Pregabalin-induced neuroprotection and gait improvement in dystrophic MDX mice

Autor(es)

Assis, Alex Dias ^[1] ; Chiarotto, Gabriela Bortolanca ^{[1, 2]} ; Simoes, Gustavo Ferreira ^[1] ; Rodrigues Oliveira, Alexandre Leite ^[1]

Afiliação do(s) autor(es)

^[1] Univ Campinas UNICAMP, Lab Nerve Regenerat, Cidade Univ Zeferino Vaz, Rua Monteiro Lobato 255, BR-13083970 Campinas, SP - Brazil

^[2] Univ Ctr Herminio Ometto Fdn FHO, Biomed Sci Grad Program, Araras, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Molecular and Cellular Neuroscience; v. 114, JUL 2021.
• Citações Web of Science: 0

Resumo

Duchenne muscular dystrophy (DMD) is a genetic disease linked to the X chromosome induced by mutations in the dystrophin gene. Neuroprotective drugs, such as pregabalin (PGB), can improve motor function through the modulation of excitatory synapses, together with anti-apoptotic and anti-inflammatory effects. The present work studied the effects of PGB in the preservation of dystrophic peripheral nerves, allowing motor improvements in MDX mice. Five weeks old MDX and C57BL/10 mice were treated with PGB (30 mg/kg/day, i.p.) or vehicle, for 28 consecutive days. The mice were sacrificed on the 9th week, the sciatic nerves were dissected out and processed for immunohistochemistry and qRT-PCR, for evaluating the expression of proteins and gene transcripts related to neuronal activity and Schwann cell function. The lumbar spinal cords were also processed for qRT-PCR to evaluate the expression of neurotrophic factors and pro- and anti-inflammatory cytokines. Cranial tibial muscles were dissected out for endplate evaluation with alpha-bungarotoxin. The recovery of motor function was monitored throughout the treatment, using a spontaneous walking track test (Catwalk system) and a forced locomotion test (Rotarod). The results showed that treatment with PGB reduced the retrograde effects of muscle degeneration/regeneration on the nervous system from the 5th to the 9th week in MDX mice. Thus, PGB induced protein expression in neurons and Schwann cells, protecting myelinated fibers. In turn, better axonal morphology and close-to-normal motor endplates were observed. Indeed, such effects resulted in improved motor coordination of dystrophic animals. We believe that treatment with PGB improved the balance between excitatory and inhibitory inputs to spinal motoneurons, increasing motor control. In addition, PGB enhanced peripheral nerve homeostasis, by positively affecting Schwann cells. In general, the present results indicate that pregabalin is effective in protecting the PNS during the development of DMD, improving motor coordination, indicating possible translation to the clinic. (AU)

• Processo FAPESP: 18/05006-0 - Recuperação sensório-motora após axotomia de raízes medulares: emprego de diferentes abordagens experimentais
• Beneficiário: Alexandre Leite Rodrigues de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/14385-7 - Estudo dos efeitos protetores da Pregabalina no Sistema Nervoso Central e Periférico e Sistema Muscular Esquelético de Camundongos MDX
• Beneficiário: Gustavo Ferreira Simoes
• Modalidade de apoio: Auxílio à Pesquisa - Regular