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Oxidative stress is the critical marker of neurological complications such as Alzheimer's disease (AD). Apple cider vinegar (ACV) is known to have health benefits due to its antidiabetic, anti-inflammatory, and high antioxidant properties. Therefore, we hypothesized that regular consumption of ACV would protect against AD-like neurological diseases via inhibition of oxidative stress. Authors have compared the efficacy of ACV with that of Chrysin and Rivastigmine in cellular and animal studies. In the cellular study, oxidative stress was induced in Neuro2A cells (1 × 107 ) via H2 O2 (50 μM) treatment. Subsequently, acetylcholinesterase (AChE) activity was performed, and cell viability, SOD, GSH, lipid peroxidation (MDA) levels were measured. Similarly, in the animal study, oxidative stress was introduced in Swiss albino mice (10-11 weeks old, 20-25 g, n = 30) via scopolamine (1 mg/kg). Subsequently, histopathological experiments were performed; cognitive ability, AChE activity, and SOD, GSH, and MDA levels were measured. The in vitro results indicated that ACV (2 μM) provided better protection than Chrysin and Rivstigmine in cell viability. ACV has also performed better in restoring the antioxidants markers (SOD, GSH levels) and reducing MDA and AChE levels. In the in vivo study, test compounds (ACV, Chrysin, and Rivastigmine) improved cognitive impairment, increased the SOD and GSH level, reduced the MDA level and AChE activity, and protected the cortex-hippocampal neurons from degeneration. Here also, ACV (0.7%) showed better neuroprotection than the other two compounds. Therefore, these results supported our hypothesis that moderate consumption of ACV might prove to be beneficial prophylaxis against AD-like neurological diseases.

In most animal species, opioids alter colonic motility via the inhibition of excitatory enteric motor neurons. The mechanisms by which opioids alter human colonic motility are unclear. The aim of this study was to describe the effects of loperamide on neuromuscular function in the human colon.Tissue specimens of human colon from 10 patients undergoing an anterior resection were divided into three inter-taenial circular muscle strips. Separate organ baths were used to assess: (1) excitatory transmission (selective blockade of inhibitory transmission: L-NOARG/MRS2179); (2) inhibitory transmission (selective blockade of excitatory transmission: hyoscine hydrobromide); and (3) a control bath (no drug additions). Neuromuscular function was assessed using force transducer recordings and electrical field stimulation (EFS; 20 V, 10 Hz, 0.5 ms, 10 s) prior to and following loperamide and naloxone.In human preparations with L-NOARG/MRS2179, loperamide had no significant effects on isometric contractions. In preparations with hyoscine hydrobromide, loperamide reduced isometric relaxation during EFS (median difference + 0.60 g post-loperamide, Z = -2.35, p = 0.019).Loperamide had no effect on excitatory neuromuscular function in human colonic circular muscle. These findings suggest that loperamide alters colonic function by acting primarily on inhibitory motor neurons, premotor enteric neurons, or via alternative non-opioid receptor pathways.

Purpose: Bowel motion is a significant source of artifacts in mouse abdominal MRI. Fasting and administration of hyoscine butylbromide (BUSC) have been proposed for bowel motion reduction, but with inconsistent results and limited efficacy assessments. Here, we evaluate these regimes for mouse abdominal MRI at high field. Methods: Thirty-two adult C57BL/6J mice were imaged on a 9.4T scanner with a FLASH sequence, acquired over 90 minutes with ~19s temporal resolution. During MRI acquisition, eight mice were injected with a low-dose and eight mice with a high-dose bolus of BUSC (0.5 and 5 mg/kg, respectively). Eight mice were food deprived for 4.5-6.5h before MRI and another group of 8 mice was injected with saline during MRI acquisition. Two expert readers reviewed the images and classified bowel motion, and quantitative voxel-wise analyses were performed for identification of moving regions. After defining the most effective protocol, high-resolution T2-weighted and diffusion-weighted images were acquired from four mice. Results: High-dose BUSC was the most effective protocol for bowel motion reduction, for up to 45 minutes. Fasting and saline protocols were not effective in suppressing bowel motion. High-resolution abdominal MRI clearly demonstrated improved image quality and ADC quantification with the high-dose BUSC protocol. Conclusion: Our data show that BUSC administration is advantageous for abdominal MRI in the mouse. Specifically, it endows significant bowel motion reduction, with relatively short onset timings after injection (~8.5 minutes) and relatively long duration of the effect (~45 minutes). These features improve the quality of high-resolution images of the mouse abdomen., Carlos Bilreiro and Francisca F. Fernandes contributed equally to this work

