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Histamine H3 receptor (H3R) antagonists, such as betahistine (BHTE), have shown significant potential in treating central nervous system (CNS) disorders due to their neuroprotective properties. This study investigated BHTE’s effects on lipopolysaccharide (LPS)-induced neurotoxicity, which is associated with neuroinflammation and neurodegeneration. Rats were divided into groups and pre-treated with BHTE (5 or 10 mg/kg, p.o.) for 30 days, followed by LPS administration (1 mg/kg, i.p.) for 4 consecutive days to induce neurotoxicity. LPS exposure resulted in cognitive impairment, as evidenced by performance deficits in maze tests, and a significant reduction in brain acetylcholine (ACh) levels. Additionally, LPS led to increased neuroinflammation, oxidative stress, mitochondrial dysfunction, and apoptosis. Pre-treatment with BHTE effectively counteracted these effects, improving cognitive performance and restoring ACh levels. BHTE significantly reduced LPS-induced increases in pro-inflammatory markers (COX-2, TNF-α, and IL-6) while enhancing anti-inflammatory cytokines (IL-10 and TGF-β1). Furthermore, BHTE improved mitochondrial function by increasing enzyme levels (MRCC-I, II, and IV) and boosted anti-apoptotic (Bcl-2) and antioxidant defenses (GSH and catalase). BHTE also reduced apoptosis markers, including pro-apoptotic protein caspase-3, and oxidative stress marker malondialdehyde (MDA). Molecular modeling studies revealed that BHTE effectively binds to key enzymes involved in neuroinflammation and apoptosis (AChE, COX-2, and caspase-3), with binding free energies between 4 and 5 kcal/mol, interacting with critical residues. These findings underscore BHTE’s multifaceted neuroprotective effects against LPS-induced neurotoxicity, offering potential therapeutic avenues for managing neuroinflammation and related neurodegenerative disorders.

Tobacco and alcohol have been identified as health risk behaviors associated with significant unfavorable health consequences, ranking within the list of the top ten causes of mortality and disability-adjusted life years (DALY). The combustion of tobacco leads to the formation of acrylamide (ACR), which is well known for its neurotoxic effects. Similarly, alcohol consumption has also been widely recognized for its neurotoxic effects. Both substances can affect neurons and neuroglia cells through various pathways. This study sought to examine the impacts of co-administration of ACR and intermittent-access ethanol (IAE) consumption over a period of one month. The experimental group received 20 mg/kg of ACR, administered orally, along with IAE of 20% ethanol sessions lasting 24 h, three times per week. The cognitive outcomes were assessed utilizing the elevated plus maze (EPM), which was employed as a means of assessing the capability to learn and remember, the novel object recognition (NOR) test, which was employed to assess recognition memory, and the Y-maze, which was used to explore a new environment and navigate. Additionally, ELISA assays were performed to examine underlying mechanisms, including markers associated with inflammation (NF-κB, PGE2, and TNF-α), apoptosis (Bcl2, Bax, and Caspase-3), and oxidative stress (MDA, catalase, and GSH). These markers were assessed in the brain homogenate as part of the investigation. Furthermore, a histopathological study was conducted. The findings indicated that NF-κB levels increased significantly in the combination of ACR and IAE groups (ACR + IAE) compared to either the ACR-alone or IAE-alone groups. However, parallel changes were observed in TNF-α, PGE2, Bax, Bcl-2, Caspase-3, GSH, and CAT levels when comparing the ACR + IAE group to the ACR-alone group. Comparable alterations were noted between the ACR + IAE treatment and IAE-alone groups in TNF-α, Bcl-2, MDA, GSH, and CAT levels. Moreover, the histopathological analysis revealed significant changes between the ACR + IAE and the ACR- or IAE-alone groups. Regarding memory parameters assessed using tests including EPM, NOR, and Y-maze, considerable changes were observed across all treatment groups as opposed to the control. Surprisingly, there were no notable differences in the NOR and Y-maze tasks between the alone and combination treatment. Further study is necessary to explore the long-term alteration of co-administering ACR and IAE on behavior, memory, and neurotoxicity-related mechanisms, in order to elucidate their combined effects more clearly.

