The effects of nimodipine, a calcium channel blocker, on noise-induced hearing loss were examined in gerbils. Animals were implanted subcutaneously with a timed-release pellet containing either nimodipine (approximately 10 mg/kg/day) or placebo and exposed to either 102 or 107 dBA noise. Serum levels were tested in two subjects and were in the range known to protect humans from cerebral artery vasospasm and ischemia-related neurologic deficits. Nimodipine and control groups had similar amounts of noise-induced (a) permanent threshold shift; (b) reductions in distortion product otoacoustic emissions; (c) reductions in tuning and suppression of the compound action potential; and (d) loss of outer hair cells. The results suggest that nimodipine, at a dose which results in clinically relevant serum levels, does not provide protection from the effects of moderately intense noise exposures.

The analytical test procedures currently established for the determination of the dihydropyridine calcium antagonist nimodipine in biological fluids are presented. Method of choice which has been dominantly used in pharmacokinetic investigations and drug interaction studies is gas chromatography with electron-capture detection (GC-ECD) subsequent to simple toluene extraction. The limit of quantification of 0.1 ng/ml in plasma conveniently allows to follow concentration/time profiles in the nano/subnanogram per ml-range after therapeutic doses. If not restricted by its markedly higher limit of quantification of approx. 1-5 ng/ml, high-performance liquid chromatography with either UV- or amperometric detection may be an attractive alternative for therapeutic drug monitoring or compliance control. A combined approach of HPLC and GC--chiral stationary-phase HPLC with GC-MS as off-line detection mode--has proven adequate and efficient to obtain pharmacokinetic data for nimodipine enantiomers after administration of the racemic drug.

The L-type calcium channel gene, CACNA1C, is a validated risk gene for schizophrenia and the target of calcium channel blockers. Carriers of the risk-associated genotype (rs1006737 A allele) have increased frontal cortical activity during working memory and higher CACNA1C mRNA expression in the prefrontal cortex. The aim of this study was to determine how the brain-penetrant calcium channel blocker, nimodipine, changes brain activity during working memory and other cognitive and emotional processes. We conducted a double-blind randomized cross-over pharmacoMRI study of a single 60 mg dose of oral nimodipine solution and matching placebo in healthy men, prospectively genotyped for rs1006737. With performance unchanged, nimodipine significantly decreased frontal cortical activity by 39.1% and parietal cortical activity by 42.8% during the N-back task (2-back > 0-back contrast; PFWE < 0.05; n = 28). Higher peripheral nimodipine concentrations were correlated with a greater decrease in activation in the frontal cortex. Carriers of the risk-associated allele, A (n = 14), had a greater decrease in frontal cortical activation during working memory compared to non-risk allele carriers. No differences in brain activation were found between nimodipine and placebo for other tasks. Future studies should be conducted to test if the decreased cortical brain activity after nimodipine is associated with improved working memory performance in patients with schizophrenia, particularly those who carry the risk-associated genotype. Furthermore, changes in cortical activity during working memory may be a useful biomarker in future trials of L-type calcium channel blockers.

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.

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.

To determine adherence to nimodipine administration in patients admitted with aneurysmal subarachnoid hemorrhage (aSAH).

