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

Carvalho, Nahanna Zimmermann Menezes; Chiarotto, Gabriela Bortolança; Bernardes, Danielle; Kempe, Paula Regina Gelinski; Oliveira, Alexandre Leite Rodrigues de

doi:10.1016/j.brainresbull.2020.08.014

Cited by 10 publications

(6 citation statements)

References 69 publications

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“…The majority of spinal MNs survive after a more distal injury, such as a sciatic nerve axotomy [37,38], but 60-80% of MNs dye following a root avulsion that traumatically detaches the axons from its entrance into the spinal cord [3,6,39]. In a model of milder lesion, a lumbar ventral root crush, it was found 25% neuronal loss at 7 days after injury, which increased to 50% at 28 days [40][41][42]. Our model of postganglionic rhizotomy is produced more distally but it avoids intraspinal surgery, and induces slower degeneration affecting 40% of MN at 42 days.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice

Gaja-Capdevila

Hernández

Zamanillo³

et al. 2021

IJMS

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Loss of motor neurons (MNs) after spinal root injury is a drawback limiting the recovery after palliative surgery by nerve or muscle transfers. Research based on preventing MN death is a hallmark to improve the perspectives of recovery following severe nerve injuries. Sigma-1 receptor (Sig-1R) is a protein highly expressed in MNs, proposed as neuroprotective target for ameliorating MN degenerative conditions. Here, we used a model of L4–L5 rhizotomy in adult mice to induce MN degeneration and to evaluate the neuroprotective role of Sig-1R ligands (PRE-084, SA4503 and BD1063). Lumbar spinal cord was collected at 7, 14, 28 and 42 days post-injury (dpi) for immunohistochemistry, immunofluorescence and Western blot analyses. This proximal axotomy at the immediate postganglionic level resulted in significant death, up to 40% of spinal MNs at 42 days after injury and showed markedly increased glial reactivity. Sig-1R ligands PRE-084, SA4503 and BD1063 reduced MN loss by about 20%, associated to modulation of endoplasmic reticulum stress markers IRE1α and XBP1. These pathways are Sig-1R specific since they were not produced in Sig-1R knockout mice. These findings suggest that Sig-1R is a promising target for the treatment of MN cell death after neural injuries.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice

Gaja-Capdevila

Hernández

Zamanillo³

et al. 2021

IJMS

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“…Murine EAE[8,104], Human PBMCs[24], Human RRMS PBMCs[25], Murine EAN & macrophage cell line[94], Human psoriatic T cells[104], Murine spinal cord damage model[133] …”

mentioning

confidence: 99%

Calming the (Cytokine) Storm: Dimethyl Fumarate as a Therapeutic Candidate for COVID-19

Timpani

Rybalka

2020

Pharmaceuticals

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COVID-19 has rapidly spread worldwide and incidences of hospitalisation from respiratory distress are significant. While a vaccine is in the pipeline, there is urgency for therapeutic options to address the immune dysregulation, hyperinflammation and oxidative stress that can lead to death. Given the shared pathogenesis of severe cases of COVID-19 with aspects of multiple sclerosis and psoriasis, we propose dimethyl fumarate as a viable treatment option. Currently approved for multiple sclerosis and psoriasis, dimethyl fumarate is an immunomodulatory, anti-inflammatory and anti-oxidative drug that could be rapidly implemented into the clinic to calm the cytokine storm which drives severe COVID-19.

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“…Furthermore, these authors observed an increase in the expression of antioxidant enzymes and the NRF2 factor, showing a decrease in malondialdehyde, a marker for lipid stress [68,76]. In addition, the control or reduction in inflammatory responses provides a pro-regenerative environment that allows improvements in functional performance [29,81,82].…”

Section: Discussionmentioning

confidence: 97%

Ultrastructural Evidence of Synapse Preservation and Axonal Regeneration Following Spinal Root Repair with Fibrin Biopolymer and Therapy with Dimethyl Fumarate

et al. 2023

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Spinal cord injury causes critical loss in motor and sensory function. Ventral root avulsion is an experimental model in which there is the tearing of the ventral (motor) roots from the surface of the spinal cord, resulting in several morphological changes, including motoneuron degeneration and local spinal cord circuitry rearrangements. Therefore, our goal was to test the combination of surgical repair of lesioned roots with a fibrin biopolymer and the pharmacological treatment with dimethyl fumarate, an immunomodulatory drug. Thus, adult female Lewis rats were subjected to unilateral ventral root avulsion of L4–L6 roots followed by repair with fibrin biopolymer and daily treatment with dimethyl fumarate (15 mg/Kg; gavage) for 4 weeks, the survival time post-surgery being 12 weeks; n = 5/group/technique. Treatments were evaluated by immunofluorescence and transmission electron microscopy, morphometry of the sciatic nerve, and motor function recovery. Our results indicate that the combination between fibrin biopolymer and dimethyl fumarate is neuroprotective since most of the synapses apposed to alfa motoneurons were preserved in clusters. Also, nerve sprouting occurred, and the restoration of the ‘g’ ratio and large axon diameter was achieved with the combined treatment. Such parameters were combined with up to 50% of gait recovery, observed by the walking track test. Altogether, our results indicate that combining root restoration with fibrin biopolymer and dimethyl fumarate administration can enhance motoneuron survival and regeneration after proximal lesions.

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

Cited by 10 publications

References 69 publications

Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice

Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice

Calming the (Cytokine) Storm: Dimethyl Fumarate as a Therapeutic Candidate for COVID-19

Ultrastructural Evidence of Synapse Preservation and Axonal Regeneration Following Spinal Root Repair with Fibrin Biopolymer and Therapy with Dimethyl Fumarate

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