Effect Of Nimodipine Research Articles

Phenytoin and Cognitive Decline

To the Editor: We read with great interest the article by Naidech et al1 on the association of phenytoin exposure and cognitive disability after subarachnoid hemorrhage. The authors speculate on a number of reasons for this association, to which we would like to add the possibility of a pharmacokinetic interaction compromising the protective effects of nimodipine. Phenytoin induces the hepatic microsomal enzyme system (cytochrome p-450 isozymes). Induction of the CYP isozyme system may …

Antioxidant effect of nimodipine in young rats after pilocarpine-induced seizures

Nimodipine (ND) is a centrally active calcium antagonist that blocks the voltage-dependent L-type channels. Its antiepileptic properties have been proved in various animal models, including pilocarpine-induced seizures in adult rats. In order to investigate protective effects of the ND (10 (ND10) and 30 mg/kg (ND30), i.p.), young male rats (21-day-old) received ND injections before pilocarpine administration (400 mg/kg, s.c., pilocarpine group (P400)). The pretreatment with ND10 and ND30 prolonged the latencies of seizures and death on this seizure model. ND pretreatment in two doses decreased the levels of lipid peroxidation when compared to pilocarpine group. The P400 administration increased the striatal catalase activity. However, the administration of ND, in dose of 30 mg/kg, 30 min before pilocarpine, preserved catalase activity in normal levels. On the other hand, no change was detected in the animals treated with the dose of 10 mg/kg. Our results confirm the neuroprotective effect of ND on the seizures in young rats, suggesting that this drug acts positively on lipid peroxidation. Our observations shows that nimodipine cannot induces these effects via blockade of Ca 2+-channel.

Dynamic CT Perfusion imaging in subarachnoid hemorrhage related vasospasm

Vasospasm (VSP) and changes in cerebral blood flow (CBF) are complications of subarachnoid hemorrhage (SAH) that can lead to delayed ischemic deficits (DID). In many institutions, nimodipine is the standard treatment used to prevent DIDs subsequent to SAH. However, there are discrepancies regarding the ability of nimodipine to improve outcome in all SAH patients. As new therapies become available for the treatment of DIDs associated with SAH, it will be necessary to develop a method to assess the need for, and the response to, therapy. In response to this need, we attempt to demonstrate the feasibility of using a functional computed tomography (CT) imaging protocol to quantify the effects of nimodipine on VSP and CBF in a rabbit model of SAH. SAH was induced by injecting autologous blood into the cistern magna in New Zealand White rabbits randomized to two groups: nimodipine (n=14) or control (n=12). Subcutaneous nimodipine (2.5 mg/kg) was given one hour after SAH, and every 24 hours after this for the duration of the study. CT Perfusion (CTP) and CT angiography (CTA) were used to measure CBF and basilar artery (BA) diameter at baseline, 10, 30, and 60 minutes after SAH, and on day 3,5,7,9, and 16. Neurological assessments were performed by a blinded observer on each day of scanning. There was no difference in the incidence or severity of VSP between the control and nimodipine groups (p > 0.05). When VSP >15%, nimodipine significantly increased CBF in the brainstem, cerebellum, parieto-occipital cerebrum, and subcortical regions (p < 0.05) (See figure 1). Nimodipine had no effect on CBF when all degrees of VSP were included in the analysis. The degree of neurological deficit was less in the nimodipine group compared to the control group (p < 0.05). We demonstrated that CTP and CTA imaging can quantify arterial VSP and CBF changes in a rabbit SAH model and that these techniques may be useful for evaluating the potential of new therapies for SAH compared to, or in the presence of, nimodipine. Specifically, we showed that nimodipine improves neurological outcome and increases CBF in the presence of moderate or severe VSP.

