Applications of isradipine in human addiction studies: A systematic literature review.

Given the personal and public health burden of addictive disorders, innovative approaches to treatment are sorely needed. This systematic review examined the use of the pharmacological agent isradipine in the context of potential applications for addiction treatment. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guided a comprehensive search of PubMed, Cochrane Library, and PsycINFO between the years 1985 to July 2022. Studies were included if isradipine was administered to adults with a current Diagnostic and Statistical Manual of Mental Disorders-5th edition diagnosis of a substance use disorder and/or to healthy volunteers alone and in conjunction with a substance (i.e, cocaine, methamphetamine, alcohol). A total of 16 studies with 252 participants were included in this review. Substantial variability was identified with study designs, isradipine dosages/dosing, and addictive substance of interest. Outcomes clustered in four categories: (a) cerebral blood flow (CBF), (b) hemodynamic effects, (c) subjective effects, and (d) cognitive effects. Isradipine was found to improve CBF in individuals with cocaine-induced hypoperfusion and in several studies was found to reduce parameters of blood pressure elevation after stimulant use. There were no significant findings on isradipine's effect on subjective reporting (i.e., craving, mood, drug affect) or cognition/attention. Given the limited number of studies identified in this review, there is insufficient data to draw clear conclusions. The direct effects of isradipine as a pharmacologic agent for addictive disorder treatment appear minimal, however, future work may benefit from examining the impact of isradipine as an augmentative agent within existing cue exposure paradigms for preventing cue-induced drug relapse. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Re-Analysis of the STEADY-PD II Trial-Evidence for Slowing the Progression of Parkinson's Disease.

BACKGROUND: Recent examination of the STEADY-PD III isradipine clinical trial data concluded that early-stage Parkinson's disease (PD) participants who had longer exposure to isradipine had a significant delay in their need for symptomatic medication, as well as a lower medication burden at the end of the trial. These findings suggest that greater exposure to isradipine might slow disease progression. OBJECTIVES: To test this hypothesis, the data from the STEADY-PD II isradipine clinical trial, in which an extended-release (ER) formulation of the drug was used, was re-examined. METHODS: The re-analysis of the STEADY-PD II data was restricted to participants assigned placebo or tolerable isradipine treatment (10 mg isradipine/day or less). The effect of isradipine treatment was assessed by Unified Parkinson's Disease Rating Scale (UPDRS) at the end of the 52-week trial, rather than by last observation carried forward at the beginning of symptomatic therapy. RESULTS: Participant cohorts were well-matched for baseline disability, initial disease progression, and time to initiation of symptomatic therapy. Participants given 10 mg/day ER isradipine had significantly smaller total and part 3 UPDRS scores at the end of the trial than did the placebo cohort. Post hoc adjustment for symptomatic therapy diminished the statistical significance of these differences. In those participants not taking a monoamine oxidase B inhibitor, the progression in UPDRS scores also was significantly reduced. CONCLUSIONS: These results are consistent with the recent secondary analysis of the STEADY-PD III clinical trial-suggesting that clinically attainable brain exposure to isradipine may slow early-stage PD progression. © 2021 International Parkinson and Movement Disorder Society.

Adjunctive Raloxifene and Isradipine Improve Cognitive Functioning in Patients With Schizophrenia: A Pilot Study.

BACKGROUND: Cognitive impairment is the most important feature of schizophrenia leading to severe functional disability. To identify pathways that improve pathophysiological neurocognition in schizophrenia is a current challenge for the development of goal-directed clinical interventions. In the present study, we investigated the effects of raloxifene (a selective estrogen modulator) and isradipine (a voltage-gated L-type calcium channel blocker) on cognitive deficits in patients with schizophrenia. METHOD: We designed a double-blind, randomized, parallel, placebo-controlled trial. We randomized 60 patients with schizophrenia into 3 groups including isradipine 5 mg, raloxifine 60 mg, and placebo for 6 consequent weeks, all in the same shape capsules, 2 times a day, along with treatment as usual. The initial and final results of blood tests, electrocardiograms, and cognitive tests in specific domains, such as attention, processing speed, executive function, and verbal memory were evaluated. RESULTS: Our findings revealed a remarkable association between adjunctive raloxifene treatment and the alleviation of verbal memory deficits. Isradipine treatment significantly improved the verbal memory and attention dysfunction in some variables of the Stroop test, compared with the placebo. However, no effect was observed in processing speed and executive function deficits. CONCLUSIONS: To the best of our knowledge, this study provides the first evidence that isradipine is a novel therapy option improving verbal memory and attention, both related to its activity in the hippocampus and the cerebellum. Further investigations are necessary to elucidate the mechanisms of action for both drugs in schizophrenia.

