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Cyclo (His-Pro) Protects SOD1G93A Microglial Cells from Paraquat–Induced Toxicity

Silvia Grottelli, Ilaria Bellezza, Giulio Morozzi, Matthew J Peirce, Cristina Marchetti, Ivana Cacciatore, Egidia Costanzi  and Alba Minelli

Cyclo (His-Pro), an endogenous cyclic dipeptide produced by the cleavage of the hypothalamic thyrotropin releasing hormone, crosses the blood brain barrier and improves recovery in models of traumatic injury to the brain and LPS-induced neuroinflammation. The protective effects are sustained by the ability of the cyclic dipeptide to interfere with the Nrf2–NF-κB signalling systems, the former governing the antioxidant and the latter the proinflammatory cellular response. Amyotrophic lateral sclerosis is a fatal disease which affects motor neurons and causes death of the patient from respiratory failure within a few years following diagnosis. Most patients suffer from sporadic amyotrophic lateral sclerosis, but about 5–10% of all amyotrophic lateral sclerosis cases can be attributed to familial forms, which are caused by mutations in the gene encoding for superoxide dismutase1. Transgenic mice overexpressing the human gene encoding for superoxide dismutase1 mutated in Gly93-Ala recapitulate several aspects of the disease. By exposing microglial cells overexpressing the mutated human gene superoxide dismutase1 to paraquat, we investigated whether cyclo (His-Pro) is able to alleviate the oxidative stress in a pathological environment. We found that cyclo (His-Pro) was effective in triggering, through Nrf2 activation, the antioxidant response which resulted primarily in the elevation of the intracellular glutathione levels. Intriguingly, we also found that cyclo (His-Pro) acts as a neurotrophic agent by inducing neuronal differentiation in PC12 cells.