Calcium Antagonists in Aneurysmal Subarachnoid Hemorrhage

Section Editors: Geoffrey A. Donnan MD, FRACP Stephen M. Davis MD, FRACP Secondary ischemia is a frequent cause of poor outcome in patients with subarachnoid hemorrhage (SAH). The cause of secondary ischemia is unknown, but may be related to vasospasm, at least in part. In experimental studies calcium antagonists prevent or reverse vasospasm and have neuroprotective properties. Various types of calcium antagonists have been studied in several clinical trials. To determine the effectiveness of calcium antagonists for improving outcome in patients with aneurysmal SAH. ### Search Strategy We searched the Cochrane Stroke Group Trials Register (September 2003). In addition, we searched MEDLINE (1966 to October 2003) and EMBASE (1980 to October 2003), hand-searched two Russian journals (1990 to 2003), and contacted trialists …

Nimodipine selectively stimulates β-amyloid 1–42 secretion by a mechanism independent of calcium influx blockage

Several lines of evidence indicate that perturbed cellular Ca 2+ homeostasis may play a prominent role in synaptic dysfunction and neuronal death in Alzheimer's disease (AD), suggesting a potential benefit of drugs capable to stabilize Ca 2+ homeostasis. We here investigated the effects of a panel of L-type Ca 2+ channel antagonists on the secretion of the amyloid β-peptide (Aβ), which abnormally accumulates in the senile plaques of the brain of AD patients. We found that, in primary and immortalized neuronal cells in culture, nimodipine robustly stimulated secretion (up to about four-fold at 30 μM) of the highly amyloidogenic 42-residue isoform of Aβ (Aβ42), while leaving largely unaffected total Aβ secretion. An analogous effect was also observed in vivo , as the administration of a single dose of nimodipine (10 mg/kg i.p.) induced a significant rise of Aβ42 levels in plasma of Tg2576 mice. The effect of nimodipine was independent of blockage of L-type Ca 2+ channels and capacitative calcium entry. Accordingly, nimodipine effect was largely Ca 2+-independent, as neither depletion nor rise of extracellular Ca 2+ abolished it. Hence, by showing that the effect of nimodipine on Aβ42 production is distinct from its ability to block Ca 2+-influx pathways, we provide evidence for a previously uncharacterized effect of this long known molecule also used in clinical practice.

Single-dose nimodipine normalizes impaired retinal circulation in normal tension glaucoma.

Several studies indicate that calcium channel blockers improve the clinical course of normal tension glaucoma (NTG), whereas the underlying mechanism is not fully investigated. Hemodynamic improvement and neuroprotective effects are discussed. In this study, we measured the hemodynamic effects of nimodipine on retinal circulation. Sixteen patients with NTG and clinical signs of vasospastic hyperreactivity, such as suffering from extremely cold hands and feet, were consecutively selected out of the local glaucoma registry. Ten healthy age-matched volunteers were included as controls. Retinal capillary blood flow was measured by Scanning Laser Doppler Flowmetry in both eyes before and 90 +/- 10 minutes after a single oral dose of 30 mg nimodipine. Before administration of nimodipine, retinal capillary blood flow was significantly reduced in NTG patients compared with controls (262 +/- 80 vs. 487 +/- 164 AU, P < 0.001). Nimodipine increased retinal capillary blood flow in NTG patients by 91 +/- 73% (P < 0.001) to values of healthy controls (440 +/- 113 vs. 439 +/- 123 AU, P = 0.635). In controls, nimodipine did not show significant effects. In NTG patients with additional vasospastic symptoms, retinal capillary blood is significantly reduced in comparison with healthy controls. Single-dose nimodipine yields to a normalization of retinal circulation in NTG patients up to values of healthy controls 90 minutes after drug administration.

Nimodipine modulates Bcl-2 and Bax mRNA expression after cerebral ischemia.

In order to explore whether the member of Bcl-2 gene family, for example, Bcl-2 and Bax, are induced after cerebral ischemia, and whether expression of genes can be modulated by calcium-antagonist, the rat cerebral ischemic models were made by occluding left middle cerebral artery. The expression of Bcl-2 and Bax mRNA was measured by RT-PCR method. After middle cerebral artery occlusion (MCAO), the expression of both Bcl-2 and Bax mRNA were induced. Level of Bcl-2 mRNA increased steadily and level of Bax mRNA increased gradually at first, reached a peak after 24 h, then decreased slowly. After administration of nimodipine, Bcl-2 mRNA was up-regulated in the hippocampus 6 and 24 h after ischemia, while Bax mRNA was down-regulated 6 and 24 h after ischemia. Focal cerebral ischemia can induce proto-oncogenes to express, which was associated with apoptosis. Calcium-antagonist can up-regulate Bcl-2 mRNA and down-regulate Bax mRNA. The increased ratio of Bcl-2 and Bax mRNA may contribute to the anti-apoptic effect of nimodipine. The study indicates that pharmacological modulation of Bcl-2 family member expression could become a new strategy to manage neuronal damage.