Our study aimed to develop a self-assembled nanomicelle for oral administration of nimodipine (NIM) with poor water solubility. Using Solutol(®) HS15, the NIM-loaded self-assembled nanomicelles displayed a near-spherical morphology with a narrow size distribution of 12.57 ± 0.21 nm (polydispersity index =0.071 ± 0.011). Compared with Nimotop(®) (NIM tablets), the intestinal absorption of NIM from NIM nanomicelle in rats was improved by 3.13- and 2.25-fold in duodenum and jejunum at 1 hour after oral administration. The cellular transport of NIM nanomicelle in Caco-2 cell monolayers was significantly enhanced compared to that of Nimotop(®). Regarding the transport pathways, clathrin, lipid raft/caveolae, and macropinocytosis mediated the cell uptake of NIM nanomicelles, while P-glycoprotein and endoplasmic reticulum/Golgi complex (ER/Golgi) pathways were involved in exocytosis. Pharmacokinetic studies in our research laboratory have showed that the area under the plasma concentration-time curve (AUC0-∞) of NIM nanomicelles was 3.72-fold that of Nimotop(®) via oral administration in rats. Moreover, the NIM concentration in the brain from NIM nanomicelles was dramatically improved. Therefore, Solutol(®) HS15-based self-assembled nanomicelles represent a promising delivery system to enhance the oral bioavailability of NIM.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). Therapy is currently limited to drugs that interfere with the immune system; treatment options that primarily mediate neuroprotection and prevent neurodegeneration are not available. Here, we studied the effects of nimodipine on the rat cell line OLN-93, which resembles young mature oligodendrocytes. Nimodipine is a dihydropyridine that blocks the voltage-gated L-type calcium channel family members Cav1.2 and Cav1.3. Our data show that the treatment of OLN-93 cells with nimodipine induced the upregulation of myelin genes, in particular of proteolipid protein 1 (Plp1), which was confirmed by a significantly greater expression of PLP1 in immunofluorescence analysis and the presence of myelin structures in the cytoplasm at the ultrastructural level. Whole-genome RNA sequencing additionally revealed the upregulation of genes that are involved in neuroprotection, remyelination, and antioxidation pathways. Interestingly, the observed effects were independent of Cav1.2 and Cav1.3 because OLN-93 cells do not express these channels, and there was no measurable response pattern in patch-clamp analysis. Taking into consideration previous studies that demonstrated a beneficial effect of nimodipine on microglia, our data support the notion that nimodipine is an interesting drug candidate for the treatment of MS and other demyelinating diseases.

Subarachnoid hemorrhage (SAH) is an uncommon and serious subtype of stroke, which leads to the loss of the patient's ability to produce and live for many years.

Prior research on 3-week hydrocephalic rats showed that behavioral deficits and white matter damage could be reduced by treatment with Ca2+ channel blocker nimodipine. We hypothesized that treatment with nimodipine would be also beneficial to young ferrets with kaolin-induced hydrocephalus. Hydrocephalus was induced at 14 days of age and animals were treated either with vehicle, low dose nimodipine (3.2 mg/kg/day), or high dose nimodipine (16 mg/kg/day) for 2 weeks from 38 to 52 days age. Hydrocephalic ferrets developed progressive ventriculomegaly, behavioral changes, and in some cases cortical blindness. These changes were not ameliorated by nimodipine. Histological examination showed damage in periventricular white matter, corpus callosum thinning, axonal damage, reactive astroglial changes, and suppressed cell proliferation compared to non-hydrocephalic controls. Treatment with nimodipine was not beneficial for any of the pathological changes mentioned above; only low dose nimodipine treatment was associated with normalized content of glial fibrillary acidic protein, despite larger ventricles. We conclude that young hydrocephalic ferrets experience behavioral impairments and structural brain damage that are not consistently improved by intermittent nimodipine treatment. Continuous delivery should be considered in further preclinical studies.

Treatment of relapses in multiple sclerosis (MS) has not advanced beyond steroid use, which reduces acute loss of function, but has little effect on residual disability. Acute loss of function in an MS model (experimental autoimmune encephalomyelitis [EAE]) is partly due to central nervous system (CNS) hypoxia, and function can promptly improve upon breathing oxygen. Here, we investigate the cause of the hypoxia and whether it is due to a deficit in oxygen supply arising from impaired vascular perfusion. We also explore whether the CNS-selective vasodilating agent, nimodipine, may provide a therapy to restore function, and protect from demyelination in 2 MS models.

The clinical application of nimodipine (NIM) is limited by several unfavorable properties, which are induced by its low aqueous solubility. In the present study, nimodipine-loaded egg phosphatidylcholine-sodium glycocholate mixed micelles (NIM-EPC-SGC-MMs) were prepared to improve the water solubility of NIM, thus allowing it to be more applicable for clinical use.

