1,3,4, Oxadiazole Compound A3 Provides Robust Protection Against PTZ-Induced Neuroinflammation and Oxidative Stress by Regulating Nrf2-Pathway

Abstract

Background Epilepsy is a common neurological disorder that is characterized by recurrent episodes of seizures. Various studies have demonstrated a direct association between oxidative stress and inflammation in several neurological disorders including epilepsy. This study aimed to investigate the neuroprotective effects of a synthetic 1,3,4, oxadiazole compound A3 against pentylenetetrazole (PTZ)-induced kindling and seizure model. Methodology PTZ was administered in a sub-convulsive dose of 40 mg/kg for 15 days, at 48-hour intervals to male Swiss-Albino mice until animals were fully kindled. Two different doses of A3 (10 mg/kg and 30 mg/kg) were administered to find out the effective dose of A3 and to further demonstrate the relative role of nuclear factor E2-related factor ( Nrf2 ) in the PTZ-induced kindled model. Results Our results demonstrated a compromised antioxidant capacity associated with a low level of catalase (CAT), superoxide dismutase (SOD), glutathione (GST), and glutathione S-transferase (GSH) in the kindled group. However, the PTZ-induced group demonstrated an elevated level of lipid peroxidation (LPO) level parallel to pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), mediators as cyclooxygenase (COX-2), and nuclear factor kappa B (NFκB). Furthermore, the A3 treatment reversed these changes and overexpressed the antioxidant Nrf2 gene and its downstream HO-1 . To further investigate the involvement of Nrf2 , we employed an Nrf2 -inhibitor, ie, all-trans retinoic acid (ATRA), that further aggravated the PTZ toxicity. Moreover, vascular endothelial growth factor (VEGF) expression was evaluated to assess the extent of BBB disruption. Conclusion The findings of this study suggest that A3 could mediate neuroprotection possibly by activating Nrf2 dependent downregulation of inflammatory cascades.

Carveol Promotes Nrf2 Contribution in Depressive Disorders through an Anti-inflammatory Mechanism

“…Similarly, carveol upregulated the LPSinduced decreased protein expression of the antioxidant enzymes HO-1. Mechanistically, both the anti-inflammatory and antioxidant activities of carveol were diminished in the ATRA-treated groups, which supports our hypothesis that carveol exerts its protective activity via activating the Nrf2/HO-1 signaling pathway [71,72].…”

“…It is well known that Nrf2 activation leads to the inhibition of inflammatory mediators via downregulating the NF- κ B signaling pathway. HO-1, downstream of Nrf2 is also known to be a potent inhibitor of proinflammatory cytokines [ 70 , 71 ]. Consistent with previous research studies, our findings demonstrated that carveol effectively reversed the LPS-induced protein expression of various inflammatory mediators such as p-NFkB, TNF- α , and COX-2.…”

DHA and EPA Prevent Seizure and Depression‐Like Behavior by Inhibiting Ferroptosis and Neuroinflammation via Different Mode‐of‐Actions in a Pentylenetetrazole‐Induced Kindling Model in Mice

“…[42] Furthermore, Nrf2 can also induce downstream hemeoxygenase-1 (HO-1) to play antioxidant functions, which has been involved in oxidative stress in PTZ-induced mice. [39] Consistently, our findings show a significantly downregulated p-Nrf2/Nrf2 and HO-1 in the PTZ group mice, while the administration of EPA significantly upregulated these proteins with a stronger effect than that of DHA. Furthermore, previous studies also demonstrated that Nrf2 is involved in the regulation of iron homeostasis through positively regulating FTH1 and FPN1.…”

“…[ 38 ] In the present study, diminished levels of GSH, GPX4, and xCT, as well as SOD activity with increased MDA content, demonstrated that PTZ administration induced oxidative stress, consistent with other studies. [ 39 ] However, DHA and EPA comparably resulted in significant elevation of these antioxidants and reduced MDA. These results suggested that the higher effect of EPA compared to that of DHA in antioxidative stress mainly accounts for its better normalization of iron homeostasis in PTZ‐induced mice.…”

Rev-erbα agonist SR9009 protects against cerebral ischemic injury through mechanisms involving Nrf2 pathway

“…After stroke, the oxidative stress plays a key role in the pathophysiology of the ischemic brain (Orellana-Urzúa et al, 2020). We used ATRA, which inhibit Nrf2 activation via activating the RARα-Nrf2 complex in the present study (Alvi et al, 2022;Wang L et al, 2022). The protective effect of SR9009 decreased when administered with ATRA.…”