Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer’s Disease and Parkinson’s Disease

Abstract

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases in the elderly. The key histopathological features of these diseases are the presence of abnormal protein aggregates and the progressive and irreversible loss of neurons in specific brain regions. The exact mechanisms underlying the etiopathogenesis of AD or PD remain unknown, but there is extensive evidence indicating that excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), along with a depleted antioxidant system, mitochondrial dysfunction, and intracellular Ca2+ dyshomeostasis, plays a vital role in the pathophysiology of these neurological disorders. Due to an improvement in life expectancy, the incidence of age-related neurodegenerative diseases has significantly increased. However, there is no effective protective treatment or therapy available but rather only very limited palliative treatment. Therefore, there is an urgent need for the development of preventive strategies and disease-modifying therapies to treat AD/PD. Because dysregulated Ca2+ metabolism drives oxidative damage and neuropathology in these diseases, the identification or development of compounds capable of restoring Ca2+ homeostasis and signaling may provide a neuroprotective avenue for the treatment of neurodegenerative diseases. In addition, a set of strategies to control mitochondrial Ca2+ homeostasis and signaling has been reported, including decreased Ca2+ uptake through voltage-operated Ca2+ channels (VOCCs). In this article, we review the modulatory effects of several heterocyclic compounds on Ca2+ homeostasis and trafficking, as well as their ability to regulate compromised mitochondrial function and associated free-radical production during the onset and progression of AD or PD. This comprehensive review also describes the chemical synthesis of the heterocycles and summarizes the clinical trial outcomes.

Computational Drug Discovery for Novel Small Molecule Inhibitors Targeting LRRK2 in Parkinson's Disease Treatment

“…In congruence with this, several studies have highlighted that heterocyclic derivatives are e cacious compounds viable for the treatment of parkinson's and other neurodegenerative diseases (Vitorrio, Dank and Lelo, 2023; Kumar et al, 2020; Babalola et al, 2021). Heterocycles like caffeine, Nifedipine, Latrepirdine and Blarcamesine have been reported to target the homeostasis of mitochondrial calcium (Tapias et al, 2023). The potency and druggability of heterocyclic derivatives have engendered its approval for the treatment of certain diseases.…”

A systematic review of the neuropathology and memory decline induced by monosodium glutamate in the Alzheimer’s disease-like animal model

“…Alzheimer’s disease’s pathogenesis has been linked to the dysregulation of intracellular calcium signaling. The hallmark lesions of this condition, such as the buildup of amyloid, the hyperphosphorylation of tau, and neuronal death, are brought on by increased intracellular calcium ( LaFerla, 2002 ; Tapias et al, 2023 ). All three studies of this review have reported increased measures of calcium signaling, i.e., calciretinin immunoreactivity and S-100β in the hippocampus and spinal ganglia of the MSG-treated animals ( Krawczyk et al, 2015 ; Rycerz et al, 2015 ; Krawczyk and Jaworska-Adamu, 2016 ).…”

Mitochondria in Alzheimer’s Disease Pathogenesis

“…There is no cure and since approaches targeting Aβ and tau have shown that these misfolded proteins are likely not causative, attention has shifted to other mechanisms, including those involving mitochondria [4]. Mitochondria are being explored because abnormalities in this organelle are found early in the course of the disease and can lead to many of the neuron-destroying consequences of AD [5][6][7]. The disruption of mitochondrial dynamics leads to mitochondrial fragmentation, generation of reactive oxygen species (ROS) and poor energy production [8].…”