A Potent Antioxidant Endogenous Neurohormone Melatonin, Rescued MCAO by Attenuating Oxidative Stress-Associated Neuroinflammation

Abstract

Ischemic stroke is an acute neurological syndrome either due to permanent or temporary obstruction of blood. Such obstruction immediately triggers abrupt pathological cascading processes, which collectively lead to neuronal cell death. Oxidative stress and neuroinflammation in ischemic stroke are critical regulating events that ultimately lead to neuronal death. Complicated interplay exists between the two processes which occur through several stages. Most often, oxidative stress precedes the inflammatory mechanisms and includes several interconnected cascades that underlie the ischemic stroke pathology. In continuation of the previously published data, here, we further ruled out the protective role of melatonin in focal cerebral ischemic injury model. Administration of 5 mg/kg dose of melatonin 30 min prior to ischemia reduced brain infarction associated with sequentially rescued neuronal apoptosis. Furthermore, melatonin attenuated neuroinflammatory markers and reactive oxygen species (ROS), induced by ischemic stroke, via halting the key players of mitogen stress family (p38/JNK). Besides, melatonin modulated the endogenously produced antioxidant enzyme, thioredoxin (Trx) pathway. These broader therapeutic efficacies of melatonin suggest that melatonin could be further investigated for its diverse therapeutic actions with multiple targets in recovering, preventing and halting the detrimental outcomes of MCAO, such as elevated oxidative stress, neuroinflammation, and neurodegeneration.

Natural Dietary Supplement, Carvacrol, Alleviates LPS-Induced Oxidative Stress, Neurodegeneration, and Depressive-Like Behaviors via the Nrf2/HO-1 Pathway

“…β-actin was used as a loading control. 45,46 The following day, membranes were incubated with secondary antibodies, and western bands were visualized on x-ray film using ECL detection reagent following the instructions of the manufacturer (Amersham Pharmacia Biotech, Piscataway, NJ, United States).…”

Carveol a Naturally-Derived Potent and Emerging Nrf2 Activator Protects Against Acetaminophen-Induced Hepatotoxicity

“…Moreover, the low energy values and relatively higher hydrogen bond formation further enhanced complex stability, as revealed through the molecular docking analysis. Additionally, previous studies have reported that targeting inflammation and oxidative stress-coupled targets could provide better therapeutic outcomes ( Ali T et al, 2020 ; Ling et al, 2020 ), which opens several avenues for the use of natural drug substances.…”

“…Moreover, role of the JNK pathway in inflammatory cascades and cellular death has been strongly established ( Ali A et al, 2020 ), and ROS and inflammatory cytokines can trigger JNK activation ( Ali A et al, 2020 ; Ali T et al, 2020 ; Ling et al, 2020 ). Furthermore, the p-JNK pathway has been implicated in various animal models and human diseases ( Shah et al, 2018 ; Li and Liu, 2019 ; Ali A et al, 2020 ; Ling et al, 2020 ; Malik et al, 2020 ), and the downregulation or inhibition of this pathway has been found to contribute to the protective strategy ( Shah et al, 2019 ). We observed similar activities in the APAP-intoxicated group, and carveol significantly reduced p-JNK expression.…”

“…APAP provokes free radical formation and subsequent proinflammatory mediators. Moreover, role of the JNK pathway in inflammatory cascades and cellular death has been strongly established , and ROS and inflammatory cytokines can trigger JNK activation Ling et al, 2020). Furthermore, the p-JNK pathway has been implicated in various animal models and human diseases (Shah et al, 2018;Li and Liu, 2019;Ling et al, 2020;Malik et al, 2020), and the downregulation or inhibition of this pathway has been found to contribute to the protective strategy (Shah et al, 2019).…”

Melatonin Protects Against Ischemic Brain Injury by Modulating PI3K/AKT Signaling Pathway via Suppression of PTEN Activity

“…Melatonin was reported to play important roles in the pathophysiological components of cellular injury after ischemic stroke via modulating oxidative stress, mitochondria, apoptosis, inflammatory response, melatonin receptors 1/2, circular RNA in ischemic injury (Kilic et al, 2020). For example, in a focal cerebral ischemic injury rat model, melatonin reduced brain infarction associated with sequentially rescued neuronal apoptosis and attenuated neuroinflammatory response by modulating oxidative stress signaling (NF-jB/COX2/iNOS) and enhancing anti-oxidative systems such as Nrf2/HO-1/Trx (Ling et al, 2020). But, the cellular mechanisms whereby melatonin protects against stroke-induced neuronal damage are not yet fully clear.…”