Clemastine Enhances Myelination, Delays Axonal Loss and Promotes Functional Recovery in Spinal Cord Injury

Abstract

Recent evidence has shown that demyelination occurs along with axonal degeneration in spinal cord injury (SCI) during the secondary injury phase. Oligodendrocyte precursor cells (OPC) are present in the lesions but fail to differentiate into mature oligodendrocytes and form new myelin. Given the limited recovery of neuronal functions after SCI in adults without effective treatment available so far, it remains unknown whether enhancing OPC differentiation and myelination could benefit the recovery of SCI. To show the significance of myelin regeneration after SCI, the injury was treated with clemastine in the rat model. Clemastine is an FDA-approved drug that is potent in promoting oligodendrocyte differentiation and myelination in vivo, for four weeks following SCI. Motor function was assessed using sloping boards and grid walking tests and scored according to the Basso, Beattie, and Bresnahan protocol. The myelin integrity and protein expression were evaluated using transmission electron microscopy and immunofluorescence, respectively. The results indicated that clemastine treatment preserves myelin integrity, decreases loss of axons and improves functional recovery in the rat SCI model. The presented data suggest that myelination-enhancing strategies may serve as a potential therapeutic approach for the functional recovery in SCI.

Clemastine Promotes Differentiation of Oligodendrocyte Progenitor Cells Through the Activation of ERK1/2 via Muscarinic Receptors After Spinal Cord Injury

“…To assume that the enhancement of ERK1/2 signaling induced by clemastine mainly occurs in oligodendroglia, our result demonstrated that the expression of p-ERK1/2 in the Cle group was higher than that in the vehicle group ( Figures 3A,B ). Notably, the infiltration of T-cells and macrophages and the activation of microglia in demyelinated lesions in SCI or experimental autoimmune encephalomyelitis (EAE) were examined; however, there is no significant difference between the vehicle and clemastine groups, suggesting that the action of clemastine does not change the inflammatory response in the aspect of cellular infiltration ( Mei et al, 2016 ; Du et al, 2022 ). As we all know, microglia and astrocytes are the major sources of CNS inflammatory response; therefore, we could assume that clemastine may not be involved in the adjustment of microglia or astrocytes.…”

“…In the sham group, the spinal cord tissues of the rats were exactly intact, just only removing the corresponding lamina. The rats in the clemastine group were treated with clemastine daily at 10 mg/kg/day by gavage ( Du et al, 2022 ) and in the vehicle group were treated with the equivalent volume of vehicle (3% DMSO in sterile saline solution), which differs from that the animals in the fourth group which were administered cevimeline (5 mg/kg/day) by i. p( Nakahara et al, 1988 ; Dawson et al, 1994 ) in advance at 30 min and then given clemastine (10 mg/kg/day) orally. Simultaneously, the rats in the cevimeline group were injected with cevimeline once daily at 5 mg/kg.…”

“…Fluorescence images were captured using a confocal laser-scanning microscope (Olympus, FV1000, Shinjuku, Tokyo) with excitation wavelengths appropriate for AlexaFluor-488 (488 nm), −596 (568 nm), or DAPI (380 nm). The quantitative method of fluorescence images was performed as previously described ( Du et al, 2022 ). We obtained photos at ×400 magnification with a fluorescence microscope.…”

“…Similarly, our group has carried out research on the efficacy of clemastine on SCI in recent years. In our latest findings, we demonstrated that clemastine treatment on SCI enhances myelination and neurobehavioral recovery, also including the significant delay of axonal degeneration (Du et al, 2022). As for muscarinic receptors (MRs), they are G protein-coupled receptors (GPCRs) broadly distributed in the central nervous system (CNS).…”

Clemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis

“…Among these is remyelination, as chronically demyelinated axons are considered less resilient to neurodegenerative mechanisms compared to their myelinated counterparts 4 . Clemastine fumarate, an over-the-counter antihistamine with anticholinergic properties against muscarinic M1 receptor, induces remyelination in-vitro 5 , in multiple animal models [6][7][8][9] and in the randomized, blinded cross-over Phase II MS trial (ReBUILD; ClinicalTrials.gov ID NCT02040298 10 . In 50 MS patients with mean age of 40.1 years who had mild disability (i.e., mean Expanded Disability Status Scale [EDSS] 2.2 on ordinal scale from 0 to 10), clemastine demonstrated remyelinating effect.…”