Stabilizers of Neuronal and Mitochondrial Calcium Cycling as a Strategy for Developing a Medicine for Alzheimer's Disease

Abstract

For the last two decades, most efforts on new drug development to treat Alzheimer's disease have been focused to inhibit the synthesis of amyloid beta (Aβ), to prevent Aβ deposition, or to clear up Aβ plaques from the brain of Alzheimer's disease (AD) patients. Other pathogenic mechanisms such as the hyperphosphorylation of the microtubular tau protein (that forms neurofibrillary tangles) have also been addressed as, for instance, with inhibitors of the enzyme glycogen synthase-3 kinase beta (GSK3β). However, in spite of their proven efficacy in animal models of AD, all these compounds have so far failed in clinical trials done in AD patients. It seems therefore desirable to explore new concepts and strategies in the field of drug development for AD. We analyze here our hypothesis that a trifunctional chemical entity acting on the L subtype of voltage-dependent Ca 2+ channels (VDCCs) and on the mitochondrial Na + /Ca 2+ exchanger (MNCX), and having additional antioxidant properties, may efficiently delay or stop the death of vulnerable neurons in the brain of AD patients. In recent years, evidence has accumulated indicating that enhanced neuronal Ca 2+ cycling (NCC) and futile mitochondrial Ca 2+ cycling (MCC) are central stage in activating calpain and calcineurin, as well as the intrinsic mitochondrial pathway for apoptosis, leading to death of vulnerable neurons. An additional contributing factor to neuronal death is the excess free radical production linked to distortion of Ca 2+ homeostasis. We propose that an hybrid compound containing a dihydropyridine moiety (to block L channels and mitigate Ca 2+ entry) and a benzothiazepine moiety (to block the MNCX and slow down the rate of Ca 2+ efflux from the mitochondrial matrix into the cytosol), as well as a polyphenol moiety (to sequester excess free radicals) could break down the pathological enhanced NCC and MCC, thus delaying the initiation of apoptosis and the death of vulnerable neurons. In so doing, such a trifunctional compound could eventually become a neuroprotective medicine capable of delaying disease progression in AD patients.

Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease

“…An interesting connection between A β , calcium, and AD has been postulated by Arispe and coworkers [ 66 ], who suggested that A β oligomers can form calcium-permeable channels in membranes. It seems that energy deficits can promote this association, consistently with the observation that neurons with low cytosolic ATP levels showed a pronounced vulnerability to A β -induced toxicity [ 67 ]. In line with these reports, studies conducted in animal models (i.e., transgenic mice) highlighted an increase in calcium resting levels in the spines and dendrites of pyramidal cortical neurons [ 68 , 69 ], supporting the hypothesis that calcium-permeable channels can form in the neuronal plasma membrane close to the A β plaques, thanks to the high concentration of A β oligomers found in these areas [ 67 ].…”

“…It seems that energy deficits can promote this association, consistently with the observation that neurons with low cytosolic ATP levels showed a pronounced vulnerability to A β -induced toxicity [ 67 ]. In line with these reports, studies conducted in animal models (i.e., transgenic mice) highlighted an increase in calcium resting levels in the spines and dendrites of pyramidal cortical neurons [ 68 , 69 ], supporting the hypothesis that calcium-permeable channels can form in the neuronal plasma membrane close to the A β plaques, thanks to the high concentration of A β oligomers found in these areas [ 67 ]. Tau protein is also able to form ion channels in planar lipid bilayer, with lack of ion selectivity and multiple channels conductance, thus contributing to lower membrane potential, dysregulate calcium, depolarize mitochondria, or deplete energy stores [ 70 ].…”

Gramine Derivatives Targeting Ca2+ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

“…[22][23] There is preclinical and clinical evidence that the blockade of voltage-gated Ca 2+ channels (VGCC) may attenuate dementia, since an excessive and prolonged Ca 2+ entry into the cytosol leads to neurodegeneration and neuronal loss. [24][25][26] The VGCC blockade, both at presynaptic (P/Q-and Ntype VGCC) and at postsynaptic sites (L-type VGCC), has shown a neuroprotective effect in different animal models of neurodegeneration and excitotoxicity, such as the blockade of ω-agatoxin IVA in a rat ischemia model (P/Q-VGCC blocker), 27 the blockade by the synthetic version of ω-conotoxin MVIIA in a traumatic diffuse brain injury model in rats (N-type VGCC blocker), 28 that of verapamil in a focal ischemia model in rats (L-type VGCC blocker), 29 or those of nivaldipine and nitrendipine (L-type VGCC blockers) in an Aβ-induced toxicity model in mice. 30 Some VGCC antagonists have been tested in clinical trials for dementia and, according to the Cochrane report published in 2002, nimodipine can be of some efficacy for the treatment of AD.…”

Dantrolene, A Treatment for Alzheimer Disease?

“…43,57,74,108,109 Dantrolene, as an antagonist of RYRs on ER, mitigates AD pathology and may serve as a probe compound for future studies to treat Alzheimer's disease.…”