Forty-seven million people are living with memory-related disorders worldwide. Phytomedicines are gaining extensive interest in the treatment of these ailments. Memory-enhancing (acute and chronic) potentials of commercial grade extracts of Bacopa monnieri (200 mg/kg, po), Ginkgo biloba (150 mg/kg, po), and Lavandula angustifolia (200 mg/kg, po) and their mixture (B. monnieri 100 mg/kg, G. biloba 75 mg/kg, and L. angustifolia 100 mg/kg, po) were compared for their synergistic/additive effects on the Morris water maze (MWM) test and elevated plus maze (EPM) test in scopolamine-induced amnesia in mice. Escape latency and accumulative path length were significantly reduced both in acute (up to day 6) and chronic trials (days 8-14) in B. monnieri-, G. biloba-, and L. angustifolia-treated animals and their mixtures (n = 8, p < .05) in MWM. Furthermore, in probe trials (acute on day 7 and chronic on day 15), the number of crossing-overs at platform position and time spent in platform quadrant were significantly increased, while transfer latency in EPM was decreased in treated animals as compared to the saline group (n = 8, p < .05). The mixture showed synergistic effects on memory enhancement as compared to each extract individually in mice. Further studies may be carried out on the active compounds of B. monnieri at the cellular and molecular levels.

International audience; Rodent models of depression are useful for the investigation of cellular and neuronal mechanisms of antidepressant drugs and for the discovery of potential new targets. In this study, we examined the antidepressant-like effect of scopolamine, a non-selective muscarinic antagonist, in a genetic mouse model of depression obtained through a selective breeding strategy and called H/Rouen. In this model, we observed that scopolamine was active both in males and females at a lower dose (0.03 mg/kg) in the tail suspension test, 30 min following its administration, than observed in CD-1 mice. In addition, we showed this antidepressant-like effect was partly inhibited by an injection of 10 mg/kg of the AMPA receptor antagonist NBQX in both males and females, suggesting the anti-depressant like effect of scopolamine was mainly driven by AMPA receptors in the H/Rouen mouse line. Altogether, our results showed the high sensitivity of the H/Rouen mouse model of depression to study the antidepressant-like effects of pharmacological compounds.

Mitochondrial dysfunction and oxidative stress are identified to contribute to the mechanisms responsible for the pathogenesis of Alzheimer's disease (AD). Scopolamine (SCO) as a potent drug for inducing memory and learning impairment is associated with mitochondrial dysfunction and oxidative stress. In AD clinical trials molecules with antioxidant properties have shown modest benefit. Betanin as a multifunctional molecule with powerful antioxidative properties may be effective in the treatment of neurodegenerative. Hence, this study was designed to investigate the possible therapeutic effect of betanin against SCO-induced AD on Wistar rats. SCO (1 mg/kg) was administrated intraperitoneally to induce the AD in Wistar rats. The rats were treated with betanin doses (25 mg/kg and 50 mg/kg) intraperitoneally for 9 consecutive days. At the end of the 9th day, the animals were subjected to behavioral examination such as novel object recognition and passive avoidance tests and killed to study the mitochondrial and histological parameters. The results showed attenuation of SCO-induced memory and learning impairment by betanin at 50 mg/kg dose. Also, mitochondrial toxicity parameters such as mitochondrial membrane potential collapse, mitochondrial swelling, decreased activity of succinate dehydrogenase, and reactive oxygen species (ROS) production were reversed by betanin (50 mg/kg) compared to the SCO group. In addition, the ameliorative effect of betanin against SCO was demonstrated in histopathological results of hippocampus. The present investigation established that the betanin ameliorates the SCO-induced memory impairments, tissue injuries, and mitochondrial dysfunction by reducing mitochondrial ROS, which may be due to the potent antioxidant action of betanin.

