Cellular and molecular mechanism in neurodegeneration: Possible role of neuroprotectants.

In recent years, neurodegeneration has been recognized as a clinical condition that is characterized by neuronal death, dementia, and gradual diminish of cognitive function, poor body coordination and motor disorders. Several studies deciphering cellular and molecular mechanisms show a promising insight for several kinds of damages including neurodegeneration in central nervous system. In addition, there has been an inflammatory key mechanism involved in neurodegenerative disorders. There is a paucity of literature in both cellular- and molecular-mediated targets in damaged neurons at both in vitro and in vivo research models. It has been notified that CNS has a very restricted magnitude of regeneration. Numerous key factors have also been studied and considered as possible culprit of neurodegeneration. Autophagy is a well-known degradation process wherein vesicular machinery as autophagosome transports cytoplasmic contents to the lysosomes. In earlier reports, a bridging connection between autophagy and its associated mechanism has been established. Natural compounds as a neuro-therapeutics have been recognized in neurodegeneration. In our review, we discuss the mechanisms for the onset and progression in neurodegeneration, via inflammation and autophagic machine available in cellular compartments in CNS. This review also discusses about the neuroprotective efficacy of natural compounds against neurodegeneration episodes displays in neuronal platform.

Screening the Efficacy of Melatonin on Neurodegeneration Mediated by Endoplasmic Reticulum Stress, Inflammation, and Oxidative Damage.

Neurodegeneration may be defined as a clinical condition wherein neurons gradually lose their structural integrity, viability, and functional abilities and the damage inflicted upon the neurons is often irreversible. The various mechanisms that have been observed to contribute to neurodegeneration include aggregation and accumulation of misfolded proteins, impaired autophagy, oxidative damage, neuroinflammation, mitochondrial defects, increased SUMOylation of proteins, impaired unfolded protein response (UPR) pathways, and disruption of axonal transport. Melatonin, a neurohormone, is involved in a variety of functions including scavenging free radicals, synchronizing the circadian rhythm, and mitigating immune response. Melatonin has shown to modulate the UPR pathway, antioxidant pathway through Nrf2 and inflammatory pathway through NFκB. The study aims to determine the efficacy of melatonin on neurodegeneration mediated by endoplasmic reticulum (ER) stress, inflammation, and oxidative damage through in silico approaches. The molecular targets chosen were ATF6, XBP1, PERK, Nrf2, and NFκB and they were docked against melatonin. Melatonin showed to have binding energy with ATF6 as - 4.8 kJ, with PERK as - 3.2 kJ, with XBP1 as - 4.8 kJ, with Nrf2 as - 4.5 kJ, and with that of NFκB as - 4.2 kJ, which implies it interacts well with them. Additionally various physiochemical analyses such as absorption, distribution, metabolism, excretion (ADME) were also carried out. Those analyses revealed that it has an optimal log P of about 1.98, optimal log S of - 2.34, is BBB permeant, has high GI absorption, is not a P-Gp substrate, has a TPSA of 54.12, has a molecular weight of 232.28, and has about 4 rotatable bonds. Also, it showed a bioactivity score of 0.06 for GPCR which implies that it is most likely to exert its function by binding GPCR. The findings imply that melatonin not only shows excellent interactions with the targets but also possesses drug-like physicochemical properties that makes it a valuable choice for the treatment of neurodegenerative disorders.

Promising Action of Cannabinoids on ER Stress-Mediated Neurodegeneration: An In Silico Investigation.

Neurodegeneration has been recognized as a clinical episode characterized by neuronal death, including dementia, cognitive impairment and movement disorder. Most of the neurodegenerative deficits, via clinical symptoms, includes common pathogenic features as protein misfolding and aggregation. Therefore, the focus highlights the cellular organelle endoplasmic reticulum (ER) critically linked with the quality control and protein homeostasis. Unfolded protein response (UPR) or ER stress have also been considered as hallmarks for neurodegenerative disorders. It has been implicated that the levels of endocannabinoids (ECB) could rise at the platform of neurodegeneration. In addition, phytocannabinoids (PCB) including cannabidiol (CBD) could also initiate the IRE1, PERK, XBP-1, and ATF6, pathways that could lead to the degradation of the misfolded proteins and termination of protein translation. Thus, our aim was to determine if cannabinoids bind to these ER arm proteins involved in UPR by molecular docking and therefore determine its drug resemblance through ADME analysis. In our study, three cannabinoid receptors (CB1, CB2, and CB3) were considered to demonstrate their neuroprotective actions. The chosen ligands were screened as PCB (Δ9-tetrahydrocannabinol or THC), CBD, and two ECB, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The current findings have advocated that the cannabinoids and their molecular targets have shown considerable binding and their ADME properties also reveals that they possess moderate drug-like properties making it as a valuable option for the treatment and management of neurodegenerative diseases.