Isradipine Versus Placebo in Early Parkinson Disease: A Randomized Trial.

Background: Studies suggest that dihydropyridine calcium-channel blockers may be associated with reduced risk for Parkinson disease (PD). Objective: To assess the effect of isradipine, a dihydropyridine calcium-channel blocker, on the rate of clinical progression of PD. Design: Multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT02168842). Setting: 57 Parkinson Study Group sites in North America. Participants: Patients with early-stage PD (duration <3 years) who were not taking dopaminergic medications at enrollment. Intervention: 5 mg of immediate-release isradipine twice daily or placebo for 36 months. Measurements: The primary outcome was change in the Unified Parkinson's Disease Rating Scale (UPDRS) parts I to III score measured in the antiparkinson medication "ON" state between baseline and 36 months. Secondary outcomes included time to initiation and use of antiparkinson medications, time to onset of motor complications, change in nonmotor disability, and quality-of-life measures. Results: 336 patients were randomly assigned (mean age, 62 years [SD, 9]; 68% men; disease duration, 0.9 year [SD, 0.7]; mean UPDRS part I to III score, 23.1 [SD, 8.6]); 95% of patients completed the study. Adjusted least-squares mean changes in total UPDRS score in the antiparkinson medication ON state over 36 months for isradipine and placebo recipients were 2.99 (95% CI, 0.95 to 5.03) points versus 3.26 (CI, 1.25 to 5.26) points, respectively, with a treatment effect of -0.27 (CI, -3.02 to 2.48) point (P = 0.85). Statistical adjustment for antiparkinson medication use did not change the findings. Secondary outcomes showed no effect of isradipine treatment. The most common adverse effects of isradipine were edema and dizziness. Limitation: The isradipine dose may have been insufficient to engage the target calcium channels associated with neuroprotective effects. Conclusion: Long-term treatment with immediate-release isradipine did not slow the clinical progression of early-stage PD. Primary Funding Source: National Institute of Neurological Disorders and Stroke.

Identification of antiparkinsonian drugs in the 6-hydroxydopamine zebrafish model.

Parkinson's disease (PD) is known as a movement disorder due to characteristic motor features. Existing therapies for PD are only symptomatic, and their efficacy decreases as disease progresses. Zebrafish, a vertebrate in which parkinsonism has been modelled, offers unique features for the identification of molecules with antiparkinsonian properties. Here, we developed a screening assay for the selection of neuroactive agents with antiparkinsonian potential. First, we performed a pharmacological validation of the phenotypes exhibited by the 6-hydroxydopamine zebrafish model, by testing the effects of known antiparkinsonian agents. These drugs were also tested for disease-modifying properties by whole mount immunohistochemistry to TH+ neurons and confocal microscopy in the dopaminergic diencephalic cluster of zebrafish. Next, we optimized a phenotypic screening using the 6-hydroxydopamine zebrafish model and tested 1600 FDA-approved bioactive drugs. We found that 6-hydroxydopamine-lesioned zebrafish larvae exhibit bradykinetic and dyskinetic-like behaviours that are rescued by the administration of levodopa, rasagiline, isradipine or amantadine. The rescue of dopaminergic cell loss by isradipine was also verified, through the observation of a higher number of TH+ neurons in 6-OHDA-lesioned zebrafish larvae treated with this compound as compared to untreated lesioned larvae. The phenotypic screening enabled us to identify several compounds previously positioned for PD, as well as, new molecules with potential antiparkinsonian properties. Among these, we selected stavudine, tapentadol and nabumetone as the most promising candidates. Our results demonstrate the functional similarities of the motor impairments exhibited by 6-hydroxydopamine-lesioned zebrafish with mammalian models of PD and with PD patients, and highlights novel molecules with antiparkinsonian potential.

Calcium antagonists for acute ischemic stroke.

