Suppression of Selective Voltage-Gated Calcium Channels Alleviates Neuronal Degeneration and Dysfunction through Glutathione S-Transferase-Mediated Oxidative Stress Resistance in a Caenorhabditis elegans Model of Alzheimer’s Disease

Zheng, Zihui; Wu, Kanglu; Ruan, Qiurong; Li, Dongfang; Liu, Weizhen; Wang, Min; Li, Yaoyao; Xia, Jintao; Yang, Dongqing; Guo, J.

doi:10.1155/2022/8287633

Cited by 6 publications

(2 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Elevated Ca 2+ concentration aggravated Aβ-mediated behavioral impairment and defective chemotaxis, resulting in a shortened lifespan in C. elegans overexpressing Aβ1-42. [421] Exposure to nimodipine extended lifespan and rescued motor lesions, synaptic deficiencies, and DAergic degeneration in worms. Furthermore, nimodipine limited Aβ aggregation via through upregulation of glutathione Stransferase activity, resulting in an attenuation of oxidative damage.…”

Section: Nimodipinementioning

confidence: 98%

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

Tapias¹,

González-Andrés²,

Peña³

et al. 2023

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Nimodipinementioning

confidence: 98%

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

Tapias¹,

González-Andrés²,

Peña³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…To date, there have been no clinical trials with nimodipine in individuals with PD. Elevated Ca 2+ content worsened Aβ-mediated behavioral impairment and defective chemotaxis, but exposure to nimodipine extended lifespan and rescued motor lesions, synaptic deficiencies, and DAergic degeneration [ 157 ]. Subcutaneous delivery of nimodipine reversed behavioral abnormalities and preserved the number of DAergic neurons in the locus coeruleus [ 158 ].…”

Section: Modulation Of Calcium Signaling and Homeostasis By Heterocyc...mentioning

confidence: 99%

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

et al. 2023

View full text Add to dashboard Cite

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.

show abstract

Calcium Channels as a Potential Therapeutic Target for Alzheimer’s Disease

Sharma,

Thapak,

Chandwani

et al. 2023

Deciphering Drug Targets for Alzheimer’s Disease

View full text Add to dashboard Cite

Suppression of Selective Voltage-Gated Calcium Channels Alleviates Neuronal Degeneration and Dysfunction through Glutathione S-Transferase-Mediated Oxidative Stress Resistance in a Caenorhabditis elegans Model of Alzheimer’s Disease

Cited by 6 publications

References 49 publications

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

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

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

Calcium Channels as a Potential Therapeutic Target for Alzheimer’s Disease

Contact Info

Product

Resources

About