Quercetin prevents spinal motor neuron degeneration induced by chronic excitotoxic stimulus by a sirtuin 1-dependent mechanism

Rafael Lazo-Gomez, Ricardo Tapia

Excitotoxicity is a mechanism of foremost importance in the selective motor neuron degeneration characteristic of motor neuron disorders. Effective therapeutic strategies are an unmet need for these disorders. Polyphenols, such as quercetin and resveratrol, are plant-derived compounds that activate sirtuins (SIRTs) and have shown promising results in some models of neuronal death, although their effects have been scarcely tested in models of motor neuron degeneration. In this work we investigated the effects of quercetin and resveratrol in an in vivo model of excitotoxic motor neuron death induced by the chronic infusion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) into the rat spinal cord tissue. Quercetin and resveratrol were co-infused with AMPA and motor behavior and muscle strength were assessed daily for up to ten days. Then, animals were fixed and lumbar spinal cord tissue was analyzed by histological and immunocytological procedures. We found that the chronic infusion of AMPA [1 mM] caused a progressive motor neuron degeneration, accompanied by astrogliosis and microgliosis, and motor deficits and paralysis of the rear limbs. Quercetin infusion ameliorated AMPA-induced paralysis, rescued motor neurons, and prevented both astrogliosis and microgliosis, and these protective effects were prevented by EX527, a very selective SIRT1 inhibitor. In contrast, neither resveratrol nor EX527 alone improved motor behavior deficits or reduced motor neuron degeneration, albeit both reduced gliosis. These results suggest that quercetin exerts its beneficial effects through a SIRT1-mediated mechanism, and thus SIRT1 plays an important role in excitotoxic neurodegeneration and therefore its pharmacological modulation might provide opportunities for therapy in motor neuron disorders.