Ratanasampil alleviates cognitive impairment in mice induced by chronic hypoxia by modulating inflammatory responses

Chronic hypoxia at high altitudes contributes to cognitive decline, but effective therapies are lacking. The traditional Tibetan medicine Ratanasampil (RNSP) has neuroprotective properties, yet its effects on hypoxia-induced cognitive impairment and associated inflammation remain unknown.

Aged C57BL/6J mice were exposed to chronic hypobaric hypoxia with or without RNSP pretreatment (7 mg/kg/d, 7 days plus concomitant administration). Cognitive function was assessed by Morris water maze and open field tests. Neuroinflammation, amyloid-β (Aβ) pathology, peripheral immune cell profiles (spleen and blood), and serum cytokine levels were analyzed.

RNSP treatment significantly improved spatial learning and memory deficits and reduced anxiety-like behavior induced by chronic hypoxia. In the brain, RNSP lowered the expression of IL-1β, IL-6, and TNF-α in the hippocampus and cortex. In peripheral tissues, RNSP reversed hypoxia-induced reductions in splenic and circulating CD3⁺/CD4⁺ T cells, decreased CD11b⁺ myeloid cell accumulation in the spleen, and attenuated gut inflammation. Moreover, RNSP rebalanced the serum cytokine milieu by decreasing pro-inflammatory mediators (IL-1β, IL-6, TNF-α) while restoring anti-inflammatory cytokines (IL-4, IL-10, TGF-β).

RNSP alleviates chronic hypoxia-induced cognitive impairment through dual anti-inflammatory actions on both the central nervous system and peripheral immune compartments. These findings support RNSP as a promising therapeutic candidate for high-altitude cognitive decline and possibly other inflammation-related neurological disorders.