Efeito neuroprotetor da inibição do transportador de prolina (SLC6A7)

Abstract

This study investigates the role of L-proline and the proline transporter (PROT, Slc6a7) in modulating glutamatergic neurotransmission and explores potential therapeutic approaches for neurodegenerative diseases. We demonstrated that L-proline influences intracellular calcium content in cortical and hippocampal synaptosomes of mice, observing an increase in intracellular calcium content at higher doses. We also assessed the impact of L-proline on motor and exploratory behavior in mice using the open field test. High concentrations of L-proline were found to reduce animal mobility without inducing anxious behaviors. In contrast, lower concentrations showed a stimulatory, though not significant, effect, suggesting a dual concentration-dependent effect of L-proline. We performed gene and protein expression analyses to elucidate the distribution and function of PROT in the brain. Our findings revealed that PROT is highly expressed in the cortex, striatum, and hippocampus, indicating possible regional specialization of its function. Furthermore, we investigated the interaction of PROT with potential inhibitors, such as iPROT, LQFM215, and LX6171, through modeling and molecular docking. These analyses revealed that both inhibitors bind effectively to PROT, with implications for modulating glutamatergic neurotransmission. Analyzing the effects of the proline transporter inhibitor (iPROT) in synaptosomes, we observed that iPROT mimics the effects of L-proline, increasing intracellular calcium content. We also explored the behavioral impact of iPROT, noting reductions in motor and exploratory behavior in mice without inducing anxiety-like behavior. Finally, we evaluated the neuroprotective potential of iPROT in an animal model of neurodegeneration induced by intrahippocampal Aβ injection. Pretreatment with iPROT demonstrated memory preservation and prevention of dendritic spine loss, indicating significant therapeutic potential. The analysis of key proteins involved in glutamatergic neurotransmission and the Brain-Derived Neurotrophic Factor (BDNF) pathway suggests a neuroprotection mechanism associated with these pathways. This study provides valuable insights into the neurobiology of L-proline and PROT, paving the way for new therapeutic approaches in neurodegeneration.