Benzimidazole Derivatives as New Potential NLRP3 Inflammasome Inhibitors That Provide Neuroprotection in a Rodent Model of Neurodegeneration and Memory Impairment

Abstract

The study investigated the effect of newly synthesized benzimidazole derivatives against ethanol-induced neurodegeneration. According to evidence, ethanol consumption may cause a severe insult to the central nervous system (CNS), resulting in mental retardation, neuronal degeneration, and oxidative stress. Targeting neuroinflammation and oxidative stress may be a useful strategy for preventing ethanol-induced neurodegeneration. Methodology: Firstly, the newly synthesized compounds were subjected to molecular simulation and docking in order to predict ligand binding status. Later, for in vivo observations, adult male Sprague Dawley rats were used for studying behavioral and oxidative stress markers. ELIZA kits were used to analyse tumour necrosis factor-alpha (TNF-), nuclear factor-B (NF-B), interleukin (IL-18), and pyrin domain-containing protein 3 (NLRP3) expression, while Western blotting was used to measure IL-1 and Caspase-1 expression. Results: Our findings suggested that altered levels of antioxidant enzymes were associated with elevated levels of TNF-α, NF-B, IL-1, IL-18, Caspase-1, and NLRP3 in the ethanol-treated group. Furthermore, ethanol also caused memory impairment in rats, as measured by behavioural tests. Pretreatment using selected benzimidazole significantly increased the combat of the brain against ethanol-induced oxidative stress. The neuroprotective effects of benzimidazole derivatives were promoted by their free radical scavenging activity, augmentation of endogenous antioxidant proteins (GST, GSH), and amelioration of lipid peroxide (LPO) and other pro-inflammatory mediators. Molecular docking and molecular simulation studies further supported our hypothesis that the synthetic compounds Ca and Cb had an excellent binding affinity with proper bond formation with their targets (TNF-α and NLRP3). Conclusion: It is revealed that these benzimidazole derivatives can reduce ethanol-induced neuronal toxicity by regulating the expression of cytokines, antioxidant enzymes, and the inflammatory cascade.

Assessment of the potential prophylactic and therapeutic effects of kaempferol on experimental Trichinella spiralis infection

“…The level of NLRP3 in the intestinal tissue of infected mice that were given either ABZ or KPF decreased. The inhibitory effect of ABZ on NLRP3 was documented previously, and the suggested mechanism is via nuclear factor kappa B inhibition, which regulates the expression of NLRP3, caspase 1 and pro-interleukin-1β (pro-IL-1β) (Ullah et al , 2022). For KPF, the inhibitory effect on NLRP3 is through inhibition of IL-1β production and apoptosis-associated speck-like protein containing caspase recruitment domain oligomerization (Lim et al , 2018).…”

Synthesis of Selenium-Based Small Molecules Inspired by CNS-Targeting Psychotropic Drugs and Mediators

“…The scaffold of 1 and 2 consists of a disubstituted benzimidazole. Throughout the years, the benzimidazole moiety has been used as a scaffold to synthesize a wide variety of compounds involved in biological processes; in the literature, many examples support the antioxidant properties and neuroprotective role of derivatives from this class [21,22]. Notably, 3 and 4 have similar motifs formed by two condensed rings bearing nitrogen atoms.…”

Establishment of a chronic insomnia rat model of sleep fragmentation using unstable platforms surrounded by water

“…The Morris water maze test can be used to study dysfunction of learning and memory ability ( 35-40 ). Increased expression levels of pro-inflammatory factors contribute to dysfunction of learning and memory ability ( 26 , 27 ). In the present study, the night-time Morris water maze training and test experiment indicated that the memory dysfunction in the model rats was accompanied by a longer escape latency and reduced number of times crossing the target regions.…”

“…It has been reported that the levels of inflammatory cytokines, namely IL-1, IL-6, TNF-α and IL-10, are affected by insomnia (25). The abnormal levels of these cytokines further affect brain function, such as learning and memory (26,27). Furthermore, orexin A and its receptors play important roles in the regulation of food intake, circadian rhythms, arousal and sleep (28)(29)(30)(31)(32).…”