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Epilepsy is a neurodegenerative brain disorder characterized by recurrent seizure attacks. Numerous studies have suggested a strong correlation between oxidative stress and neuroinflammation in several neurodegenerative disorders including epilepsy. This study is aimed at investigating the neuroprotective effects of the natural compound carveol against pentylenetetrazole- (PTZ-) induced kindling and seizure model. Two different doses of carveol (10 mg/kg and 20 mg/kg) were administered to male rats to determine the effects and the effective dose of carveol and to further demonstrate the mechanism of action of nuclear factor E2-related factor ( Nrf2 ) in PTZ-induced kindling model. Our results demonstrated reduced levels of innate antioxidants such as superoxide dismutase (SOD), catalase, glutathione-S-transferase (GST), and glutathione (GSH), associated with elevated lipid peroxidation (LPO) and inflammatory cytokines level such as tumor necrosis factor-alpha (TNF- α ), and mediators like cyclooxygenase (COX-2) and nuclear factor kappa B (NF κ B). These detrimental effects exacerbated oxidative stress and provoked a marked neuronal alteration in the cortex and hippocampus of PTZ-intoxicated animals that were associated with upregulated Nrf2 gene expression. Furthermore, carveol treatment positively modulated the antioxidant gene Nrf2 and its downstream target HO-1 . To further investigate the role of Nrf2 , an inhibitor of Nrf2 called all-trans retinoic acid (ATRA) was used, which further exacerbated PTZ toxicity. Moreover, carveol treatment induced cholinergic system activation by mitigating acetylcholinesterase level which is further linked to attenuated neuroinflammatory cascade. The extent of blood-brain barrier disruption was evaluated based on vascular endothelial growth factor (VEGF) expression. Taken together, our findings suggest that carveol acts as an Nrf2 activator and therefore induces downstream antioxidants and mitigates inflammatory insults through multiple pathways. This eventually alleviates PTZ-induced neuroinflammation and neurodegeneration., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Arooj Mohsin Alvi et al.)

This study aims to delineate the effects of Manilkara zapota Linn. (Sapodilla) fruit chloroform (Mz.CHCl 3 ) and aqueous (Mz.Aq) extracts tested through different techniques. Antidiarrheal activity and intestinal fluid accumulation were examined by using castor oil-induced diarrhea and castor oil fluid accumulation models. Isolated rabbit jejunum tissues were employed for in vitro experiments. Antimotility and antiulcer were performed through charcoal meal transient time and ethanol-induced ulcer assay, molecular studies were conducted through proteomic analysis, and virtual screening was performed by using a discovery studio visualizer (DSV). Mz.CHCl 3 and Mz.Aq extracts attributed dose-dependent (50-300 mg/kg) protection (20-100%) against castor oil-induced diarrhea and dose-dependently (50-300 mg/kg) inhibited intestinal fluid secretions in mice. Mz.CHCl 3 and Mz.Aq extracts produce relaxation of spontaneous and K + (80 Mm) induced contractions in isolated tissue preparations and decreased the distance moved by charcoal in the gastrointestinal transit model in rats. It showed gastroprotective effect in ulcerative stomach of rats and decreased levels of IL-18 quantified by proteomic analysis. Histopathological results showed ethanol-induced significant gastric injury, leading to cloudy swelling, hydropic degeneration, apoptosis, and focal necrosis in all gastric zones using hematoxylin and eosin (H&E) staining. Moreover, ethanol increased the activation and the expression of tumor necrotic factor (TNF- α ), cyclooxygenase (COX-2), and nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF κ B). In silico results were comparative to in vitro results evaluated through virtual screening. Moreover, ethanol increased the activation and expression of tumor necrotic factor, cyclooxygenase, and nuclear factor kappa-light-chain-enhancer of activated B cells. This study exhibits the gastroprotective effect of Manilkara zapota extracts in the peritoneal cavity using a proteomic and in silico approach which reveals different energy values against target proteins, which mediate the gastrointestinal functions., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Sameen Fatima Ansari et al.)

Crude extract of Lens culinaris (Lc.Cr), which tested positive for presence of anthraquinones, flavonoids, saponins, sterol, tannins, and terpenes exhibited protective effect against castor oil-induced diarrhea in mice at 100-1000 mg/kg. In rabbit jejunum preparations, Lc.Cr caused relaxation of spontaneous contractions at 0.03-5.0 mg/mL. Lc.Cr inhibited carbachol (CCh, 1 μM) and K(+) (80 mM)-induced contractions in a pattern similar to dicyclomine, but different from verapamil and atropine. Lc.Cr shifted the Ca(++) concentration-response curves to the right, like dicyclomine and verapamil. Pretreatment of tissues with Lc.Cr (0.03-0.1 mg/mL) caused leftward shift of isoprenaline-induced inhibitory CRCs, similar to papaverine. In guinea-pig ileum, Lc.Cr produced rightward parallel shift of CCh curves, followed by non-parallel shift at higher concentration with suppression of maximum response, similar to dicyclomine, but different from verapamil and atropine. Lc.Cr (3.0-30 mg/kg) caused suppression of carbachol (CCh, 100 µg/kg)-induced increase in inspiratory pressure of anesthetized rats. In guinea-pig trachea, Lc.Cr relaxed CCh and high K(+) -induced contractions, shifted CCh curves to right and potentiated isoprenaline response. These results suggest that L. culinaris possesses antidiarrheal, antispasmodic, and bronchodilator activities mediated possibly through a combination of Ca(++) antagonist, anticholinergic, and phosphodiesterase inhibitory effects, and this study provides sound mechanistic background to its medicinal use in disorders of gut and airways hyperactivity, like diarrhea and asthma., (Copyright © 2014 John Wiley & Sons, Ltd.)