BACKGROUND: The sudden loss of blood supply in ischemic stroke is associated with an increase of calcium ions within neurons. Inhibiting this increase could protect neurons and might reduce neurological impairment, disability, and handicap after stroke. OBJECTIVES: To assess the effects of calcium antagonists for reducing the risk of death or dependency after acute ischemic stroke. We investigated the influence of different drugs, dosages, routes of administration, time intervals after stroke, and trial design on the outcomes. SEARCH METHODS: The evidence is current to 6 February 2018. We searched the Cochrane Stroke Group Trials Register (6 February 2018), Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 2), MEDLINE Ovid (1950 to 6 February 2018), Embase Ovid (1980 to 6 February 2018), and four Chinese databases (6 February 2018): Chinese Biological Medicine Database (CBM-disc), China National Knowledge Infrastructure (CNKI), Chinese Scientific Periodical Database of VIP information, and Wanfang Data. We also searched the following trials registers: ClinicalTrials.gov, EU Clinical Trials Register, Stroke Trials Registry, ISRCTN registry, WHO International Clinical Trials Registry Platform, and Chinese Clinical Trial Registry, and we contacted trialists and researchers. SELECTION CRITERIA: Randomized controlled trials comparing a calcium antagonist versus control in people with acute ischemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, assessed risk of bias, and applied the GRADE approach to assess the quality of the evidence. We used death or dependency at the end of long-term follow-up (at least three months) in activities of daily living as the primary outcome. We used standard Cochrane methodological procedures. MAIN RESULTS: We included 34 trials involving 7731 participants. All the participants were in the acute stage of ischemic stroke, and their age ranged from 18 to 85 years, with the average age ranging from 52.3 to 74.6 years across different trials. There were more men than women in most trials. Twenty-six trials tested nimodipine, and three trials assessed flunarizine. One trial each used isradipine, nicardipine, PY108-608, fasudil, and lifarizine. More than half of these trials followed participants for at least three months. Calcium antagonists showed no effects on the primary outcome (risk ratio (RR) 1.05; 95% confidence interval (CI) 0.98 to 1.13; 22 trials; 22 studies; 6684 participants; moderate-quality evidence) or on death at the end of follow-up (RR 1.07, 95% CI 0.98 to 1.17; 31 trials; 7483 participants; moderate-quality evidence). Thirteen trials reported adverse events, finding no significant differences between groups. Most trials did not report the allocation process or how they managed missing data, so we considered these at high risk of selection and attrition bias. Most trials reported double-blind methods but did not state who was blinded, and none of the trial protocols were available. AUTHORS' CONCLUSIONS: We found no evidence to support the use of calcium antagonists in people with acute ischemic stroke.

Try to Remember: Interplay between Memory and Substance Use Disorder.

Memories associated with substance use disorders, or substance-associated cues increase the likelihood of craving and relapse during abstinence. There is a growing consensus that manipulation of synaptic plasticity may reduce the strength of substance abuse-related memories. On the biological front, there are new insights that suggest memories associated with substance use disorder may follow unique neurobiological pathways that render them more accessible to pharmacological intervention. In parallel to this, research in neurochemistry has identified several potential candidate molecules that could influence the formation and maintenance of long-term memory. Drugs that target these molecules (blebbistatin, isradipine and zeta inhibitory peptide) have shown promise at the preclinical stage. In this review, we shall provide an overview of the evolving understanding on the biochemical mechanisms involved in memory formation and expound on the premise that substance use disorder is a learning disorder.

Increasing Efficiency of Recruitment in Early Parkinson's Disease Trials: A Case Study Examination of the STEADY-PD III Trial.

BACKGROUND: Challenges in clinical trial recruitment threaten the successful development of improved therapies. This is particularly true in Parkinson's disease (PD) studies of disease modification where the population of interest is difficult to find and study design is more complex. OBJECTIVE: This paper seeks to understand how STEADY PD III, a National Institute of Neurological Disorders and Stroke (NINDS) funded phase 3 trial evaluating the efficacy of isradipine as a disease modifying agent for PD, was able to recruit their full target population 6 months ahead of schedule. METHODS: STEADY PD III aimed to enroll 336 individuals with early stage idiopathic PD within 18 months using 57 sites across the United States and Canada. The study included a 10% NIH minority recruitment goal. Eligible participants agreed to be followed for up to 36 months, complete 12 in-person visits and 4 telephone visits. A Recruitment Committee of key stakeholders was critical in the development of a comprehensive recruitment strategy involving: multi-modal outreach, protocol modifications and comprehensive site selection and activation. Efforts to increase site-specific minority recruitment strategies were encouraged through additional funding. RESULTS: A total of 336 individuals, including 34 minorities, were enrolled within 12 months - 6 months ahead of the projected timeline. Quantitative analysis of recruitment activity questionnaires found that of the sites that completed them (n = 54), (20.4%) met goals, (24.1%) exceeded goals, and (55.6%) fell below projected goals. Referral sources completed at time of screening indicate top four study referral sources as: site personnel (53.8%); neurologists (24%); Fox Trial Finder (10.2%); and communications from The Michael J. Fox Foundation (3.9%). CONCLUSIONS: STEADY PD III serves as an important example of methods that can be used to increase clinical trial recruitment. This research highlights a continued need to improve site infrastructure and dedicate more resources to increased participation of minorities in clinical research.

