Far-infrared radiation-mediated GPx-1/eNOS/ERK signaling contributes to the protective potential against methamphetamine-caused impairments in recognition memory in mice.

Abstract

Far-infrared radiation (FIR) induces glutathione peroxidase-1 (GPx-1) expression and enhances microcirculation by upregulating endothelial nitric oxide synthase (eNOS). However, the role of eNOS in FIR-mediated neuroprotection remains unclear. Here, we investigated whether FIR upregulates eNOS and extracellular signal-regulated kinase (ERK) signaling to mitigate recognition memory impairment caused by methamphetamine (MA). FIR significantly reduced MA-induced oxidative stress, which was primarily associated with GPx-1 inhibition. FIR or genetic overexpression of GPx-1 (GPx-1 TG) in mice significantly attenuated the MA-induced reduction in phospho-eNOS (p-eNOS) and phospho-ERK (p-ERK). Triple-label immunostaining revealed colocalization of p-eNOS, p-ERK, and GPx-1 within the same cellular populations in the prefrontal cortex. In non-transgenic (non-TG) mice, FIR exposure improved MA-induced cholinergic and memory deficits. However, FIR did not provide additional cognitive benefits in GPx-1 TG mice, and the GPx-1 inhibitor mercaptosuccinate blocked FIR-mediated cholinergic effects. Inhibitors of eNOS (i.e. L-NAME) and ERK (i.e. U0126) also significantly blocked the FIR-driven memory-enhancing effects in non-TG mice. Unlike L-NAME, which inhibits phosphorylation of both eNOS and ERK, U0126 did not affect FIR-induced eNOS phosphorylation, suggesting that eNOS is an upstream molecule for ERK signaling. Our finding suggests that GPx-1 is an essential mediator of FIR-induced memory enhancement, and that FIR exposure attenuates MA-induced cognitive impairments via cholinergic upregulation associated with GPx-1/eNOS/ERK signaling.