The effect of Riluzole on functional recovery of locomotion in the rat sciatic nerve crush model

Ghayour, Mohammad Bagher; Abdolmaleki, Arash; Rassouli, Morteza Behnam

doi:10.1007/s00068-016-0691-4

Cited by 20 publications

(11 citation statements)

References 35 publications

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“…Selective inhibitors of INaP have been found to be effective in cardiac diseases 38,41,[50][51][52] , epilepsies [53][54][55] , pain syndromes [56][57][58] , nerve injuries and neurodegenerative diseases. Riluzole has been found to be especially effective in preventing damage in spinal cord and peripheral nerve injury [59][60][61][62] . Riluzole represents an entirely new class among INaP selective inhibitors, because the non-blocking modulation mechanism endows it with an "ultrafast" offset kinetics, which, however is not based on actual dissociation.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of non-blocking inhibition of sodium channels revealed by conformation-selective photolabeling

Foldi

Pesti

Zboray

et al. 2020

Preprint

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Sodium channel inhibitor drugs can exert their effect by either blocking, or modulating the channel. The extent of modulation versus channel block is crucial regarding the therapeutic potential of drug candidates. Modulation can be selective for pathological hyperactivity, while channel block affects vital physiological function as much as pathological activity. Previous results indicated that riluzole, a drug with neuroprotective and antiepileptic effects, may have a unique mechanism of action, where modulation is predominant, and channel block is negligible. We studied the effects of riluzole on rNaV1.4 channels expressed in HEK cells. We observed that inhibition by riluzole disappeared and reappeared at a rate that could not be explained by association/dissociation dynamics. In order to verify the mechanism of non-blocking modulation, we synchronized photolabeling with the voltage clamp protocol of patch-clamp experiments. Using this method, we could bind a photoreactive riluzole analog covalently to specific conformations of the channel. Photolabeling was ineffective at resting conformation, but effective at inactivated conformation, as judged from persisting modulated gating after removal of unbound photoactive drug from the solution. Mutation of the key residue of the local anesthetic binding site (F1579A) did not fully prevent ligand binding and inhibition, however, it eliminated most of the modulation caused by ligand binding. Our results indicate that riluzole binds with highest affinity to the local anesthetic binding site, which transmits inhibition by the unique non-blocking modulation mechanism. Our results also suggest the existence of one or more additional binding sites, with lower affinity, and different inhibition mechanism.

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Section: Discussionmentioning

confidence: 99%

Mechanism of non-blocking inhibition of sodium channels revealed by conformation-selective photolabeling

Foldi

Pesti

Zboray

et al. 2020

Preprint

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“…It is well known that once the sciatic nerve has been injured, the CMAP amplitude and MNCV decrease and CMAP latency is delayed (Ghayour, Abdolmaleki, & Behnam-Rassouli, 2016). It is well known that once the sciatic nerve has been injured, the CMAP amplitude and MNCV decrease and CMAP latency is delayed (Ghayour, Abdolmaleki, & Behnam-Rassouli, 2016).…”

Section: Changes Of Sciatic Nerve Electrophysiology In Sfi Mice Aftmentioning

confidence: 99%

“…The feature of miconazole to protect sciatic nerve injury was assessed by response electrophysiology in the sciatic nerve at day 7 and 28 postinjury. It is well known that once the sciatic nerve has been injured, the CMAP amplitude and MNCV decrease and CMAP latency is delayed (Ghayour, Abdolmaleki, & Behnam-Rassouli, 2016).…”

