Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and Neurodegeneration

Abstract

Ischemic stroke is categorized by either permanent or transient blood flow obstruction, impeding the distribution of oxygen and essential nutrients to the brain. In this study, we examined the neuroprotective effects of compound A3, a synthetic polyphenolic drug product, against ischemic brain injury by employing an animal model of permanent middle cerebral artery occlusion (p-MCAO). Ischemic stroke induced significant elevation in the levels of reactive oxygen species and, ultimately, provoked inflammatory cascade. Here, we demonstrated that A3 upregulated the endogenous antioxidant enzymes, such as glutathione s-transferase (GST), glutathione (GSH), and reversed the ischemic-stroke-induced nitric oxide (NO) and lipid peroxidation (LPO) elevation in the peri-infarct cortical and striatal tissue, through the activation of endogenous antioxidant nuclear factor E2-related factor or nuclear factor erythroid 2 (Nrf2). In addition, A3 attenuated neuroinflammatory markers such as ionized calcium-binding adapter molecule-1 (Iba-1), cyclooxygenase-2 (COX-2), tumor necrotic factor-α (TNF-α), toll-like receptors (TLR4), and nuclear factor-κB (NF-κB) by down-regulating p-JNK as evidenced by immunohistochemical results. Moreover, treatment with A3 reduced the infarction area and neurobehavioral deficits. We employed ATRA to antagonize Nrf2, which abrogated the neuroprotective effects of A3 to further assess the possible involvement of the Nrf2 pathway, as demonstrated by increased infarction and hyperexpression of inflammatory markers. Together, our findings suggested that A3 could activate Nrf2, which in turn regulates the downstream antioxidants, eventually mitigating MCAO-induced neuroinflammation and neurodegeneration.

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

“…This notion was further demonstrated when ATRA treatment wore off the hepatoprotective effects of carveol and elevated the expression of the inflammatory markers. These results are consistent with other experimental models, in which Nrf2 shields against inflammation ( Mohsin Alvi et al, 2020 ). Thus, its activation, either pharmacological or signaling cascades, rescues the tissue from the hallmarks of inflammation and oxidative stress, while its pharmacological inactivation deteriorates the pathological conditions in several other related degenerative models.…”

“…Consistent literature suggests that activation of the antioxidant machinery, such as Nrf2, could downregulate oxidative stress and the inflammatory cascade machinery, such as the NFκB pathway and cytokines (TNF-α and COX-2) ( Ali A et al, 2020 ). The critical role of carveol in mediating the antioxidative effect of Nrf2 was further validated with the Nrf2 antagonist ATRA ( Mohsin Alvi et al, 2020 ). ATRA administration removed the hepatoprotective effect of carveol, abolished the increased levels of Nrf2 and HO-1, and further exaggerated p-NFκB and TNF-α levels.…”

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

“…20 Previous studies revealed the involvement of Nrf2-ARE signaling in attenuating inflammation in several pathologies such as stroke and other disorders. [21][22][23] Hence, dysregulation of Nrf2 signaling results in increased susceptibility to oxidative stress and inflammatory damage. 24,25 Moreover, the neuroprotective role of Nrf2 in various neurodegenerative disease models has been reported.…”

“…In our previous study, we demonstrated that ATRA increased infarction area by mediating neuroinflammation in the ischemic stroke model possibly by antagonizing the Nrf2 pathway. 21 Furthermore, Nrf2 can also modulate the level of serotonin, noradrenaline, and dopamine, which are the key targets of the monoamine hypothesis. A significant reduction in the level of these neurotransmitters was shown along with an elevated level of glutamate in Nrf2 KO mice.…”

1,3,4-Oxadiazole Derivative Attenuates Chronic Constriction Injury Induced Neuropathic Pain: A Computational, Behavioral, and Molecular Approach

“…Further dehydration was carried out by a series of serial ethanol dilutions (70%, 95%, and 100%) fixed in xylene and cover with slip. An Olympus light microscope was used for capturing images and analysis of the picture was carried out through ImageJ software [ 17 ].…”