Effects of nimodipine on the behavioral sequalae of experimental status epilepticus in prepubescent rats

Objective. The goal of this study was to investigate the potential protective effects of nimodipine (ND), a calcium channel blocker, on the acute manifestations and long-term behavioral sequalae of experimental status epilepticus (SE). Methods. Three groups of Postnatal Day (P) 35 rats undergoing kainic acid (KA)-induced SE were injected with phenobarbital (PB) and/or ND, and were subsequently compared with rats injected with KA alone and normal control rats. Behavioral parameters were assessed by the Morris water maze, open field, and handling tests at P125–P135. Acute seizures and spontaneous recurrent seizures (SRS) were assessed by videotape techniques. Results. PB reduced the severity of SE acutely, and protected completely against subsequent long-term SRS, memory impairment, and hyperactivity, and partially against aggressivity. ND alone had no effect on acute seizure activity, but did protect against subsequent SRS and memory impairment, and partially against aggressivity. When administered together, PB and ND had effects similar to those seen with PB alone. However, in addition, and unlike the PB- and ND-alone groups, the PB–ND group was completely protected against KA-induced increased aggressivity. Conclusions. Activation of L-type calcium channels contributes to the long-term behavioral sequalae of KA-induced SE, but is not essential for the development and maintenance of SE. ND has protective effects in SE when given alone or in conjunction with a traditional antiepileptic drug. Calcium channel blockers should be further investigated as add-on protective agents in models of SE and possibly in clinical trials.

Nimodipine does not affect the flow-metabolism couple in permanent cerebral ischemia.

Despite widespread investigational and clinical usage of the calcium channel blocker nimodipine, its effects on cerebral physiology in normal and ischemic brain remain poorly understood. In order to gain insight into this subject we examined the effects of nimodipine on glucose metabolism and cerebral blood flow-metabolism coupling in the rat during conditions of reproducible focal ischemia. Nimodipine-treated animals were then matched with vehicle-treated controls for both study conditions. Animals were subjected to permanent occlusion of the middle cerebral artery (MCA) along with occlusion of the common carotid arteries. Five minutes into ischemia, an intravenous infusion of nimodipine (1 micro g/kg per min, n=9) or vehicle ( n=9) was initiated and continued until the end of the study. Seventy-five minutes after the occlusion, [14C]2-deoxyglucose was injected into the venous catheter for the measurement of the local cerebral metabolic rate for glucose (LCMRgl), followed 25 min later by the injection of N-isopropyl-[123I] p-iodoamphetamine for the measurement of local cerebral blood flow (LCBF). The animals were killed at the end of 2 h of ischemia, and the brains were processed for double-labeled autoradiography. In all animals, permanent MCA occlusion produced significant decrements in LCBF, LCMRgl, and LCBF/LCMRgl ratio in both the core of the ischemia as well as regions peripheral to the ischemia within the same cerebral hemisphere when compared with non-ischemic brain. There were no significant differences between the nimodipine-treated and vehicle-treated groups. In conclusion, nimodipine does not appear to alter cerebral blood flow or cerebral metabolism in ischemic brain.

Effect of Nimodipine on Histological Alterations in Basilar Artery Following the Bilateral Common Carotid Artery Ligation (Preliminary Study)

The blood supply to tissues is reduced as a result of arterial occlusions. Angiogenesis, collateral circulation and reverse flow mechanisms go into operation to restore a continued adequate supply of blood. Ca++ channels undertake the major part of this function. As a result of the increasing tension on the arterial walls, vascular autonomy is affected, and ischemia and even necrosis are observed. Adult 100 male hybrid rabbits were used in this study. The bilateral carotid arteries were ligated at the carotid bifurcation. The rabbits were divided into 2 main groups: treatment and control, and then both groups were further divided into 5 subgroups consisting of 10 rabbits each. The rabbits were sacrificed between the first day and the end of 8 weeks for histopathological examination of the basilar artery in two groups. In control groups, after 24 hours of the occlusion partial swelling and minor endothelial damage were observed in histopathological sections of the basilar artery. Luminal flattening started to decrease, and expanding of the diameter continued. The increase in the diameters of the basilar artery was higher in animals treated by nimodipine, and that difference was statistically significant (P=0,000). This study revealed that the intimal and medial alterations arising from the increased blood flow rate in the basilar artery might be lessened and even partially prevented by the use of nimodipine.

