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

Abstract

SUMMARYA 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 (Ca2+) 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 Ca2+ 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 β-amyloid accumulation in all four model systems without inducing deleterious side effects. Our results provide new evidence in support of the Ca2+ 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 Ca2+ regulatory machinery and that therefore might be beneficial in the treatment of AD.

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

“…Treatment with Aβ 1-42 induces concentration-dependent perturbations in the extent of migration and outgrowth of enteric nervous system. A simultaneous treatment with isradipine prevents the deleterious effects of Aβ [93]. Our studies further show that subcutaneous administration of isradipine (3 μg/g/day; 60-day release) to 3xTgAD mice was well-tolerated and isradipine became available to the brain [29, 93].…”

“…We also tested isradipine for its neuroprotective functions in four evolutionarily divergent species including models for AD: human neuroblastoma/MC65 cells, transgenic Drosophila , Monduca , and 3xTg-AD mice [93]. In transgenic Drosophila model, 250 μM isradipine increased the survival of flies from 6.5% to 12% (p<0.5) against APP 695 toxicity [93].…”

“…In transgenic Drosophila model, 250 μM isradipine increased the survival of flies from 6.5% to 12% (p<0.5) against APP 695 toxicity [93]. In moth/ Monduca sexta experiments, embryonic culture preparations were exposed to exogenous Aβ 1-42 peptide to determine the toxic effects of this peptide on neuronal development and growth in the presence or absence of 10 μM isradipine [93]. Treatment with Aβ 1-42 induces concentration-dependent perturbations in the extent of migration and outgrowth of enteric nervous system.…”

Calcium channel blockers and dementia

“…The finding that nimodipine can prevent Aβ-mediated neurotoxicity was confirmed in cortical neurons by use of a more relevant, stable oligomeric Aβ preparation (Fu et al, 2006). Other calcium antagonists (verapamil, diltiazem and isradipine) all dose dependently protected Aβ-induced cellular degeneration in cultured cells (Anekonda et al, 2011;Copenhaver et al, 2011), strengthening the conclusion that L-type channels may mediate the toxic effect. Using calciumsensitive dyes, several groups showed that Aβ25-35 increases intracellular calcium levels, and different classical calcium antagonists prevent this increase in vitro (Silei et al, 1999;Yagami et al, 2002;Fu et al, 2006).…”

Parkinson's disease and Alzheimer disease: environmental risk factors

“…57 Isradipine limits the neurotoxic damage caused by A␤ in cell cultures and animal models. 58 Nimodipine, despite its effects on LTCC, stimulates A␤ secretion through another mechanism. A CC study demonstrated lower risk of PD among CCA users, while another CC study and 2 prospective studies found no associations.…”