Nimodipine Reappraised: An Old Drug With a Future

Abstract

Nimodipine is a dihydropyridine calcium channel antagonist that blocks the flux of extracellular calcium through L-type, voltage-gated calcium channels. While nimodipine is FDAapproved for the prevention and treatment of neurological deficits in patients with aneurysmal subarachnoid hemorrhage (aSAH), it affects myriad cell types throughout the body, and thus, likely has more complex mechanisms of action than simple inhibition of cerebral vasoconstriction. Newer understanding of the pathophysiology of delayed ischemic injury after a variety of acute neurologic injuries including aSAH, traumatic brain injury (TBI) and ischemic stroke, coupled with advances in the drug delivery method for nimodipine, have reignited interest in refining its potential therapeutic use. In this context, this review seeks to establish a firm understanding of current data on nimodipine’s role in the mechanisms of delayed injury in aSAH, TBI, and ischemic stroke, and assess the extensive clinical data evaluating its use in these conditions. In addition, we will review pivotal trials using locally administered, sustained release nimodipine and discuss why such an approach has evaded demonstration of efficacy, while seemingly having the potential to significantly improve clinical care.

Nimodipine Promotes Functional Recovery After Spinal Cord Injury in Rats

“…This study suggests that long-term treatment with NMD can promote functional recovery after SCI in rats, presumably due to its actions on tissue preservation, gliosis and CGRP + fiber sprouting in the lumbar spinal cord, and expression of KCC2 on lumbar motor neurons. Due to the increasing interest in its possible usefulness in neurological diseases (Schampel et al, 2017;Carlson et al, 2020;Desai et al, 2020;Marcantoni et al, 2020), our data indicate that NMD may merit additional study as a possible therapeutic agent for the treatment of SCI.…”

“…NMD efficiently passes the blood-brain barrier (Langley and Sorkin, 1989;Tomassoni et al, 2008). Thus, it has been increasingly recognized as a potential therapeutic approach for neurological diseases, including stroke, neurodegenerative diseases, traumatic brain injury, and SCI (Carlson et al, 2020;Desai et al, 2020;Marcantoni et al, 2020). NMD mainly acts on L-/T-type calcium channels (Gurkoff et al, 2013).…”

“…Nimodipine (NMD) is an L-/T-type calcium channel blocker and has been approved for the treatment of subarachnoid hemorrhage (SAH) by the U.S. Food and Drug Administration ( Macdonald and Schweizer, 2017 ). The effects of NMD mainly include central nervous system (CNS)-specific vasodilation and blockade of the flux of extracellular calcium through L-/T-type calcium channels ( Gurkoff et al, 2013 ; Carlson et al, 2020 ). Recent studies have shown that it also prevents the development of spasticity after SCI and reduces CNS inflammatory responses ( Schampel et al, 2017 ; Marcantoni et al, 2020 ; Zamora et al, 2020 ).…”

Clinical Pharmacology of Clazosentan, a Selective Endothelin A Receptor Antagonist for the Prevention and Treatment of aSAH-Related Cerebral Vasospasm

“…The precise mechanism of action of nimodipine has not been deciphered yet but may involve neuronal as well as vascular effects ( Carlson et al, 2020 ). Nimodipine inhibits calcium ion transfer into smooth muscle cells and thus inhibits contractions of vascular smooth muscle.…”

“…An extended-release microparticle formulation of nimodipine that can be administered intraventricularly or intracisternally was developed but failed to show superiority compared to the oral formulation ( Hanggi et al, 2017 ; Hanggi et al, 2019 ). Further studies are required to develop newer formulations or potential combination of drugs to improve the clinical outcome of aSAH ( Carlson et al, 2020 ).…”