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Epilepsy is a neurological disorder characterized by recurrent spontaneous seizures alongside other neurological comorbidities. Cognitive impairment is the most frequent comorbidity secondary to progressive neurologic changes in epilepsy. Sigma 1 receptors (σ1 receptors) are involved in the neuroprotection and pathophysiology of both conditions and targeting these receptors may have the potential to modulate both seizures and comorbidities. The current research demonstrated the effect of clemastine (10 mg/kg, P.O.), a non-selective σ1 receptor agonist, on pentylenetetrazol (PTZ) (35 mg/kg, i.p., every 48 h for 14 doses)-kindling rats by acting on σ1 receptors through its anti-inflammatory/antioxidant capacity. Clemastine and phenytoin (30 mg/kg, P.O.) or their combination were given once daily. Clemastine treatment showed a significant effect on neurochemical, behavioural, and histopathological analyses through modulation of σ1 receptors. It protected the kindling animals from seizures and attenuated their cognitive impairment in the Morris water maze test by reversing the PTZ hippocampal neuroinflammation/oxidative stress state through a significant increase in inositol-requiring enzyme 1 (IRE1), x-box binding protein 1 (XBP1), along with a reduction of total reactive oxygen species (TROS) and amyloid beta protein (Aβ). The involvement of σ1 receptors in the protective effects of clemastine was confirmed by their abrogation when utilizing NE-100, a selective σ1 receptor antagonist. In light of our findings, modulating σ1 receptors emerges as a compelling therapeutic strategy for epilepsy and its associated cognitive impairments. The significant neuroprotective effects observed with clemastine underscore the potential of σ1 receptor-targeted treatments to address both the primary symptoms and comorbidities of neurological disorders., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cleome amblyocarpa Barr. and Murb. from the family Cleomaceae is used in folk medicine as it has analgesic, anti-inflammatory, antibacterial and antioxidant activities. In this study, ten compounds from the whole plant of C. amblyocarpa , a wild plant that grows in the Sinai Peninsula of Egypt, were isolated. Six compounds, β-sitosterol 3- O -β-d-glucoside 2, calycopterin 5, rhamnocitrin 6, 17α-hydroxycabraleahy-droxylactone 7, cleogynol 8, and β-sitosterol 10 were first isolated from this species. In addition, four previously reported compounds, kaempferol-3, 7-dirhamnoside 1, 15α-acetoxycleomblynol A 3, and 11-α-acetylbrachy-carpone-22(23)-ene 4, as well as cleocarpanol 9, were isolated and identified. Isolated compounds were evaluated to determine their analgesic properties utilizing a hot-plate test method, and their anti-inflammatory effects utilizing rat paw edema. In a hot-plate test, compounds 3, 4, 7, 8, and 9 showed significant pain inhibition in latency time as compared to the normal group. Compounds 3-9 exhibited a significant inhibition of carrageenan-induced inflammation. According to the results of this work, compounds 3 and 4 (Dammarane triterpenoid) have the strongest analgesic/anti-inflammatory activity as compared to the other tested compounds. These results give support to the medicinal benefits of the plant as an analgesic along with an anti-inflammatory agent in traditional therapy. Molecular modelling studies of the isolated compounds 3 and 4 assessed the molecular affinity and binding interaction patterns for these compounds towards COX-2 as compared to specific COX-2 inhibitors and in relation to COX-1 isozyme. Compound 3 revealed extended accommodation across COX-2's hydrophobic sub-pockets and preferential thermodynamic stability across molecular dynamics simulations., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Epilepsy is a chronic widely prevalent neurologic disorder, affecting brain functions with a broad spectrum of deleterious consequences. High mobility group box1 (HMGB1) is a nuclear non-histone protein that targets vital cell receptor of toll-like receptor 4 (TLR4) and advanced glycation end products (RAGE). HMGB1 mediated TLR4/RAGE cascade has been scored as a key culprit in neuroinflammatory signalling that critically evokes development of impaired cognition and epilepsy. The current study aimed to investigate the neuroprotective effect of pentoxifylline (PTX) on pentylenetetrazol (PTZ)-kindling rats by its anti-inflammatory/antioxidant capacity and its impact on memory and cognition were investigated, too. PTZ was intraperitoneally injected 35 mg/kg, every 48 h, for 14 doses, to evoke kindling model. Phenytoin (30 mg/kg, i.p.) and PTX (60 mg/kg, i.p.) or their combination were given once daily for 27 days. PTX treatment showed a statistically significant effect on behavioural, histopathological and neurochemical analysis. PTX protected the PTZ kindling rats from epileptic seizures and improved memory and cognitive impairment through the Morris water maze (MWM) test. Furthermore, PTX reversed PTZ hippocampal neuronal loss by decreasing protein expression of amyloid-β peptide (Aβ), Tau and β site-amyloid precursor protein cleavage enzyme 1 (BACE1), associated with a marked reduction in expression of inflammatory mediators such as HMGB1, TL4, and RAGE proteins. Furthermore, PTX inhibited hippocampal apoptotic caspase 1 protein, total reactive oxygen species (TROS) along with upregulated erythroid 2-related factor 2 (Nrf2) content. In conclusion, PTX or its combination with phenytoin represent a promising drug to inhibit the epilepsy progression via targeting the HMGB1/TLR4/RAGE signalling pathway., (© 2021 John Wiley & Sons Australia, Ltd.)