Neuroprotective and Neuro-restorative Effects of Minocycline and Rasagiline in a Zebrafish 6-Hydroxydopamine Model of Parkinson's Disease.

Parkinson's disease is a common, debilitating, neurodegenerative disorder for which the current gold standard treatment, levodopa (L-DOPA) is symptomatic. There is an urgent, unmet need for neuroprotective or, ideally, neuro-restorative drugs. We describe a 6-hydroxydopamine (6-OHDA) zebrafish model to screen drugs for neuroprotective and neuro-restorative capacity. Zebrafish larvae at two days post fertilization were exposed to 6-OHDA for three days, with co-administration of test drugs for neuroprotection experiments, or for 32 h, with subsequent treatment with test drugs for neuro-restoration experiments. Locomotor activity was assessed by automated tracking and dopaminergic neurons were visualized by tyrosine hydroxylase immuno-histochemistry. Exposure to 6-OHDA for either 32 h or 3 days induced similar, significant locomotor deficits and neuronal loss in 5-day-old larvae. L-DOPA (1 mM) partially restored locomotor activity, but was neither neuroprotective nor neuro-restorative, mirroring the clinical situation. The calcium channel blocker, isradipine (1 µM) did not prevent or reverse 6-OHDA-induced locomotor deficit or neuronal loss. However, both the tetracycline analog, minocycline (10 µM), and the monoamine oxidase B inhibitor, rasagiline (1 µM), prevented the locomotor deficits and neuronal loss due to three-day 6-OHDA exposure. Importantly, they also reversed the locomotor deficit caused by prior exposure to 6-OHDA; rasagiline also reversed neuronal loss and minocycline partially restored neuronal loss due to prior 6-OHDA, making them candidates for investigation as neuro-restorative treatments for Parkinson's disease. Our findings in zebrafish reflect preliminary clinical findings for rasagiline and minocycline. Thus, we have developed a zebrafish model suitable for high-throughput screening of putative neuroprotective and neuro-restorative therapies for the treatment of Parkinson's disease.

Calcium Channel Antagonists as Disease-Modifying Therapy for Parkinson's Disease: Therapeutic Rationale and Current Status.

Parkinson's disease is a disabling hypokinetic neurological movement disorder in which the aetiology is unknown in the majority of cases. Current pharmacological treatments, though effective at restoring movement, are only symptomatic and do nothing to slow disease progression. Electrophysiological, epidemiological and neuropathological studies have implicated CaV1.3 subtype calcium channels in the pathogenesis of the disorder, and drugs with some selectivity for this ion channel (brain-penetrant dihydropyridine calcium channel blockers) are neuroprotective in animal models of the disease. Dihydropyridines have been safely used for decades to treat hypertension and other cardiovascular disorders. A phase II clinical trial found that isradipine was safely tolerated by patients with Parkinson's disease, and a phase III trial is currently underway to determine whether treatment with isradipine is neuroprotective and therefore able to slow the progression of Parkinson's disease. This manuscript reviews the current information about the use of dihydropyridines as therapy for Parkinson's disease and discusses the possible mechanism of action of these drugs, highlighting CaV1.3 calcium channels as a potential therapeutic target for neuroprotection in Parkinson's disease.

A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development.

l-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of 'brain-selective' LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes.

[Huntington's disease: cellular and molecular basis of pathology].

Huntington's disease (HD) is an inherited autosomal dominant neurodegenerative disorder caused by a polyQ expansion (>36 glutamine repeats) in Huntingtin (Htt) protein. It is believed that dysfunction of corticostriatal system is one of the main pathological events. Special attention is paid to synaptic dysfunction of transmission between cortical and striatal neurons. This review focuses on modern concepts of molecular and cellular mechanisms of HD pathology and especially on alterations in corticostriatal connectivity. Calcium hypothesis of HD and new pharmacological targets are described.

