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

Abstract

The brain is a complex organ that controls body functions and homeostasis through the action of neuronal and glial cells. Neuronal activity is highly energy-dependent and requires large numbers of functional mitochondria to provide substantial amount of energy via mitochondrial oxidative phosphorylation (OXPHOS), the most efficient metabolic process to generate adenosine triphosphate (ATP). Under stress conditions, neurons are particularly vulnerable to mitochondrial dysfunction, leading to decreased ATP synthesis, excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and intracellular Ca2+ dyshomeostasis, although not necessarily in this order. Alzheimer's disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases in elderly and are characterized by 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 compromised mitochondrial energy metabolism along with a depleted antioxidant system play a vital role in the pathophysiology of these neurological disorders. Toxic accumulation of proteins such as amyloid β peptides (Aβ) or amyloid precursor protein (APP) in AD and α-synuclein (α-syn) or leucine-rich repeat kinase 2 (LRRK2) in PD cause mitochondrial deficits through direct inhibition of electron transport chain (ETC) assembly and function, thereby resulting in further generation of ROS/RNS and disturbance of Ca2+ influx. Due to the improvement in life expectancy, the incidence of age-related neurodegenerative diseases has significantly increased. There is no effective protective treatment or therapy available but rather only very limited palliative treatment. There is an urgent need for the development of preventive strategies and disease-modifying therapies (both neuroprotective and neurorestorative interventions) to treat AD/PD. Here, we review the capability of some heterocyclic compounds to modulate Ca2+ homeostasis and signaling with a potential role in regulating mitochondrial function and associated free radical production during the development and onset of AD or PD. Moreover, we have included the chemical synthesis of a series of heterocycles and their derivatives.