Glycine transporter-1 inhibition by NFPS promotes neuroprotection against striatal damage models

Author(s):Show less -

Ribeiro, Raul Izidoro ; Carvalho, Gustavo Almeida ; Chiareli, Raphaela Almeida ; Lima, Isabel Vieira de Assis ; Bellozi, Paula Maria Quaglio ; Oliveira-Lima, Onesia Cristina ; Giacomelli, Agatha Oliveira ; Birbrair, Alexander ; Gomez, Renato Santiago ; de Oliveira, Antonio Carlos Pinheiro ; Ulrich, Henning ; Pinto, Mauro Cunha Xavier

• Document type: Journal article
• Source: Neuroscience Letters; v. 826, p. 7-pg., 2024-03-10.

Abstract

The striatum, an essential component of the brain's motor and reward systems, plays a pivotal role in a wide array of cognitive processes. Its dysfunction is a hallmark of neurodegenerative diseases like Parkinson's disease (PD) and Huntington's disease (HD), leading to profound motor and cognitive deficits. These conditions are often related to excitotoxicity, primarily due to overactivation of NMDA receptors (NMDAR). In the synaptic cleft, glycine transporter type 1 (GlyT1) controls the glycine levels, a NMDAR co-agonist, which modulates NMDAR function. This research explored the neuroprotective potential of NFPS, a GlyT1 inhibitor, in murine models of striatal injury. Employing models of neurotoxicity induced by 6-hydroxydopamine (PD model) and quinolinic acid (HD model), we assessed the effectiveness of NFPS pre-treatment in maintaining the integrity of striatal neurons and averting neuronal degeneration. The results indicated that NFPS pre-treatment conferred significant neuroprotection, reducing neuronal degeneration, protecting dopaminergic neurons, and preserving dendritic spines within the striatum. Additionally, this pre-treatment notably mitigated motor impairments resulting from striatal damage. The study revealed that GlyT1 inhibition led to substantial changes in the ratios of NMDAR subunits GluN2A/GluN1 and GluN2B/GluN1, 24 h after NFPS treatment. These findings underscore the neuroprotective efficacy of GlyT1 inhibition, proposing it as a viable therapeutic strategy for striatum-related damage. (AU)

• FAPESP's process: 18/07366-4 - Purine and kinin receptors as targets of study and therapeutic interventions in neurological diseases
• Grantee: Alexander Henning Ulrich
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/08426-0 - Indole alkaloid sub products of Maqui (Aristotelia chilensis) processing as food additives to Alzheimer's Disease treatment
• Grantee: Alexander Henning Ulrich
• Support Opportunities: Regular Research Grants