Neuroprotection and muscle preservation by modulation of KCC2 in combination with pregabalin in MDX mice

• Grant number: 23/10689-8
• Support Opportunities: Scholarships in Brazil - Support Program for Fixating Young Doctors
• Start date: August 01, 2023
• Status: Discontinued
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Agreement: CNPq
• Principal Investigator: Alexandre Leite Rodrigues de Oliveira
• Grantee: Alex Dias Assis
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 23/01380-3 - Neuroprotection and muscle preservation by modulation of KCC2 in combination with pregabalin in MDX mice, AP.R

Abstract

Duchenne Muscular Dystrophy (DMD) is a severe genetic muscle disease characterized by failures in the synthesis of the protein dystrophin, inducing progressive muscle degeneration and weakness, leading the patient to death. The progression of the disease results in synaptic changes in the CNS as well as in the neuromuscular junctions. In addition, the axons of the neurons enter into a cycle of degeneration/regeneration. Pregabalin, a GABA analog drug, binds to subunits of calcium channels, attenuating ion influx into the nerve cell that uniquely possesses the chloride carrier molecule KCC2, responsible for the extrusion of CL-. The prodrug CLP257, which has a neuroprotective effect, restores chloride eflux by positively modulating KCC2, regulating GABA-mediated hyperpolarization. This occurs in analogy to PGB, inhibiting synaptic transmission via reduction of excess Cl-, responsible for interfering with synaptic signaling in several neurological diseases. The present project aims to control and, mainly, to prevent CL- and CA+2 alterations in the generation of hyperexcitability, which contributes to the aggravation of the degeneration of dystrophic muscle fibers. Furthermore, the stimulus for increased KCC2 activity will occur by means of 3D bio-printed intradermal implants with controlled release of CLP257. We seek to understand the molecular, metabolic, morphological and functional responses in the presence of pharmacological therapy with CLP257 and PGB to balance excitatory and inhibitory inputs in response to cycles of muscle degeneration and regeneration occurring in MDX mice. We believe that, from the results obtained in this project, we will be able to provide subsidies to better understand the synaptic modulation involved in the recruitment of dystrophic skeletal muscles in MDX mice and DMD patients.