To observe the effect of L-type calcium channel blocker like nimodipine on morphine's withdrawal when it was administered continuously along with morphine versus a single bolus dose of nimodipine, which was administered at the end of the experiment before the precipitation of withdrawal reaction in morphine-dependent rats.

Acute cerebral hypoxia causes rapid calcium shifts leading to neuronal damage and death. Calcium channel antagonists improve outcomes in some clinical conditions, but mechanisms remain unclear. In 18 healthy participants we: (i) quantified with multiparametric MRI the effect of hypoxia on the thalamus, a region particularly sensitive to hypoxia, and on the whole brain in general; (ii) investigated how calcium channel antagonism with the drug nimodipine affects the brain response to hypoxia. Hypoxia resulted in a significant decrease in apparent diffusion coefficient (ADC), a measure particularly sensitive to cell swelling, in a widespread network of regions across the brain, and the thalamus in particular. In hypoxia, nimodipine significantly increased ADC in the same brain regions, normalizing ADC towards normoxia baseline. There was positive correlation between blood nimodipine levels and ADC change. In the thalamus, there was a significant decrease in the amplitude of low frequency fluctuations (ALFF) in resting state functional MRI and an apparent increase of grey matter volume in hypoxia, with the ALFF partially normalized towards normoxia baseline with nimodipine. This study provides further evidence that the brain response to acute hypoxia is mediated by calcium, and importantly that manipulation of intracellular calcium flux following hypoxia may reduce cerebral cytotoxic oedema.

Multiple sclerosis is characterised by inflammatory neurodegeneration, with axonal injury and neuronal cell death occurring in parallel to demyelination. Regarding the molecular mechanisms responsible for demyelination and axonopathy, energy failure, aberrant expression of ion channels and excitotoxicity have been suggested to lead to Ca2+ overload and subsequent activation of calcium-dependent damage pathways. Thus, the inhibition of Ca2+ influx by pharmacological modulation of Ca2+ channels may represent a novel neuroprotective strategy in the treatment of secondary axonopathy. We therefore investigated the effects of the L-type voltage-gated calcium channel blocker nimodipine in two different models of mouse experimental autoimmune encephalomyelitis (EAE), an established experimental paradigm for multiple sclerosis. We show that preventive application of nimodipine (10 mg/kg per day) starting on the day of induction had ameliorating effects on EAE in SJL/J mice immunised with encephalitic myelin peptide PLP139-151 , specifically in late-stage disease. Furthermore, supporting these data, administration of nimodipine to MOG35-55 -immunised C57BL/6 mice starting at the peak of pre-established disease, also led to a significant decrease in disease score, indicating a protective effect on secondary CNS damage. Histological analysis confirmed that nimodipine attenuated demyelination, axonal loss and pathological axonal β-amyloid precursor protein accumulation in the cerebellum and spinal cord in the chronic phase of disease. Of note, we observed no effects of nimodipine on the peripheral immune response in EAE mice with regard to distribution, antigen-specific proliferation or activation patterns of lymphocytes. Taken together, our data suggest a CNS-specific effect of L-type voltage-gated calcium channel blockade to inflammation-induced neurodegeneration.

