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 (NFκB). 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.

Epilepsy is a neurological disorder involving persistent spontaneous seizures and uncontrolled neuronal excitability that leads to cognitive impairments and blood–brain barrier (BBB) disruption. Currently available antiepileptic drugs present side effects and researchers are trying to discover new agents with properties to overcome these drawbacks. The aim was to synthesize magnesium oxide (MgO) and zinc oxide (ZnO) nanoparticles from Datura alba fresh leaf extracts and evaluate their anti-epileptic potential in mice kindling or a repetitive seizures model. The phytoassisted synthesized nanoparticles were characterized using spectroscopy; FT-IR, XRD, SEM, and EDX. Analysis of the NPs confirmed the crystalline pleomorphic shape using the salts of both zinc and magnesium possibly stabilized, functionalized and reduced by bioactive molecules present in plant extract. By using several characterization techniques, NPs were confirmed. UV-Vis spectroscopy of biologically produced ZnO and MgO revealed distinctive peaks at 380 nm and 242 nm, respectively. Our findings categorically demonstrated the reductive role of biomolecules in the formation of ZnO and MgO NPs. The mice kindling model was induced using seven injections of Pentylenetetrazole (PTZ, 40 mg/kg, i.p) for 15 days alternatively. The results showed that mice post-treated with either ZnO or MgO nanoparticles (10 mg/kg, i.p) significantly improved in respect of behavior and memory as confirmed in the Morris water maze (MWM), open field (OF), novel object recognition (NOR) test compared with PTZ treated mice. Furthermore, the ZnO and MgO nanoparticle treatment also maintained the integrity of the BBB, reducing the leakage, as confirmed by Evans blue dye (EBD) compared with PTZ treated mice only. In summary, the current finding demonstrates that green synthesized ZnO and MgO nanoparticles have neuroprotective, ant-epileptic potential, molecular mechanisms, and clinical implications need to be further explored.

This study aimed to appraise the anti-leishmanial potentials of benzoic acid derivatives, including methyl 3,4-dihydroxybenzoate (compound 1) and octadecyl benzoate (compound 2), isolated from the ethnomedicinally important plant Ifloga spicata (I. spicata). Chemical structures were elucidated via FT-IR, mass spectrometry, and multinuclear (¹H and ¹³C) NMR spectroscopy. Anti-leishmanial potentials of the compounds were assessed using Leishmania tropica promastigotes. Moreover, acridine orange fluorescent staining was performed to visualize the apoptosis-associated changes in promastigotes under a fluorescent microscope. A SYTOX assay was used to check rupturing of Leishmania promastigote cell membranes using 0.1% Triton X-100 as positive control. A DNA interaction assay was carried out to assess DNA attachment potential. AutoDock software was used to check the binding affinity of compounds with surface enzyme leishmanolysin gp63 (1LML). Both compounds exhibited considerable anti-leishmanial potential, with LD₅₀ values of 10.40 ± 0.09 and 14.11 ± 0.11 μg/mL for compound 1 and compound 2, respectively. Both compounds showed higher binding affinity with the leishmanolysin (gp63) receptor/protease of Leishmania, as assessed using computational analysis. The binding scores of compounds 1 and 2 with target gp63 were −5.3 and −5.6, respectively. The attachment of compounds with this receptor resulted in their entry into the cell where they bound with Leishmania DNA, causing apoptosis. The results confirmed that the investigated compounds have anti-leishmanial potential and are potential substitutes as natural anti-leishmanial agents against L. tropica.

Major depressive disorder (MDD) is a progressive deteriorating mental state with a feeling of worthlessness and frequent mood swings. Several studies reported the favorable effects of natural drug substances on MMD associated oxidative stress and neuroinflammation. The present study is attempted to examine whether carveol could affect lipopolysaccharide‐ (LPS‐) induced depression, and if so, how nuclear factor E2‐related factor (Nrf2) contributed to the neuroprotective effects of carveol mechanistically. Two experimental cohorts were used using the SD rats: first to evaluate the promising dose of carveol (whether 20 mg/kg or 50 mg/kg) and secondly to determine the effect of carveol on Nrf2‐mediated antidepression. Significant neuronal alterations were noticed in the cortex and hippocampus regions in the LPS‐treated group, accompanied by elevated inflammatory cytokine levels such as tumor necrosis factor‐alpha (TNF‐α), cyclooxygenase (COX‐2), and c‐Jun N‐terminal kinase (p‐JNK). Moreover, amassing of free radicals exacerbated lipid peroxidase (LPO) and oxidative stress with a limited antioxidant capacity. Carveol (20 mg/kg) significantly ameliorated these detrimental effects by promoting the antioxidant Nrf2 gene and protein, which critically regulate the downstream antioxidant and anti‐inflammatory pathway. To further elaborate our hypothesis, we employed all‐trans retinoic acid (ATRA), an Nrf2 inhibitor, and we found that ATRA exaggerated LPS‐induced depressive‐like effects associated with elevated neuroinflammatory markers. Our results demonstrated that carveol (20 mg/kg) could activate the endogenous antioxidant Nrf2, which regulates the downstream antioxidant signaling pathway, eventually leading to amelioration of LPS‐induced neuroinflammation and neurodegeneration.

Traumatic brain injury (TBI) is the major and leading cause of mortality and an alarming public health challenge. TBI leads to permanent cognitive, motor, sensory and psychotic disabilities. Patients suffering from the various and long-term repercussions of TBI currently have limited therapy choices. The current research work was designed to evaluate the beneficial and neuroprotective role of Troxerutin (Trox) (a natural flavonoid) in a closed brain injury mouse model. The male BALB/c 8-weeks old mice (n꞊150) were randomly distributed in three experimental groups. Control group of mice (n꞊50), TBI group (n꞊50) and Trox pre-treated mice group (Trox + TBI, n꞊50). The mice in Trox + TBI were pre-treated with Trox (150 mg/kg, 7 days) before TBI. The weight-drop mechanism was used to induce mild-moderate injury in mice in both the groups. Our results showed that the mice pre-treated with troxerutin significantly improved neurological severity score, blood glucose level, food intake and brain edema as compared to the mice in the TBI group. Furthermore, compared to the TBI group, the mice treated with troxerutin improved cognitive behavior as evaluated by Open field test, Shallow Water Maze and Y-Maze, decreased brain-infarct volume and blood-brain barrier (BBB) permeability, significantly decreased Reactive Oxygen Species (ROS), improved neuronal morphology and survival in the brain regions such as cortex and hippocampus. In summary, our data provided evidence that pre-treatment with troxerutin improved neurological functions, decreased the BBB permeability, improved behavior, reduced ROS and increased neuronal survival in the weight-drop close head traumatic injury mouse model.