Cognitive decline is one of the serious complications associated with diabetes mellitus (T2DM) of type-2. In this reported work, the effect of aqueous sukkari dates seed extract (ASSE) was evaluated in T2DM-induced rats. T2DM was induced using intraperitoneal injection of nicotinamide and streptozocin (STZ) administration. The diabetic rats were then treated orally with 200 mg/kg and 400 mg/kg of dates seed extract for 30 days and results were compared with metformin-treated groups. The memory functions were assessed using three maze models. Glucose and insulin levels in the blood and acetylcholine, acetylcholinesterase brain homogenates were estimated. The results showed a significant reduction in transfer latency (TL) (p 0.05) with novel objects and a higher discrimination index (p > 0.05). The Y-maze test also showed a significant increase in the number of entries to the novel arm (p > 0.05) and the total number of entries in the trial (p > 0.01) as well as in test (p > 0.05) sessions. Reduction in blood glucose (p > 0.05) and improvement in blood insulin (p > 0.05) levels were also noted. Improvement in ACh levels (p > 0.001) with 400 mg/kg of ASSE and reduction in AChE (p > 0.001) with both doses of ASSE were also observed in the brain homogenates. The results of ASSE were found comparable with the metformin-treated rats. The estimation of phytochemical constituents displayed a significant presence of phenolic content. Further, molecular modeling studies showed ellagic acid, catechin, and epicatechin as the potential molecule interacting with GSK-3β, α-amylase, and AChE and may be responsible for observed bioactivity. In conclusion, ASSE has the ability to alleviate T2DM-related cognitive impairments.

The ATP-binding cassette is the major class of transporters responsible for the efflux of chemotherapeutic agents from cancer cells, resulting in treatment failures of cancer’s patients. Suaeda vermiculata Forssk. ex. J. F. Gmel. is traditionally known for its liver protective activity. The LC-MS based chemical profilings of the sequentially partitioned sub-extracts obtained from the alcoholic extract of S. vermiculata using n-hexane, chloroform, ethyl acetate, and n-butanol as fractionating solvents, identified a total of thirty six compounds. These sub-extracts were evaluated for their anti-hepatocarcinoma activity against the sensitive HepG2 and doxorubicin (DOX)-resistant, HepG-2/ADR cell lines. A mixture of doxorubicin and sub-extracts at 20 μg/ml doses were also tested for their anti-hepatocarcinoma activity. The exhibited IC50 values for the chloroform, ethyl acetate, n-hexane, and n-butanol sub-extracts, and the doxorubicin against HepG2, and HepG-2/ADR cell lines were found at 64.5, 66.8, 81.25, 125, 1.3 μg/ml, and 110.1, 91.82, 138.2, 265.7, 4.77 μg/ml levels, respectively. However, the treatment of resistant cells with 20 μg/ml of different sub-extracts in combination with the doxorubicin showed significant improvements in the doxorubicin activity against the resistant cells, and the IC50 values for DOX + chloroform, DOX + ethyl acetate, DOX + n-hexane, and DOX + n-butanol against resistant cells, were at 1.77, 2.05, 2.66, and 2.71 μg/ml levels, respectively. The IC50 values exhibited 2.69x, 2.33x, 1.79x and 1.76x-folds reversal of the sensitivity in the resistant cancer cell lines. The molecular docking studies of the compounds identified in the LC-MS chemical profilings, against three ATP-binding cassette proteins i.e., ABCB1, ABCC1, and ABCG2, showed that flavonoids as the major class of compounds responsible for reversal of the resistant cells sensitivities. The predicted binding affinity for the flavonoids against the above mentioned three ATP-binding cassette proteins’ are in the ranges of ∼−8 to −11 kcal/mol. Our results clearly indicate that the presence of flavonoids, as the major class of compounds in the S. vermiculata is responsible for the chemosensitization of the resistant HCC-cell lines. Moreover, the structures, 21 (5‐O‐methyl visamminol), 22 (N-trans-feruloyl tyramine), 27 (atractylenolide-III), and 32 (ginsenoside-Rh2) were also identified among the potential ATP-binding cassette’s modulators during the current study. These observations put the S. vermiculata in perspective with the traditionally claimed liver protective efficacy of the plant.

Islamic literature has indicated that daily consumption of Ajwa dates heals a variety of chronic diseases and disorders. The current research investigates the neuroprotective effect of methanolic Ajwa seed extract (MASE) on lipopolysaccharide (LPS)-induced cognitive deficits using multiple approaches. For animal studies, MASE (200 and 400 mg/kg, p.o.) was administrated for thirty consecutive days, and four doses of LPS (250 µg/kg, i.p.) were injected to induce neurotoxicity. Memory functions were evaluated using elevated plus-maze and novel object recognition tests. Acetylcholine (ACh) and neuroinflammatory markers (cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and transforming growth factor (TGF)-β1) were estimated in brain tissues. Studies of molecular docking and dynamics were conducted to provide insight into the molecular-level mechanisms. MASE administration resulted in a significant reversal of LPS-induced memory impairment in both maze models. Both doses of MASE elevated the ACh levels in an LPS-treated rat brain. In addition, the extract lowered COX-2 and proinflammatory cytokines (TNF-α and IL-6) while increasing anti-inflammatory cytokines (IL-10 and TGF-β1) in LPS-treated brain tissues. Molecular modeling results revealed that the compound’s ellagic acid, epicatechin, catechin, kaempferol, quercetin, and apigenin have the potential to act as a dual inhibitor of acetylcholinesterase (AChE) and COX-2 and can be responsible for the improvement of both cholinergic and inflammatory conditions, while the cinnamic acid, hesperidin, hesperetin, narengin, and rutin compounds are responsible only for the improvement of cholinergic transmission. The above compounds acted by interacting with the key residues Trp84, Asp72, Gly118, Ser200, Tyr334, and His440, which are responsible for the hydrolysis of ACh in AChE, while the COX-2 is inhibited by interacting with the residues (Val349, Leu352, Tyr355, Tyr385, Ala527, Ser530, and Leu531) of the hydrophobic channel. By promoting cholinergic activity and protecting neuroinflammation in the rat brain, MASE provides neuroprotection against LPS-induced cognitive deficits. Our preliminary findings will help with further drug discovery processes related to neuroinflammation-related neurodegeneration.

