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

Abstract

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 Cav1.2 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 autophagyIsradipine is a Federal Drug Administration-approved dihydropyridine calcium channel blocker that binds selectively to Cav1.2 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 Cav1.2 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 Cav1.2 channel overexpression, the accumulation of hyperphosphorylated tau and suppression of autophagy in Alzheimer’s disease and modulation of this pathway by isradipine.

A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY‐PD III)

“…The mechanism of neuroprotection is linked to selective vulnerability of substantia nigra pars compacta neurons that preferentially express L‐type calcium channels. Neuroprotective effects of isradipine are achieved at the plasma concentration that is obtained within the safe dose range for human administration10, 11 and consistent with the tolerable dosage identified in our phase II study of isradipine in PD (STEADY‐PDII) 12. Isradipine is the most potent of the clinically available Cav1.3 DHPs and has excellent central nervous system penetration suggesting it is the optimal DHP to target this novel mechanism of neuroprotection 13, 14…”

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

“…Among non-APOE4 carriers, nilvadipine also improved short-term cognitive functions [106]. Another dihydropyridine CCB, isradipine, conferred neuroprotective effects in vitro [107], and also attenuated the levels of hyperphosphorylated tau and suppressed autophagy of tau [108].…”

Potential genetic biomarkers in the early diagnosisof Alzheimer disease: APOE and BIN1

“…Additionally, understanding the BIN1 roles in other pathways possibly associated with AD might help us to elucidate its role in AD pathogenesis. A recent study showed that BIN1 increases the risk of AD by interacting with tau protein and by affecting neurofibrillary tangles (60)(61)(62). However, further studies are needed to determine the mechanism of interaction between BIN1 and tau, and neurofibrillary tangles, which might be promising for novel treatment approaches.…”