Calcium channel blockers for acute traumatic brain injury.

Acute traumatic brain injury is a major cause of death and disability. Calcium channel blockers have been used in an attempt to prevent cerebral vasospasm after injury, maintain blood flow to the brain and so prevent further damage. To estimate the effects of calcium channel blockers in patients with acute traumatic brain injury and in a subgroup of brain injury patients with traumatic subarachnoid haemorrhage. Hand searching and electronic searching for randomized controlled trials available by October 1997. Randomized controlled trials in patients with all levels of severity of clinically diagnosed acute traumatic brain injury. Two reviewers (JL and CG) independently assessed the identified studies for eligibility and extracted data from each study. Summary odds ratios were calculated using the Mantel-Haenszel method. Four RCTs were identified as eligible for inclusion in the systematic review. The effect of calcium channel blockers on the risk of death was reported in all RCTs. The pooled odds ratio for the four studies was 0.91 (95% confidence interval 0. 70 to 1.17). For the three RCTs that reported death and severe disability the pooled odds ratio was 0.85 (95% CI 0.68 to 1.07). In the two RCTs which reported the risk of death in a sub group of traumatic subarachnoid haemorrhage patients, the pooled odds ratio was 0.59 (95% CI 0.37 to 0.94). Three RCTs reported death and severe disability as an outcome in this subgroup, and the pooled odds ratio was 0.67 (95% CI 0.46 to 0.98). This systematic review of randomized controlled trials of calcium channel blockers in acute traumatic head injury patients shows that considerable uncertainty remains over their effects. The effect of nimodipine in a subgroup of brain injury patients with subarachnoid haemorrhage shows a beneficial effect, though the increase in adverse reactions suffered by the intervention group may mean that the drug is harmful for some patients.

The effects of nimodipine on coronary flow, nitrite outflow and superoxide anion release in isolated rat heart

The effects of Ca2+ channel antagonist nimodipine (also known as phosphodiesterase-1 inhibitor-PDE1) were examined on coronary flow, endothelial NO production (nitrite outflow) and superoxide anion production. The experiments were performed on isolated rat hearts from male Wistar albino rats (BM about 200 g, 8 weeks) and perfused with buffer at constant pressure. The nitrite outflow and superoxide anion release were estimated by spectrophotometry. The coronary autoregulation (CA) was investigated with follow-up of coronary perfusion pressure (CPP) changes from 40 to 120 cm H2O. After first sequence of CPP changes (basic protocol), the hearts were perfused with nimodipine (in concentration known to elicit PDE1 inhibition, 2 mM) alone or in combination with nitric oxide synthase inhibitor (L-NAME, 30 mM). During control state the hearts exhibit CA between 50 and 90 cm H2O; with basal coronary flow at 60 cm H2O of 4.42±0.71 ml/min. Basal nitrite outflow and superoxide anion release (O2-) were 0.64±0.18 nmol/min/g wt and 19.72 nmol/min/g wt, respectively. Nimodipine induced significant vasodilatation at all values of CPP (from 26 % to 36 %). Nimodipine-induced dilation was accompanied with significant decrease of nitrite outflow at all values of CPP (from 59 % at 40 cm H2O to 40 % at 120 cm H2O) and with significant increase of O2- release (from 186 % at 40 cm H2O to 117 % at 120 cm H2O). However, perfusion with L-NAME completely reversed the effects of nimodipine-induced inhibition. Nimodipine-induced dilation was decreased under L-NAME (from 3 % at 40 cm H2O to 11 % at 120 cm H2O) without changes in autoregulatory range. Nitrite outflow was significantly increased under L-NAME until 90 cm H2O (from 69 % at 40 cm H2O to 36 % at 90 cm H2O) as well as O2- release was significantly decreased at all CPP-values (from 50 % at 40 cm H2O to 43 % at 120 cm H2O).The findings show that effects of nimodipine on coronary flow should be significantly influenced by NO and O2- release in isolated rat heart.

