Potential of Therapeutic Small Molecules in Apoptosis Regulation in the Treatment of Neurodegenerative Diseases: An Updated Review

Abstract

Neurodegenerative disorders (NDs) include Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) and the common feature of NDs is the progressive death of specific neurons in the brain. Apoptosis is very important in developing the nervous system, nonetheless an elevated level of cell death has been observed in the case of NDs. NDs are different in terms of their neuronal vulnerability and clinical manifestations, however they have some overlapping neurodegenerative pathways. It has been demonstrated by several studies with cell lines and animal models that apoptosis has a significant contribution to make in advancing AD, ALS, HD, and PD. Numerous dying neurons were also identified in the brains of individuals with NDs and these conditions were found to be linked with substantial cell loss along with common characteristics of apoptosis including activation of caspases and cysteine-proteases, DNA fragmentation, and chromatin condensation. It has been demonstrated that several therapeutic agents including antioxidants, minocycline, GAPDH ligands, p53 inhibitors, JNK (c-Jun N-Terminal Kinase) inhibitors, glycogen synthase kinase-3 inhibitor, non-steroidal anti-inflammatory drugs, D2 dopamine receptor agonists, FK506, cell cycle inhibitors, statins, drugs targeting peroxisome proliferator-activated receptors, and gene therapy have the potential to provide protection to neurons against apoptosis. Therefore, the use of these potential therapeutic agents might be beneficial in the treatment of NDs. In this review, we have summarized the pathways that are linked with apoptotic neuronal death in the case of various NDs. We have particularly focused on the therapeutic agents that have neuroprotective properties and the potential to regulate apoptosis in NDs.

Multiple Metabolites Derived from Mushrooms and Their Beneficial Effect on Alzheimer’s Diseases

“…With regard to apoptosis, there is increasing evidence to confirm that neural cells with typical characteristics of apoptosis (DNA fragmentation, chromatin condensation, etc.) are present in AD and other NDs [ 73 , 74 ]. Apoptosis, an important process of programmed cell death (PCD), is thought to be the pathway of neuron loss in all NDs [ 75 , 76 ].…”

“…Apoptosis, an important process of programmed cell death (PCD), is thought to be the pathway of neuron loss in all NDs [ 75 , 76 ]. For example, overexpression of proapoptotic protein and downregulated antiapoptotic protein were detected in the brains of individuals with AD [ 73 ]. In addition, necrosis and autophagy are also reported to play critical roles in AD.…”

Influence of Guanine-Based Purines on the Oxidoreductive Reactions Involved in Normal or Altered Brain Functions

“…However, the activation of this kinase loop may lead to a different outcome. While a prolonged stimulation of these kinases has been associated with apoptosis and inflammation in numerous organs, including the brain where they can contribute to neurodegenerative disorder development [123], p38 and JNK kinase phosphorylation can be important for pro-survival signals inducing autophagy, a lysosomal pathway to degrade damaged proteins, lipids and organelles [124].…”

Inhibition of PERK Kinase, an Orchestrator of the Unfolded Protein Response (UPR), Significantly Reduces Apoptosis and Inflammation of Lung Epithelial Cells Triggered by SARS-CoV-2 ORF3a Protein

“…Apoptosis can be either triggered through an “extrinsic pathway”, characterized by the activation of membrane death receptors, or through increased mitochondria outer membrane permeability (MOMP) and cytochrome c release (“intrinsic” or “mitochondrial” pathway) [ 11 , 12 , 13 ]. Nevertheless, both mechanisms of apoptosis are driven by the cleavage of specific members of cysteinyl aspartate proteases family, known as caspases [ 12 , 14 , 15 ]. Pyroptosis is an inflammatory form of cell death, which is triggered by danger signals that are recognized by NOD-Like Receptors (NLR) and induce the release of pro-inflammatory factors [ 16 ].…”