Targeting glutamatergic and serotoninergic signaling to treat neurodegenerative and metabolic disorders.

This PhD project aimed to demonstrate the validity of targeting two well-known central and peripheral systems (particularly, glutamatergic and serotoninergic signaling) as innovative therapeutic approaches for the treatment of ALS and MASLD. ALS is a rapidly progressing and debilitating neurodegenerative disorder, characterized by progressive irreversible loss of motor neurons, leading to paralysis and death. Although an increasing incidence of ALS has been reported worldwide, to date only few therapeutic approaches are available. REL-1017, the dextro-isomer of racemic methadone, is a low-affinity NMDAR antagonist with much lower affinity for the µ opioid receptor compared to the levo-isomer, and it has synaptogenic and antioxidant properties that support REL-1017 possible beneficial role in ALS. During this study REL-1017 effect was assessed in in vitro and in vivo models of ALS. Preliminary results supported sex-dependent effects of REL-1017 on molecular markers of neuronal plasticity and NMDAR subunits, in association with decreased expression of enzymes promoting oxidative radical damage at lower dose of REL-1017. For what concerns MASLD, this pathology is currently recognized as the most widespread chronic liver disease, with an estimated incidence of 47 cases per 1,000 individuals worldwide and is becoming one of the main causes of liver transplantation. The absence of approved drug on the market for MASLD treatment underlie the importance to find and study effective innovative targets for preventing its onset and progression. Recently, the role of serotoninergic system in metabolic-related disorders gained a renewed interest, and some research groups started investigating the 5-HTR agonist psilocybin as a promising treatment for obesity. In this study, psilocybin and later its chemically modified derivative (unable to cross the blood brain barrier) were tested in in vitro and in vivo models of lipid accumulation and MASLD. Preclinical results supported beneficial effect of microdoses of psilocybin for treating MASLD and concomitant comorbidities, including obesity and type 2 diabetes. Moreover, treatment with the non-psychedelic P8P corroborated the hypothesis that metabolic effects might mainly be due to the peripheral modulation of serotoninergic signaling, as the treatment with P8P induced an even stronger reduction of liver steatosis and an improvement of insulin sensitivity more evident than that observed after psilocybin treatment. In conclusion, both REL-1017 and serotonergic agonists provided interesting insights on their therapeutic potential, demanding for future preclinical and clinical studies.