L-type voltage-gated calcium channels are involved in the in vivo and in vitro expression of fear conditioning.

Fear conditioning, a behavioral model of fear learning and cue-related anxiety, causes enhanced neuronal transmission in the thalamic to lateral amygdala pathway.(1,2) In the expression phase of learned fear, this increased transmission recorded in vitro is revealed in increased amplitudes of excitatory postsynaptic currents (EPSCs) and occlusion of paired-pulse facilitation (PPF) implicating a presynaptic increase in transmitter release. Here we examined the contribution of L-type calcium channels in fear conditioning. We measured the effect of nimodipine (Nim, 1.5-20 mg/kg), an L-type calcium channel antagonist, on fear-potentiated startle in which startle was assessed in animals receiving paired or unpaired tone and foot shock. Nim administered intraperitoneally blocked fear-potentiated startle but not baseline startle in a dose-dependent manner. We also analyzed the effect of Nim (10 micro M) in vitro on synaptic facilitation of EPSCs and PPF in slices from naïve control, unpaired control, and fear-conditioned animals. In neurons from naïve control animals, Nim had no effect on EPSC amplitude or PPF, but in slices from fear-conditioned rats, Nim reduced EPSC amplitude, suggesting the recruitment of L-type calcium channels within the fear-conditioning pathway. Nim increased PPF in slices from fear-conditioned animals, suggesting that L-type calcium channels may contribute to increased probability of release in fear conditioning. In slices from unpaired animals, Nim decreased synaptic transmission but had little effect on PPF, suggesting that stress or contextual fear learning may induce L-type channel activity in fear-conditioned and unpaired control animal groups. We also analyzed protein expression of the alpha(1C) and alpha(1D) L-type calcium channel subunits isolated from the amygdala and found that alpha(1C) protein was significantly increased in fear-conditioned animals. These findings suggest that L-type calcium channels play a role in the amygdala in cued fear conditioning and have important implications in the treatment of anxiety and in emotional learning and plasticity.

The effects of calcium channel antagonist nimodipine on end-plate vascularity of the degenerated intervertebral disc in rats

The vascular channels at the end-plate of the intervertebral disc are very important in maintaining a healthy disc. With age, a reduction of the nutrition of the avascular nucleus pulposus is inevitable. On the other hand the calcium channel antagonist nimodipine has been shown to have a positive effect on blood flow in the region of the vertebral end-plate. To evaluate the effects of nimodipine on the end-plate vascularity in the degenerative discs, we have produced an experimental disc degeneration and evaluated the radiological and histopathological features of the end-plate of the degenerated discs. Adult rats were divided into 3 groups: control ( n=5), operated degeneration ( n=5), and nimodipine treatment ( n=5). Using a posterior approach, a cut was made parallel to the end-plates in the posterior annulus fibrosus in 5 consecutive intervertebral discs between the 5th and 10th vertebral segments of the tails of adult Swiss Albino rats. At 8 weeks, 5 of these animals were treated with nimodipine. In each experimental group, 1 animal was examined using computed tomography (CT) to study the density of the cartilage end-plate of the disc. Then, the animals were sacrificed for subsequent histopathological evaluation. We found that the vascular channel counts and percentage areas from animals treated with nimodipine were higher than from both the non-operative control and operated degeneration groups, although these were not statistically different. Accordingly, the profile of the density histogram in the nimodipine-treated group showed a wide plateau, indicating an increase in the vascularity in this region. From our results, we suggest that nimodipine enhances vascularisation of the cartilage end-plate in the disc. It is possible that the increased proportion of vascular contacts at the end-plate has a beneficial effect in the nutrition of the disc. However, further experimental studies will be needed to determine the validity of this statement in animals or human beings.

Effects of nimodipine on quinine ototoxicity.

