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Neuroprotection and immunomodulation by dimethyl fumarate and a heterologous fibrin biopolymer after ventral root avulsion and reimplantation.
J Venom Anim Toxins Incl Trop Dis. 2020 May 20; 26:e20190093.JV

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.

Authors+Show Affiliations

Laboratory of Nerve Regeneration, University of Campinas (UNICAMP), Campinas, SP, Brazil.Laboratory of Nerve Regeneration, University of Campinas (UNICAMP), Campinas, SP, Brazil.Center for the Study of Venoms and Venomous Animals (CEVAP), São Paulo State University (UNESP), Botucatu, SP, Brazil.Center for the Study of Venoms and Venomous Animals (CEVAP), São Paulo State University (UNESP), Botucatu, SP, Brazil.Laboratory of Nerve Regeneration, University of Campinas (UNICAMP), Campinas, SP, Brazil.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32518556

Citation

Kempe, Paula R G., et al. "Neuroprotection and Immunomodulation By Dimethyl Fumarate and a Heterologous Fibrin Biopolymer After Ventral Root Avulsion and Reimplantation." The Journal of Venomous Animals and Toxins Including Tropical Diseases, vol. 26, 2020, pp. e20190093.
Kempe PRG, Chiarotto GB, Barraviera B, et al. Neuroprotection and immunomodulation by dimethyl fumarate and a heterologous fibrin biopolymer after ventral root avulsion and reimplantation. J Venom Anim Toxins Incl Trop Dis. 2020;26:e20190093.
Kempe, P. R. G., Chiarotto, G. B., Barraviera, B., Ferreira, R. S., & de Oliveira, A. L. R. (2020). Neuroprotection and immunomodulation by dimethyl fumarate and a heterologous fibrin biopolymer after ventral root avulsion and reimplantation. The Journal of Venomous Animals and Toxins Including Tropical Diseases, 26, e20190093. https://doi.org/10.1590/1678-9199-JVATITD-2019-0093
Kempe PRG, et al. Neuroprotection and Immunomodulation By Dimethyl Fumarate and a Heterologous Fibrin Biopolymer After Ventral Root Avulsion and Reimplantation. J Venom Anim Toxins Incl Trop Dis. 2020 May 20;26:e20190093. PubMed PMID: 32518556.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuroprotection and immunomodulation by dimethyl fumarate and a heterologous fibrin biopolymer after ventral root avulsion and reimplantation. AU - Kempe,Paula R G, AU - Chiarotto,Gabriela Bortolança, AU - Barraviera,Benedito, AU - Ferreira,Rui Seabra,Jr AU - de Oliveira,Alexandre L R, Y1 - 2020/05/20/ PY - 2020/6/11/entrez PY - 2020/6/11/pubmed PY - 2020/6/11/medline KW - Dimethyl-fumarate KW - Fibrin sealant KW - Immunomodulation KW - Neuroprotection KW - Ventral root avulsion SP - e20190093 EP - e20190093 JF - The journal of venomous animals and toxins including tropical diseases JO - J Venom Anim Toxins Incl Trop Dis VL - 26 N2 - 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. SN - 1678-9199 UR - https://www.unboundmedicine.com/medline/citation/32518556/Neuroprotection_and_immunomodulation_by_dimethyl_fumarate_and_a_heterologous_fibrin_biopolymer_after_ventral_root_avulsion_and_reimplantation L2 - https://jvat.biomedcentral.com/articles/10.1590/1678-9199-JVATITD-2019-0093 DB - PRIME DP - Unbound Medicine ER -
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