Achillea millefolium Linn. (Asteraceae) is used in folk medicine for the treatment of overactive cardiovascular and respiratory ailments. This study describes its hypotensive, cardio-depressant, vasodilatory and bronchodilatory activities. The crude extract of Achillea millefolium (Am.Cr) caused a dose-dependent (1-100 mg/kg) fall in arterial blood pressure of rats under anaesthesia. In spontaneously beating guinea-pig atrial tissues, Am.Cr exhibited negative inotropic and chronotropic effects. In isolated rabbit aortic rings, Am.Cr at 0.3-10 mg/mL relaxed phenylephrine (PE, 1 µm) and high K(+) (80 mm)-induced contractions, as well as suppressed the PE (1 µm) control peaks obtained in Ca(++) -free medium, like that caused by verapamil. The vasodilator effect of Am.Cr was partially blocked by N(ω) -nitro-l-arginine methyl ester in endothelium intact preparations. In guinea-pig tracheal strips, Am.Cr inhibited carbachol (CCh, 1 µm) and K(+) -induced contractions. These results indicate that Achillea millefolium exhibits hypotensive, cardiovascular inhibitory and bronchodilatory effects, thus explaining its medicinal use in hyperactive cardiovascular and airway disorders, such as hypertension and asthma., (Copyright © 2010 John Wiley & Sons, Ltd.)

This study describes the gut, airways and cardiovascular modulatory activities of Zanthoxylum armatum DC. (Rutaceae) to rationalize some of its medicinal uses. The crude extract of Zanthoxylum armatum (Za.Cr) caused concentration-dependent relaxation of spontaneous and high K(+) (80 mM)-induced contractions in isolated rabbit jejunum, being more effective against K(+) and suggestive of Ca(++) antagonist effect, which was confirmed when pretreatment of the tissues with Za.Cr shifted Ca(++) concentration-response curves to the right, like that caused by verapamil. Za.Cr inhibited the castor-oil-induced diarrhea in mice at 300-1000 mg/kg. In rabbit tracheal preparations, Za.Cr relaxed the carbachol (1 microM) and high K(+)-induced contractions, in a pattern similar to that of verapamil. In isolated rabbit aortic rings, Za.Cr exhibited vasodilator effect against phenylephrine (1 microM) and K(+)-induced contractions. When tested in guinea pig atria, Za.Cr caused inhibition of both atrial force and rate of spontaneous contractions, like that caused by verapamil. These results indicate that Zanthoxylum armatum exhibits spasmolytic effects, mediated possibly through Ca(++) antagonist mechanism, which provides pharmacological base for its medicinal use in the gastrointestinal, respiratory and cardiovascular disorders., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

The crude extract of Achillea millefolium (Am.Cr) was studied for its possible hepatoprotective effect against d-galactosamine (d-GalN) and lipopolysaccharide (LPS) induced hepatitis in mice and antispasmodic effect in isolated gut preparations to rationalize some of the folklore uses. Co-administration of d-GalN (700 mg/kg) and LPS (25 microg/kg) produced 100% mortality in mice. Pre-treatment of animals with Am.Cr (300 mg/kg) reduced the mortality to 40%. Co-administration of d-GalN (700 mg/kg) and LPS (1 microg/kg) significantly raised the plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with values in the control group (p < 0.05). Pre-treatment of mice with Am.Cr (150-600 mg/kg) significantly prevented the toxins induced rise in plasma ALT and AST (p < 0.05). The hepatoprotective effect of Am.Cr was further verified by histopathology of the liver, which showed improved architecture, absence of parenchymal congestion, decreased cellular swelling and apoptotic cells, compared with the toxin group of animals. In isolated rabbit jejunum preparations, Am.Cr caused a concentration-dependent (0.3-10 mg/mL) relaxation of both spontaneous and K(+)-induced contractions as well as shifting the Ca(++) concentration-response curves (CRCs) to the right, similar to that caused by verapamil. These results indicate that the crude extract of Achillea millefolium exhibits a hepatoprotective effect, which may be partly attributed to its observed calcium channel blocking activity.