Pilot investigation of isradipine in the treatment of bipolar depression motivated by genome-wide association.

OBJECTIVES: Motivated by genetic association data implicating L-type calcium channels in bipolar disorder liability, we sought to estimate the tolerability, safety, and efficacy of isradipine in the adjunctive treatment of bipolar depression. METHODS: A total of 12 patients with bipolar I or II depression entered this pilot, proof-of-concept eight-week investigation and 10 returned for at least one post-baseline visit. They were initiated on isradipine at 2.5 mg and titrated up to 10 mg daily, with blinded assessments of depression using the Montgomery-Åsberg Depression Rating Scale (MADRS) as well as adverse effects. RESULTS: Among the 10 patients, three had bipolar II disorder; all but two reported current episode duration longer than six months. In all, four of 10 completed the study; no significant adverse events were observed, although one subject discontinued treatment per protocol because of possible hypomanic symptoms which had resolved prior to study visit. In a mixed-effects model, mean improvement in depression severity, assessed by MADRS, was 2.1 (standard error = 0.36) points/week (p < 0.001). Two of the 10 subjects remitted and four of the 10 subjects experienced 50% or greater symptomatic improvement with treatment. CONCLUSIONS: Isradipine merits further investigation for the treatment of bipolar depression. This preliminary trial illustrates the potential utility of genetic investigation in identifying psychiatric treatment targets.

L-type calcium channel blockade alleviates molecular and reversal spatial learning and memory alterations induced by entorhinal amyloid pathology in rats.

The entorhinal cortex (EC) is one of the most vulnerable brain regions that is affected by beta amyloid (Aß) in the early phases of Alzheimer's disease (AD). Calcium dyshomeostasis is one reason of Aß pathology and the role of calcium channel blockers (CCBs) in this phenomenon has not fully understood. In this study, we investigated the possible neuroprotective effect of CCBs, nimodipine and isradipine against amyloid pathogenesis in EC. The Aß 1-42 was injected bilaterally into the EC of male rats and spatial performance was assessed between 7 and 12 days after Aß injection by Morris water maze test. Animals were daily treated by injection of various doses of nimodipine or isradipine (both at 3, 10, or 30 µg/2 µl) or their vehicles into the lateral ventricle until the start of behavioral test. Lesion in EC was assessed by measuring some proteinases involved in calcium dependent apoptotic pathway (calpain 2, caspase 12 and 3). Despite normal performance in probe test, Aß treated rats showed delayed acquisition in a spatial reference memory task. Aß treated rats revealed delayed acquisition in reversal memory and had deficit in probe test. The observed impairments were attenuated by isradipine (10 and 30 µg but not 3 µg) and nimodipine (30 µg). Calpain 2, caspase 12 and 3 were increased in the Aß treated animals which was partially antagonized by isradipine and nimodipine. It is concluded that CCBs might have beneficial therapeutic effects in AD especially in the early phases of this disease.

Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: the case for isradipine.

Alzheimer's disease is the most devastating neurodegenerative disorder in the elderly, yet treatment options are severely limited. The drug development effort to modify Alzheimer's disease pathology by intervention at beta amyloid production sites has been largely ineffective or inconclusive. The greatest challenge has been to identify and define downstream mechanisms reliably predictive of clinical symptoms. Beta amyloid accumulation leads to dysregulation of intracellular calcium by plasma membrane L-type calcium channels located on neuronal somatodendrites and axons in the hippocampus and cortex. Paradoxically, L-type calcium channel subtype Ca(v)1.2 also promotes synaptic plasticity and spatial memory. Increased intracellular calcium modulates amyloid precursor protein processing and affects multiple downstream pathways including increased hyperphosphorylated tau and suppression of autophagy. Isradipine is a Federal Drug Administration-approved dihydropyridine calcium channel blocker that binds selectively to Ca(v)1.2 in the hippocampus. Our studies have shown that isradipine in vitro attenuates beta amyloid oligomer toxicity by suppressing calcium influx into cytoplasm and by suppressing Ca(v)1.2 expression. We have previously shown that administration of isradipine to triple transgenic animal model for Alzheimer's disease was well-tolerated. Our results further suggest that isradipine became bioavailable, lowered tau burden, and improved autophagy function in the brain. A better understanding of brain pharmacokinetics of calcium channel blockers will be critical for designing new experiments with appropriate drug doses in any future clinical trials for Alzheimer's disease. This review highlights the importance of Ca(v)1.2 channel overexpression, the accumulation of hyperphosphorylated tau and suppression of autophagy in Alzheimer's disease and modulation of this pathway by isradipine.

