Kinesin-5 inhibition improves neural regeneration in experimental autoimmune neuritis

Abstract

Background Autoimmune neuropathies can result in long-term disability and incomplete recovery, despite adequate first-line therapy. Kinesin-5 inhibition was shown to accelerate neurite outgrowth in different preclinical studies. Here, we evaluated the potential neuro-regenerative effects of the small molecule kinesin-5 inhibitor monastrol in a rodent model of acute autoimmune neuropathies, experimental autoimmune neuritis. Methods Experimental autoimmune neuritis was induced in Lewis rats with the neurogenic P2-peptide. At the beginning of the recovery phase at day 18, the animals were treated with 1 mg/kg monastrol or sham and observed until day 30 post-immunisation. Electrophysiological and histological analysis for markers of inflammation and remyelination of the sciatic nerve were performed. Neuromuscular junctions of the tibialis anterior muscles were analysed for reinnervation. We further treated human induced pluripotent stem cells-derived secondary motor neurons with monastrol in different concentrations and performed a neurite outgrowth assay. Results Treatment with monastrol enhanced functional and histological recovery in experimental autoimmune neuritis. Motor nerve conduction velocity at day 30 in the treated animals was comparable to pre-neuritis values. Monastrol-treated animals showed partially reinnervated or intact neuromuscular junctions. A significant and dose-dependent accelerated neurite outgrowth was observed after kinesin-5 inhibition as a possible mode of action. Conclusion Pharmacological kinesin-5 inhibition improves the functional outcome in experimental autoimmune neuritis through accelerated motor neurite outgrowth and histological recovery. This approach could be of interest to improve the outcome of autoimmune neuropathy patients.

Blood nerve barrier permeability enables nerve targeting of circulating nanoparticles in experimental autoimmune neuritis

“…However, the investigated therapies themselves are not feasible treatment options due to supraphysiological required doses ranging from 40-300 mg/kg [8, 10,34,35], in some cases twice a day dosing [8,9]. Further, many compounds exhibit off target effects and toxicity [7,10,11,27]. While some examples, such as sphingosine-1-phosphate inhibitors [27] or peroxisome proliferator-activated receptor gamma (PPARγ) antagonists [36], act systemically on immune organs and circulating immune cells, several examples act on sites within affected nerves.…”

“…The non-nitrogen containing bisphosphonate, clodronate, was shown to eliminate nerve macrophages and attenuate EAN when administered therapeutically after symptom onset [6]. The kinesin-5 inhibitor monastrol reduced EAN by enhancing neurite outgrowth within axons [7]. Importantly, this therapy was administered at peak of disease, which re ects the time when most patients are diagnosed with EAN.…”

“…Experimental autoimmune neuritis (EAN) is a wellestablished preclinical model of the acute in ammatory demyelinating polyneuropathy (AIDP) subtype of GBS that has advanced our understanding of mechanism by which pathology develops and progresses [3][4][5]. Several previous studies have shown attenuation of EAN with systemic administration of potential therapeutic compounds that span a range of anti-in ammatory or immunomodulatory strategies [6][7][8][9][10][11]. While shedding light on the mechanisms of disease, clinical advancement of these ndings is limited by dosing that is not translatable to humans or is associated with off-target and toxic effects.…”

Monastrol: Unveiling the Mechanisms, Efficacy, and Therapeutic Potential – A Comprehensive Review

“…While there are no currently available clinical trials for monastrol specifically (Kohle et al, 2023), other HsEg5 inhibitors, such as ispinesib and quinazoline ring-containing compounds have entered clinical trials (Zhang et al, 2005). However, these inhibitors have shown little clinical success.…”

Identifying and characterising promising small molecule inhibitors of kinesin spindle protein using ligand-based virtual screening, molecular docking, molecular dynamics and MM‑GBSA calculations

“…It was found that Eg5 inhibition in the human xenograft models, causes cell death and demonstrates anti-cancer activity [ 7 ]. Eg5 inhibitors are characterised by their selectivity and safety, because Eg5 functions only during mitosis; and does not affect the non-proliferative cells, which renders Eg5 inhibitors as selective inhibitors [ 8 ]. In addition, Eg5 does not induce neuropathic side effects, which are found with microtubules inhibitors, due to the absence of the Eg5 protein in the adult peripheral nervous system [ 9 , 10 ].…”