Section: Changes Of Sciatic Nerve Electrophysiology In Sfi Mice Aftmentioning

confidence: 99%

Miconazole alleviates peripheral nerve crush injury by mediating a macrophage phenotype change through the NF‐κB pathway

et al. 2019

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Background Peripheral nerve injury (PNI) causes motor and sensory defects, has strong impact on life quality and still has no effective therapy. Miconazole is one of the most widely used antifungal drugs; the aims of the study were to investigate the effects of miconazole during sciatic nerve regeneration in a mouse model of sciatic nerve crush injury. Methods We established peripheral nerve crush model and investigated the effects of miconazole by multiple aspects. We further studied the potential mechanism of action of miconazole by Western blotting, fluorescence immunohistochemistry, and PCR analysis. Results Miconazole improves the symptoms of crushed nerve by improving inflammatory cell infiltration and demyelinating myelin of sciatic nerve. Affected by miconazole, the proportion of inflammatory M1 macrophages in the distal part of the sciatic nerve was reduced, and the proportion of anti‐inflammatory M2 macrophages was increased. Finally, the neuroprotective properties of miconazole may be regulated by the nuclear factor (NF)‐κB pathway. Conclusions Our data suggest that miconazole can effectively alleviate PNI, and the mechanism involves mediating a phenotype change of M1/ M2 macrophages. Thus, miconazole may represent a potential therapeutic intervention for nerve crush injury.

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“…In addition, riluzole inhibits neuro-excitotoxicity in animal models of neural injury, and soon after its administration, it can sufficiently reduce pain from nerve root compression and can prevent development of neuronal dysfunction in the nerve root and the spinal cord [138]. Recently, riluzole was clinically approved for the treatment of motor neuron disease, and experimental research is now underway for the assessment of its role on nerve regeneration processes after peripheral nerve injury [46].…”

Section: Riluzolementioning

confidence: 99%

“…Drugs commonly used for this purpose include tacrolimus [26][27][28][29], hyaluronic acid and its derivatives [30][31][32], melatonin [33][34][35], methylprednisolone [36][37][38][39], vitamin B complex and vitamin B12, [40][41][42], calcium and potassium channel blockers [43,44] and riluzole [45,46]. These substances have neuroprotective and neuroregenerative properties, though different mechanisms contribute markedly to nerve regeneration.…”

Section: Introductionmentioning

confidence: 99%

The Role of Pharmacological Agents in Nerve Regeneration after Peripheral Nerve Repair

Mekaj¹

2017

Peripheral Nerve Regeneration - From Surgery to New Therapeutic Approaches Including Biomaterials and Cell-Based Therapies Deve

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Peripheral nerve injuries are frequent and represent a significant pathology of the peripheral nervous system because, despite operative techniques and successful microsurgical repair, in most cases, the nerve repair is followed by scar formation. Numerous investigations have been carried out with the aim of finding pharmacological substances that can prevent scar formation and speed up the regeneration of repaired nerves. This chapter is dedicated to the efforts of many researchers to find different pharmacological agents with local effects on the improvement of nerve regeneration. Numerous experiments have been carried out in mice and rabbits using hyaluronic acid, tacrolimus, cyclosporin A, melatonin, vitamin B12, methylprednisolone, riluzole and potassium and calcium channel blockers. In the experimental animal studies, topical pharmacological agents were used at the site of peripheral nerve repair. The effect of these substances is most commonly studied in sciatic nerve injury in experimental animals. Their effects were evaluated using a variety of methods, such as morphological, biomechanical, electrophysiological and functional evaluation, and the above-mentioned substances, have been shown to have neuroprotective and neuroregenerative properties though different mechanisms.

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The effect of Riluzole on functional recovery of locomotion in the rat sciatic nerve crush model

Abstract: These findings suggest that early administration of even a single dose of Riluzole after sciatic nerve crush injury can delay motor function recovery. This effect may not depend on its anti-nociceptive activity.

Cited by 20 publications

References 35 publications

Mechanism of non-blocking inhibition of sodium channels revealed by conformation-selective photolabeling

Mechanism of non-blocking inhibition of sodium channels revealed by conformation-selective photolabeling

Miconazole alleviates peripheral nerve crush injury by mediating a macrophage phenotype change through the NF‐κB pathway

The Role of Pharmacological Agents in Nerve Regeneration after Peripheral Nerve Repair

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