A translational continuum of model systems for evaluating treatment strategies in Alzheimer's disease: isradipine as a candidate drug.

A growing body of evidence supports the 'calcium hypothesis' of Alzheimer's disease (AD), which postulates that a variety of insults might disrupt the homeostatic regulation of neuronal calcium (Ca(2+)) in the brain, resulting in the progressive symptoms that typify the disease. However, despite ongoing efforts to develop new methods for testing therapeutic compounds that might be beneficial in AD, no single bioassay permits both rapid screening and in vivo validation of candidate drugs that target specific components of the Ca(2+) regulatory machinery. To address this issue, we have integrated four distinct model systems that provide complementary information about a trial compound: the human neuroblastoma MC65 line, which provides an in vitro model of amyloid toxicity; a transgenic Drosophila model, which develops age-dependent pathologies associated with AD; the 3×TgAD transgenic mouse, which recapitulates many of the neuropathological features that typify AD; and the embryonic nervous system of Manduca, which provides a novel in vivo assay for the acute effects of amyloid peptides on neuronal motility. To demonstrate the value of this 'translational suite' of bioassays, we focused on a set of clinically approved dihydropyridines (DHPs), a class of well-defined inhibitors of L-type calcium channels that have been suggested to be neuroprotective in AD. Among the DHPs tested in this study, we found that isradipine reduced the neurotoxic consequences of ß-amyloid accumulation in all four model systems without inducing deleterious side effects. Our results provide new evidence in support of the Ca(2+) hypothesis of AD, and indicate that isradipine represents a promising drug for translation into clinical trials. In addition, these studies also demonstrate that this continuum of bioassays (representing different levels of complexity) provides an effective means of evaluating other candidate compounds that target specific components of the Ca(2+) regulatory machinery and that therefore might be beneficial in the treatment of AD.

L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer's disease.

There is strong evidence that intracellular calcium dysregulation plays an important pathological role in Alzheimer's disease, and specifically that beta amyloid may induce increases in intracellular calcium and lead to neuronal cell dysfunction and death. Here we investigated the feasibility of modifying Alzheimer's pathology with the L-type voltage-gated calcium channel blockers verapamil, diltiazem, isradipine and nimodipine. All four compounds protected MC65 neuroblastoma cells from amyloid beta protein precursor C-terminal fragment (APP CTF)-induced neurotoxicity. Isradipine was the most potent blocker, preventing APP CTF neurotoxicity at nanomolar concentrations. Intracellular beta amyloid expression was associated with increased expression of Cav 1.2 calcium channels and increased intracellular calcium influx from the extracellular space. Despite the cytoprotection afforded by calcium channel blockers, amyloid beta oligomer formation was not suppressed. The mechanism of cell death in MC65 cells is appeared to be caspase-3 independent. With the goal of determining if there is sufficient experimental support to move forward with animal trials of isradipine, we determined its bioavailability in the triple transgenic mouse model of AD. Subcutaneous implantation of carrier-bound isradipine (3 µg/g/day) for 60 days resulted in nanomolar concentrations in both the plasma and brain. Taken together, our in vitro results support the theory that calcium blockers exert protective effects downstream of the effects of beta amyloid. Isradipine's neuroprotective effect at concentrations that are clinically relevant and achievable in vitro and in vivo suggests that this particular calcium blocking agent may have therapeutic value in the treatment of Alzheimer's disease.

Tolerability of isradipine in early Parkinson's disease: a pilot dose escalation study.

Recent data suggests that isradipine, a dihydropyridine calcium channel blocker, is neuroprotective in preclinical models of parkinsonism. Isradipine has not been systematically studied in patients with Parkinson's disease (PD). The aim of this study was to evaluate safety and tolerability of isradipine controlled release (CR) in patients with early PD. Qualified subjects (n = 31) received isradipine CR, titrated from 5 to 20 mg daily dose over 8 weeks as tolerated. Eighty-one percent of subjects completed the study. Tolerability of isradipine CR was dose dependent: 94% for 5 mg dose; 87% for 10 mg; 68% for 15 mg; and 52% for 20 mg. Isradipine had no significant effect on blood pressure or PD motor disability. The two most common reasons for dose reduction were leg edema (7) and dizziness (3). There was no difference in isradipine tolerability between subjects with and without dopaminergic treatment, or with and without hypertension.