Pedra_2026_ACS.Omega_11_53798

Inosine is a purine nucleoside derived from adenosine metabolism that has been associated with neuroprotective and anti-inflammatory properties. The present study investigated the effects of inosine against lipopolysaccharide (LPS)-induced damage in primary astrocyte cultures and explored the potential contribution of adenosinergic signaling to these responses. LPS exposure impaired astrocyte viability and proliferation, altered cholinergic and purinergic enzyme activities, disrupted redox homeostasis, and increased the level of IL-6 release. Inosine treatment attenuated these alterations, restoring cell viability and proliferation, modulating acetylcholinesterase and ectonucleotidase activities, reducing oxidative damage, and preventing the LPS-induced increase in IL-6 levels. Mechanistic studies using pharmacological modulation of the adenosinergic system revealed that blockade of adenosine receptors interfered with some of the antioxidant effects of inosine, particularly those related to antioxidant enzyme activity, whereas its effects on cytokine modulation remained unchanged. Additional experiments using selective A2A receptor antagonists provided preliminary evidence that A2A receptor signaling may be involved in the antioxidant-related effects observed under inosine-treated conditions. Collectively, these findings demonstrate that inosine exerts multitarget protective effects in astrocytes, modulating oxidative stress, neurotransmission-related pathways, and inflammatory responses. These results support its potential as a promising strategy for restoring astrocyte homeostasis under neuroinflammatory conditions.