Neuroprotection by dimethyl fumarate following ventral root crush in C57BL/6J mice

Author(s)

Menezes Carvalho, Nahanna Zimmermann ^[1] ; Chiarotto, Gabriela Bortolanca ^{[1, 2]} ; Bernardes, Danielle ^{[1, 2]} ; Gelinski Kempe, Paula Regina ^[1] ; Rodrigues Oliveira, Alexandre Leite ^[1]

Affiliation

^[1] Univ Estadual Campinas, Inst Biol, Dept Struct & Funct Biol, UNICAMP, BR-13083970 Campinas, SP - Brazil

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

• Document type: Journal article
• Source: Brain Research Bulletin; v. 164, p. 184-197, NOV 2020.
• Web of Science Citations: 1

Abstract

CNS lesions usually result in permanent loss of function and are an important problem in the medical field. In order to investigate neuroprotection/degeneration mechanisms and the synaptic plasticity of motoneumns, in addition to the potential for a variety of treatments, different experimental models of axonal injury have been proposed. Recent studies have tested the immunomodulatory drug dimethyl fumarate (DMF) for the treatment of neurodegenerative diseases and have shown promising outcomes. Therefore, in this work, we investigated the effects of DMF with regard to neumprotection and its influence on the glial response in C57BL/6J animals subjected to crushing of the motor roots in the lumbar intumescence of the spinal cord. The animals were divided into a vehicle-treated injury group (0.08 % methylcellulose solution control group, n = 7) and injured groups treated with DMF at different doses (15, 30, 45, 90 and 180 mg/kg; n = 6-7 per dose). The 90 mg/kg dose showed the best neuroprotective results, so it was used for treatment over a period of eight weeks. Neuronal survival was assessed through Nissl staining, and functional recovery was evaluated with the CatWalk system (walking track test) and the von Frey test (mechanoreception). Immunohistochemistry was used to assess synaptic coverage and astroglial and microglial reactivity using the primary antibodies anti-synaptophysin (presynaptic terminal pan marker), GAD65 (GABAergic pre-synaptic terminations - inhibitory), and VGLUT1 (glutamatergic pre-synaptic terminations - excitatory). Glial reactions were evaluated with anti-IBA1 (micmglia) and GFAP (astrocytes). Gene transcript levels of IL-3, IL-4, TNF-alpha, IL-6, TGF-beta, iNOS-M1, and arginase-M2 were quantified by RT-qPCR. The results indicated that treatment with DMF, at a dose of 90 mg/kg, promoted neuroprotection and immunomodulation towards an anti-inflammatory response. It also resulted in greater preservation of inhibitory synapses and reduced astroglial reactivity, providing a more favorable environment for sensorimotor recovery. (AU)

• FAPESP's process: 14/06892-3 - Use of mesenchymal stem cells in the CNS/PNS interface: repair of proximal lesions
• Grantee: Alexandre Leite Rodrigues de Oliveira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/05006-0 - Sensorimotor recovery following spinal root axotomy: use of different experimental approaches
• Grantee: Alexandre Leite Rodrigues de Oliveira
• Support Opportunities: Research Projects - Thematic Grants