Nimodipine Promotes Functional Recovery After Spinal Cord Injury in Rats

Abstract

Spinal cord injury (SCI) is a devastating condition that results in severe motor, sensory, and autonomic dysfunction. The L-/T-type calcium channel blocker nimodipine (NMD) exerts a protective effect on neuronal injury; however, the protective effects of long-term administration of NMD in subjects with SCI remain unknown. Thus, the aim of this study was to evaluate the role of long-term treatment with NMD on a clinically relevant SCI model. Female rats with SCI induced by 25 mm contusion were subcutaneously injected with vehicle or 10 mg/kg NMD daily for six consecutive weeks. We monitored the motor score, hind limb grip strength, pain-related behaviors, and bladder function in this study to assess the efficacy of NMD in rats with SCI. Rats treated with NMD showed improvements in locomotion, pain-related behaviors, and spasticity-like symptoms, but not in open-field spontaneous activity, hind limb grip strength or bladder function. SCI lesion areas and perilesional neuronal numbers, gliosis and calcitonin gene-related peptide (CGRP+) fiber sprouting in the lumbar spinal cord and the expression of K+–Cl− cotransporter 2 (KCC2) on lumbar motor neurons were also observed to further explore the possible protective mechanisms of NMD. NMD-treated rats showed greater tissue preservation with reduced lesion areas and increased perilesional neuronal sparing. NMD-treated rats also showed improvements in gliosis, CGRP+ fiber sprouting in the lumbar spinal cord, and KCC2 expression in lumbar motor neurons. Together, these results indicate that long-term treatment with NMD improves functional recovery after SCI, which may provide a potential therapeutic strategy for the treatment of SCI.

Nimodipine Exerts Time-Dependent Neuroprotective Effect after Excitotoxical Damage in Organotypic Slice Cultures

“…Few studies analysed the mechanisms of nimodipine actions in the CNS. After spinal cord injury, nimodipine-treated rats showed improvements in gliosis, CGRP+ fibre sprouting, and an increased KCC2 expression in lumbar motor neurons [ 67 ]. Furthermore, nimodipine downregulated lncRNA nuclear paraspeckle assembly transcript 1, upregulated miR-27a, downregulated microtubule associated protein tau, inhibited brain tissue cell apoptosis and enhanced brain cell activity, resulting in improved outcomes and cognitive performance [ 68 ].…”

Spinal Cord Injury Provoked Neuropathic Pain and Spasticity, and Their GABAergic Connection

“…Additional studies in the future with nimodipine might provide further evidence for its use in SCI (Table 3). 125 Likewise, case reports suggest that ziconotide, by blocking N-type calcium channels, could also relieve spasticity-mediated pain post-SCI. (Table 4).…”

“…A recent study in SCI rats demonstrated that long-term administration of nimodipine reduced pain and spasticity, raised KCC2 expression, spared neurons with the overall promotion of functional recovery. Additional studies in the future with nimodipine might provide further evidence for its use in SCI ( Table 3 ) [ 125 ]. Likewise, case reports suggest that ziconotide, by blocking N-type calcium channels, could also relieve spasticity-mediated pain post-SCI.…”

Serotonin (5‐HT)2A/2C receptor agonist 2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropane hydrochloride improves detrusor sphincter dyssynergia by inhibiting L‐type voltage‐gated calcium channels in spinal cord injured rats

“… 6 , 8 , 9 Nimodipine, an L−/T‐type VGCC blocker, can prevent spasticity in SCI rodents when administered beforehand 10 and can promote the functional recovery in SCI rats. 11 Also, the T‐type VGCC, which is thought to be mainly implicated in pain transmission and sensitization, involves the remodeling of neuronal and reflex excitability after SCI. 12 Previous studies have reported that the expression of T and L VGCCs was changed after SCI, which might be associated with the functional alterations of neurons.…”