The compound action potential (CAP) in response to a click train stimulus was recorded at the round window of guinea pigs. Administration of quinine hydrochloride (200 mg/kg) significantly elevated the CAP thresholds by 5 to 25 dB (p < .05), and the CAP waveform elicited by the click train stimulus was abnormal. The amplitude of the CAP elicited by the second click was bigger than that elicited by the first click. These changes may be caused by an abnormally broadened N1 response to the first click in the click train. In contrast, CAP waveforms elicited by the second and subsequent clicks appeared normal. After administration of nimodipine (2 mg/kg), the CAP thresholds and waveforms elicited by the click train stimulus were unchanged. Simultaneous administration of both quinine (200 mg/kg) and nimodipine (2 mg/kg) resulted in the same electrophysiological changes as those induced by quinine alone. These results suggest that nimodipine prevents neither the deterioration in the CAP nor the abnormal properties in the response to a click train stimulus.

Ischemia Triggered by Red Blood Cell Products in the Subarachnoid Space Is Inhibited by Nimodipine Administration or Moderate Volume Expansion/Hemodilution in Rats

It has been proposed that delayed ischemic neurological deficits are induced by red blood cell (RBC) products after subarachnoid hemorrhage. Prophylactic treatment with the Ca2+ antagonist nimodipine or prevention of systemic volume contraction reduces the occurrence of delayed ischemic neurological deficits. To gain insight into the underlying mechanism, we studied the effects of nimodipine or volume expansion on ischemic events induced by RBC products in rats. A cranial window was implanted in 52 rats. At the window, cerebral blood flow (measured with laser Doppler flowmetry) and the subarachnoid direct current potential were recorded; the cortical surface was superfused with artificial cerebrospinal fluid. A spreading neuronal/astroglial depolarization wave was triggered at a remote site, from which it traveled to the cranial window. In 16 rats, the depolarization wave triggered an ischemic event at the cranial window when artificial cerebrospinal fluid containing the RBC product hemoglobin and elevated K+ levels was superfused. In contrast, in animals receiving intravenously administered nimodipine (n = 12) or moderate volume expansion/hemodilution with hydroxyethyl starch (6% hydroxyethyl starch 200/0.5) (n = 10), the depolarization wave triggered brief initial hypoperfusion, followed by brief hyperemia, in the cortical area exposed to the RBC products. Under physiological conditions, the depolarization wave triggered brief hyperemia (n = 14). Spreading ischemia induced by RBC products is antagonized by measures known to be beneficial in the prophylaxis of delayed ischemic neurological deficits. Our findings suggest that a mechanism involving the cortical microcirculation might underlie the therapeutic effects of nimodipine and volume expansion.

Effects of nimodipine on salicylate ototoxicity.

The purpose of this study was to examine the effects of nimodipine on salicylate ototoxicity in guinea pigs. The compound action potential (CAP) was recorded at the round window, and the cochlear blood flow (CBF) was measured simultaneously from the lateral wall of the basal turn of the cochlea by laser Doppler flowmetry. After administration of salicylate (100 mg/kg), the CAP thresholds were significantly elevated, by 5 to 20 dB (p < .05), and the CBF was significantly decreased (p < .05). After administration of nimodipine (2 mg/kg), the CAP thresholds were unchanged, but the CBF had increased significantly (p < .05), while systemic blood pressure had decreased significantly (p < .05). Simultaneous administration of both salicylate (100 mg/kg) and nimodipine (2 mg/kg) resulted in significant elevation of the CAP thresholds (p < .05), while the CBF did not decrease. These results suggest that nimodipine prevents the decrease in CBF induced by salicylate, but that nimodipine does not prevent the deterioration in the CAP.

The L-type calcium channel blocker nimodipine mitigates “learned helplessness” in rats

We assessed the effect of nimodipine, an L-type calcium channel blocker, on the escape deficit induced by prior exposure to inescapable shock in rats in four experiments. In Experiment 1, we injected rats at each of three time points (i.e., before shock exposure, after shock exposure, and before shuttle escape testing) with one of four doses of nimodipine (0, 0.5, 2.5, 5.0 mg/kg). The 5.0-mg/kg dose was most effective, acting to reduce shuttle escape latencies of inescapably shocked rats to a level comparable with nonshocked controls. No benefit occurred in Experiment 2, however, when nimodipine was administered at only one of the three time points used in the first experiment. Moreover, escape performance did not improve when rats received injections of nimodipine on the 2 days prior the experiment, and then one additional injection at one of the three time points identified above in Experiment 3. Finally, administration of nimodipine at two of the three time points did improve escape responding, but only when injected immediately prior both to shock exposure and the shuttle escape test.

