oxidative damage. This study highlights the potential of Sal as a therapeutic candidate for neurodegenerative diseases associated with stimulant-induced neurotoxicity.