Neuroprotection and immunomodulation by dimethyl fumarate and a heterologous fibrin biopolymer after ventral root avulsion and reimplantation

Autor(es)

Paula R. G. Kempe ^[1] ; Gabriela Bortolança Chiarotto ^[2] ; Benedito Barraviera ^[3] ; Rui Seabra Ferreira Jr. ^[4] ; Alexandre L. R. de Oliveira ^[5]

Afiliação do(s) autor(es)

^[1] University of Campinas. Laboratory of Nerve Regeneration - Brasil

^[2] University of Campinas. Laboratory of Nerve Regeneration - Brasil

^[3] São Paulo State University. Center for the Study of Venoms and Venomous Animals - Brasil

^[4] São Paulo State University. Center for the Study of Venoms and Venomous Animals - Brasil

^[5] University of Campinas. Laboratory of Nerve Regeneration - Brasil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Venomous Animals and Toxins including Tropical Diseases; v. 26, 2020-05-20.

Resumo

Abstract Background: Ventral root avulsion (VRA) is an experimental approach in which there is an abrupt separation of the motor roots from the surface of the spinal cord. As a result, most of the axotomized motoneurons degenerate by the second week after injury, and the significant loss of synapses and increased glial reaction triggers a chronic inflammatory state. Pharmacological treatment associated with root reimplantation is thought to overcome the degenerative effects of VRA. Therefore, treatment with dimethyl fumarate (DMF), a drug with neuroprotective and immunomodulatory effects, in combination with a heterologous fibrin sealant/biopolymer (FS), a biological glue, may improve the regenerative response. Methods: Adult female Lewis rats were subjected to VRA of L4-L6 roots followed by reimplantation and daily treatment with DMF for four weeks. Survival times were evaluated 1, 4 or 12 weeks after surgery. Neuronal survival assessed by Nissl staining, glial reactivity (anti-GFAP for astrocytes and anti-Iba-1 for microglia) and synapse preservation (anti-VGLUT1 for glutamatergic inputs and anti-GAD65 for GABAergic inputs) evaluated by immunofluorescence, gene expression (pro- and anti-inflammatory molecules) and motor function recovery were measured. Results: Treatment with DMF at a dose of 15 mg/kg was found to be neuroprotective and immunomodulatory because it preserved motoneurons and synapses and decreased astrogliosis and microglial reactions, as well as downregulated the expression of pro-inflammatory gene transcripts. Conclusion: The pharmacological benefit was further enhanced when associated with root reimplantation with FS, in which animals recovered at least 50% of motor function, showing the efficacy of employing multiple regenerative approaches following spinal cord root injury. (AU)

• Processo FAPESP: 18/25845-7 - Efeito neuroprotetor e imunomodulatório do dimetil-fumarato (DMF) após avulsão e reimplante de raízes motoras medulares associados à terapia celular
• Beneficiário: Paula Regina Gelinski Kempe
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• 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: 16/25478-9 - Efeito neuroprotetor e imunomodulatório do dimetil-fumarato (DMF) após avulsão e reimplante de raízes motoras medulares
• Beneficiário: Paula Regina Gelinski Kempe
• Modalidade de apoio: Bolsas no Brasil - Mestrado