Chronic cerebral hypofusion (CCH) after bilateral carotid artery occlusion (2VO) causes cognitive damage and neuronal degeneration in the cortex and hippocampal CA1 area, and influences the oxygen and glucose supply in the brain which often results in metabolic alterations and oxidative stress. AMP-activated protein kinase (AMPK) phosphorylation, a sensor of cellular energy status, directs metabolic adaptation to support cellular growth and survival after CCH. Autophagy is also likely to be involved in metabolic adaptation and plays an important role in neuronal deterioration and cognitive decline after CCH. Nimodipine, an L-type calcium channel antagonist, has been reported to exert neuroprotective effects. However, the potential role of nimodipine in autophagy and the energy sensing AMPK signal is not well understood. In addition, little is known about the relationship between autophagy and AMPK signal. Here, we designed a way to evaluate these issues. Adult male Wistar rats were subjected to 2VO and randomly divided into three groups: the Vehicle (2VO), Nimodipine (2VO + nimodipine 10 mg/kg) groups. A third group served as sham controls. Each group was investigated at 2 and 4 weeks post gavage and tested using the Morris water maze. The activities of LC3B and AMPK signal were examined using immunohistochemistry and western blotting. Nimodipine significantly alleviated spatial learning and memory impairments and the number of lesion neurons. At 2 weeks of durg administration, these drug effects, suppressing AMPK activation and excessive autophagy, were more pronounced at the cortex than at hippocampal CA1 area. The effects of nimodipine were significant in the hippocampal CA1 area after 4 weeks of administration. Furthermore, nimodipine inhibited expression of eIF2α/ATF4 signaling related to energy deficit stress in 2VO rats. These results suggest that excessive autophagy has promoted neuronal and tissue injury after 2VO in rats. Nimodipine protected the brain from CCH by inhibiting the autophagy activity. The p-AMPK and eIF2α/ATF4 pathway is likely part of an integrated pro-autophagy signaling network after CCH.

That nimodipine (NMD) is potentially useful for ophthalmic treatment. However, the effect of NMD is unknown on retinal degenerative diseases.

Nimodipine (NMP) is a clinical dihydropyridine calcium antagonist. However, the clinical application of NMP is limited by poor water solubility and low oral bioavailability. To overcome these drawbacks, this study designed optimal NMP-incorporated nanostructured lipid carriers (NLCs).

The purpose of the present study was to investigate the effect of nimodipine (NMD), a calcium channel blocker, on N-methyl-N-nitrosourea (MNU)-induced retinal degeneration.

Diabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key vasoconstrictors released in the hemorrhagic blood and an important contributor to the etiology of CVSP. The combination of the ryanodine receptor blocker dantrolene and the Ca2+ channel blocker nimodipine significantly reduces phenylephrine (PHE)-induced vascular contraction in both diabetic and nondiabetic rats, but the effectiveness of this drug combination in reducing 5-HT-induced contraction is unknown. Dose-response curves for the 5-HT-induced contraction (from 0.1 nM to 100 µM) were performed on aortic rings from diabetic and non-diabetic rats after a 30-min incubation period with dantrolene, nimodipine, and both drugs in combination. In diabetic rats, 10 μM of dantrolene alone failed to reduce 5-HT-induced maximal contraction (Emax), but 50 μM reduced this parameter by 34% (n = 7, p < 0.05). In non-diabetic rats, by contrast, dantrolene did not modify the vascular response to 5-HT. 50 nM of nimodipine alone, however, reduced this parameter by 57% in diabetic rats (n = 10, p < 0.05), and by 34% in non-diabetic rats (n = 10, p < 0.05). In addition, concomitant administration of dantrolene and nimodipine reduced vascular reactivity to a similar extent in both diabetic (~ 60% reduction, n = 10, p < 0.05) and non-diabetic rats (~ 70% reduction, n = 10, p < 0.05). Moreover, the combination of nimodipine with the higher concentration of dantrolene significantly increased the EC50 values for the 5-HT-induced contraction curves in both diabetics (from 10.31 ± 1.17 µM to 19.26 ± 2.82; n = 10, p < 0.05) and non-diabetic rats (5.93 ± 0.54 µM to 15.80 ± 3.24; n = 10, p < 0.05). These results suggest that simultaneous administration of dantrolene and nimodipine has a synergistic effect in reducing 5-HT-induced vascular contraction under both diabetic and non-diabetic conditions. If our findings with rats are applicable to humans, concomitant administration of these drugs may represent a promising alternative for the management of CVSP in both diabetics and non-diabetics.