A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically-validated essential oil derived from Melissa officinalis (MO), which has shown clinical benefit in treating agitation. MO inhibited binding of [35S] t-butylbicyclophosphorothionate (TBPS) to the rat forebrain gamma-aminobutyric acid (GABA)(A) receptor channel (apparent IC50 0.040+/-0.001 mg mL(-1)), but had no effect on N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropianate (AMPA) or nicotinic acetylcholine receptors. Electrophysiological analyses with primary cultures of rat cortical neurons demonstrated that MO reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01-1 mg mL(-1)), whereas no inhibition of NMDA- or AMPA-induced currents was noted. Interestingly, MO elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classical GABA(A) antagonist picrotoxinin which evoked profound epileptiform burst firing in these cells). The anti-agitation effects in patients and the depressant effects of MO in in-vitro we report in neural membranes are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here.

Evidence demonstrated that glial cells, mainly astrocytes, regulate glutamate uptake, which is regulated by several glutamate transporters. Among these glutamate transporters, glutamate transporter 1 (GLT-1; its human homolog is excitatory amino acid transporter-2) is responsible for the majority of glutamate uptake by glial cells. Cystine-glutamate antiporter (xCT) is another glial protein critical in regulating glutamate transmission. Several studies from our laboratory demonstrated that attenuation of ethanol intkae was associated in part with upregulation of xCT and GLT suggesting the important role of these transporters in the treatment of ethanol dependence. We found recently that β-lactam antibiotic, ampicillin, upregulated GLT-1 expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) and consequently reduced ethanol intake in alcohol-preferring (P) rats. In this study, we investigated the effects of ampicillin on the expressions of xCT and GLT-1 isoforms (GLT-1a and GLT-1b) as well as on GLAST expression. We found that ampicillin reduced ethanol intake as compared to the saline (control)-treated group. In addition, we found that ampicillin induced upregulation of xCT, GLT-1a, and GLT-1b expressions in both the PFC and NAc, but had no effect on GLAST expression. Our findings provide significant role of ampicillin on upregulating xCT and GLT-1 isoforms expressions, might be suggested as possible tragets for the attenuation of ethanol consumption.

Butyrylcholinesterase (BChE) plays an important role in the progression of the Alzheimer’s disease. In this study, we used a structure-based virtual screening (VS) approach to discover new BChE inhibitors. A ligand database was filtered and docked to the BChE protein using Glide program. The outcome from VS was filtered and the top ranked hits were thoroughly examined for their fitting into the protein active site. Consequently, the best 38 hits were selected for in vitro testing using Ellman’s method, and six of which showed inhibition activity for BChE. Interestingly, the most potent hit (Compound 4) exhibited inhibitory activity against the BChE enzyme in the low micromolar level with an IC50 value of 8.3 µM. Hits obtained from this work can act as a starting point for future SAR studies to discover new BChE inhibitors as anti-Alzheimer agents.

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Inhibition of the enzyme acetylcholinesterase (AChE) has been shown to alleviate neurodegenerative diseases prompting several attempts to discover and optimize new AChE inhibitors. In this direction, we explored the pharmacophoric space of 85 AChE inhibitors to identify high quality pharmacophores. Subsequently, we implemented genetic algorithm-based quantitative structure-activity relationship (QSAR) modeling to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of explaining bioactivity variation among training compounds (r2(68)=0.94, F-statistic=125.8, r2 LOO=0.92, r2 PRESS against 17 external test inhibitors = 0.84). Two orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least two binding modes accessible to ligands within AChE binding pocket. The successful pharmacophores were comparable with crystallographically resolved AChE binding pocket. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute list of compounds. Twenty-four low micromolar AChE inhibitors were identified. The most potent gave IC50 value of 1.0 μM.

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Objectives: This study aims to provide a comprehensive overview of the hospitalization pattern of nervous system diseases from 1999 to 2019. Methods: This is ecological research based on data from the Hospital Episode Statistics database in England and the Patient Episode Database in Wales, both of which are publicly available. Data on hospital admissions were collected between April 1999 and March 2019. Diagnostic codes (G00–G09: inflammatory diseases of the central nervous system, G10–G14: systemic atrophies primarily affecting the central nervous system, G20–G26: extrapyramidal and movement disorders, G30–G32: other degenerative diseases of the nervous system, G35–G37: demyelinating diseases of the central nervous system, G40–G47: episodic and paroxysmal disorders, G50–G59: nerve, nerve root and plexus disorders, G60–G65: polyneuropathies and other disorders of the peripheral nervous system, G70–G73: diseases of myoneural junction and muscle, G80–G83: cerebral palsy and other paralytic syndromes, and G89–G99: other disorders of the nervous system) from the tenth edition of the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) were used to identify hospital admissions. A Poisson model was used to examine the trend in hospital admissions. Results: During the study period, hospital admission rate increased by 73.5% (from 474.44 (95% CI 472.58–476.31) in 1999 to 823.37 (95% CI 821.07–825.66) in 2019 per 100,000 persons, trend test, p < 0.01). The most prevalent diseases of the nervous system hospital admissions causes were episodic and paroxysmal disorders, nerve, nerve root, and plexus disorders, and demyelinating diseases of the central nervous system which accounted for 37.4%, 22.1%, and 9.3%, respectively. Hospital admission rate between females increased by 79.1% (from 495.92 (95% CI 493.25–498.58) in 1999 to 888.33 (95% CI 884.97–891.68) in 2019 per 100,000 persons). Hospital admission rate between males was increased by 67.5% (from 451.88 (95% CI 449.28–454.49) in 1999 to 756.82 (95% CI 753.69–759.96) in 2019 per 100,000 persons). Conclusion: In the United Kingdom, hospital admissions for diseases of the nervous system are on the rise. Future research is needed to identify high-risk groups and suggest effective interventions to reduce the prevalence of these disorders.