Cancer chemotherapy is known to cause cognitive defects in patients. Our study investigated the effect of piracetam (PIRA; 200 or 400 mg/kg) against doxorubicin (DOX)-induced cognitive deficits in a rat model. The cognitive parameters were analyzed using elevated plus-maze, novel object recognition, and Y-maze tests. Acetylcholinesterase (AChE), neuroinflammatory mediators (cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nuclear factor-κB (NF-κB), tumor necrosis factor-alpha (TNF-α)), apoptotic proteins (B-cell lymphoma-2 (Bcl-2), Bcl2 associated X protein (Bax), cysteine aspartate specific protease-3 (caspase-3)), oxidative parameters (malondialdehyde (MDA), catalase (CAT), and glutathione (GSH)) were also determined in the brain. PIRA administration offered significant protection against DOX-induced cognitive deficits in all maze tests and restored cholinergic functions via a significant reduction in AChE levels. Additionally, PIRA suppressed DOX-induced neuroinflammatory mediators (COX-2, PGE2, NF-κB, and TNF-α), pro-apoptotic proteins (Bax and caspase-3), and oxidative stress (MDA). Besides, it facilitated antioxidant (CAT and GSH) levels. Hence, our study highlighted that the neuroprotective activity of PIRA against DOX-induced cognitive deficits can be linked to reductions of AChE levels, neuro-inflammatory mediators, pro-apoptotic proteins, and oxidative stress.

Cancer chemotherapy-induced cognitive impairment (chemobrain) is a major complication that affects the prognosis of therapy. Our study evaluates the nootropic-like activity of levetiracetam (LEVE) against doxorubicin (DOX)-induced memory defects using in vivo and molecular modelling. Rats were treated with LEVE (100 and 200 mg/kg, 30 days) and chemobrain was induced by four doses of DOX (2 mg/kg, i.p.). Spatial memory parameters were evaluated using an elevated plus maze (EPM) and Y-maze. Additionally, acetylcholinesterase (AChE) and the neuroinflammatory biomarkers cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nuclear factor-κB (NF-κB), and tumor necrosis factor-alpha (TNF-α) were analyzed using brain homogenate. PharmMapper was used for inverse docking and AutoDock Vina was used for molecular docking. LEVE treatment significantly diminished the DOX-induced memory impairment parameters in both the EPM and Y-maze. In addition, the drug treatment significantly reduced AChE, COX-2, PGE2, NF-κB, and TNF-α levels compared to DOX-treated animals. The inverse docking procedures resulted in the identification of AChE as the potential target. Further molecular modelling studies displayed interactions with residues Gly118, Gly119, and Ser200, critical for the hydrolysis of ACh. Analysis of the results suggested that administration of LEVE improved memory-related parameters in DOX-induced animals. The ‘nootropic-like’ activity could be related to diminished AChE and neuroinflammatory mediator levels.

Clobenpropit (CLO), an antagonist on histamine H3 receptors (HH3R), has been shown to protect NMDA-induced neuronal necrosis in cortical neuronal cell culture from rats. In this work, we explored its potential on lipopolysaccharide (LPS)-induced memory deficits, neuroinflammation, and mitochondrial dysfunction in mice. CLO (1 and 3 mg/kg, p.o.) was treated continually for 30 days, and neurotoxicity was induced by four doses of LPS (250 µg/kg, i.p.). The radial arm maze (RAM) was used to access memory behaviors. After the REM test, brain tissue was collected from each mouse to estimate pro-inflammatory cytokines (TNFα and IL6), anti-inflammatory cytokines (TGF-β1 and IL-10), cyclooxygenase-2 (COX 2), and mitochondrial respiratory chain complex (MRCC- I, II and IV) enzymes. CLO treatment reversed the LPS-induced behavioral deficits by a significant reduction in time taken to consume all five bites (TTB), working memory error (WME), and reference memory error (REM) in the REM test. Regarding neuroinflammation, it attenuated the release of COX, TNF-α, and IL-6, and augmented TGF-β1 and IL-10 levels in the brain. Reversal of LPS-induced brain MRCC (I, II, and IV) levels also resulted with CLO treatment. From these findings, CLO promises neuroprotection against LPS-induced cognitive deficits by ameliorating neuroinflammation and restoring the MRCC enzymes in mice.