Intracellular Calcium Involved in the Long-Term Potentiation Induced by Securinine in Dentate Gyrus of Anesthetized Rats

The effect of nimodipine on securinine-induced long-term potentiation in rat hippocampus was studied. The rise of intracellular calcium during the induction of long-term potentiation was measured using Fura-2/AM--a Ca (2+) fluorescent chelator. Results showed that intracerebroventricular injection of nimodipine (4 nmol) blocked the induction of long-term potentiation elicited by securinine (0.4 pmol) and high-frequency stimulation (p < 0.05), but 2-amino-5-phosphonovaleric acid (5 nmol) had no inhibitory effect on securinine-induced long-term potentiation. In addition, securinine-induced intracellular calcium increment was inhibited by nimodipine (10(-6) mol. L(-1), p < 0.01), but not by 2-amino-5-phosphonovaleric acid (10(-6) mol. L(-1), p > 0.05).

Nimodipine for primary degenerative, mixed and vascular dementia.

Dementia is an age-related condition in which Alzheimer's disease (AD) and cerebrovascular disease account for the bulk of cases. The role played by calcium in regulating brain functions is well known - the calcium ion links membrane excitation to subsequent intracellular enzymatic response. Change in calcium homeostasis is one important effect of aging with repercussions on higher cortical functions. Nimodipine is an isopropyl calcium channel blocker which can easily cross the blood brain barrier. Its primary action is to reduce the number of open channels, thus restricting influx of calcium ions into the cell. The usefulness of nimodipine in patients with Alzheimer's disease and vascular dementia and unspecified dementia is still controversial with mixed results. In spite of the uncertainties about its efficacy in dementia, nimodipine is currently a frequently prescribed drug for cognitive impairment and dementia in several European countries. This review will be conducted in two phases; the current review is based on evidence from published data only. The second phase will be based on individual-patient data analysed centrally and added to this review in due course. To determine the clinical efficacy of nimodipine for the symptoms of dementia, either unclassified or according to the major subtypes - Alzheimer's disease, vascular, or mixed Alzheimer's and vascular dementia. The Cochrane Dementia Group Register of Clinical Trials was searched using the terms 'nimodipine' and 'isopropyl (2-methoxy-ethyl) 1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinedicarboxylate'. All unconfounded, double-blind, randomised trials in which treatment with nimodipine was administered for more than a day and compared to placebo in patients with dementia, either unclassified or according to the major subtypes - Alzheimer's disease, vascular, or mixed Alzheimer's and vascular dementia. Data were extracted independently by the reviewers and the odds ratio (95%CI) or the average difference (95%CI) were estimated. Both intention-to-treat and on-treatment results were extracted. This review produced no clear results. Many of the data published were not capable of being sensibly pooled. The data were compatible with nimodipine producing improvement, no change or even harm for those with Alzheimer's disease, vascular dementia, or mixed Alzheimer's and vascular dementia. It was not possible to use many of the published results in a combined analysis. For measures of overall clinical improvement, the intention-to-treat analysis, based on one study only, failed to detect any difference between nimodipine and placebo (OR 0.53; 95%CI 0.25 - 1.13). An on-treatment analysis, based on one study only, produced a statistically significant difference in favour of nimodipine (SMD 4.4; 95%CI 3.9 - 5.0). For cognitive function, the effect of nimodipine was statistically significantly different from placebo for the Mini Mental State Examination score (0-30; high =good) (SMD 0.9; 95%CI 0.59 - 1.22) and there was a statistically significant effect in favour of treatment for the Wechsler Memory Scale (SMD 0.47; 95%CI 0.17 - 0.77). These analyses were based only on those who completed the study and not intention-to-treat analyses. There were no results presented in a form suitable for pooling for functional autonomy, behaviour, quality of life dependency (eg institutionalization), effect on carer, death, acceptability of treatment (as measured by withdrawal rate, safety (as measured by the incidence of adverse effects, including side effects, leading to withdrawal). This review provides no convincing evidence that nimodipine is a useful treatment for the symptoms of dementia, either unclassified or according to the major subtypes - Alzheimer's disease, vascular, or mixed Alzheimer's and vascular dementia. (ABSTRACT TRUNCATED)