Aims Postoperative urinary retention (PUR) is a known complication of midurethral sling (MUS) placement. The use of certain perioperative medications may influence the risk of this complication. This study aimed to investigate the association of perioperative medications with urinary retention after MUS. Methods This was a retrospective study of women undergoing MUS placement for stress urinary incontinence by a fellowship-trained urologic surgeon between 2015 and 2018, under approval by the Institutional Review Board. Both retropubic and transobturator approaches were included. All patients underwent an active void trial following surgery. Intraoperative medications given by the anesthesia team were retrospectively noted. The Fisher's exact test was used to compare the association of PUR with categorical variables. Results A total of 82 patients were included, 17 (21%) of whom failed postoperative void trial due to urinary retention. Of 25 patients receiving perioperative scopolamine, 40% failed the postoperative void trial, compared to 12% of patients not receiving scopolamine (p = .048). Groups were then stratified based on scopolamine use due to the observed independent association with PUR. Subgroup analysis revealed a stronger association of postoperative retention with scopolamine in patients undergoing concomitant prolapse surgery. Notably, retention rate and scopolamine use were similar whether patients underwent sling placement alone or in combination with prolapse surgery. Rate of retention was also higher for retropubic versus transobturator slings (36% vs. 9%; p = .005). Conclusions Perioperative scopolamine may be associated with an increased risk of postoperative urinary retention following MUS, especially in the setting of a concomitant prolapse surgery.

Rh2 is a rare ginsenoside and there are few reports of its effect on cognition compared with other similar molecules. This study aimed to establish the impact of Rh2 treatment on improving scopolamine (Scop)-induced memory deficits in mice and illuminate the underlying mechanisms. First, memory-related behavior was evaluated using two approaches: object location recognition (OLR), based on spontaneous activity, and a Morris water maze (MWM) task, based on an aversive stimulus. Our results suggested that Rh2 treatment effectively increased the discrimination index of the mice in the OLR test. In addition, Rh2 elevated the crossing numbers and decreased the escape latency during the MWM task. Moreover, Rh2 markedly upregulated the phosphorylation of the extracellular signal-regulated kinase (ERK)-cAMP response element binding (CREB)-brain derived neurotrophic factor (BDNF) pathway in the hippocampus. Meanwhile, the administration of Rh2 significantly promoted the cholinergic system and dramatically suppressed oxidative stress in the hippocampus. Taken together, Rh2 exhibited neuroprotective effects against Scop-induced memory dysfunction in mice. Rh2 activity might be ascribed to several underlying mechanisms, including its effects on modulating the cholinergic transmission, inhibiting oxidative stress and activating the ERK-CREB-BDNF signaling pathway. Consequently, the ginsenoside Rh2 might serve as a promising candidate compound for Alzheimer's disease.

OBJECTIVE To assess the efficacy and safety of outpatient administration of oral hyoscine for cervical ripening. METHODS In a randomized controlled trial at a university hospital in Tehran between September 2017 and December 2018, 100 primiparous women with singleton pregnancy at 380 -400 gestational weeks and Bishop score of 5 or less were randomized to either routine expectant management (control group) or 10 mg of oral hyoscine twice daily for 1 week, followed by once daily for 1 week (hyoscine group). RESULTS Mean ± SD Bishop score in the hyoscine and control groups was, respectively, 1.19 ± 1.38 and 1.08 ± 1.70 at baseline, and 4.56 ± 2.87 and 2.76 ± 2.14 on admission for delivery (P=0.001). Duration of the first stage was 4.10 ± 5.49 hours in the hyoscine and 5.29 ± 6.48 hours in the control group (P=0.03). Duration of the second and third stages was, respectively, 0.52 ± 0.53 and 0.14 ± 0.25 hours in the hyoscine, and 0.59 ± 1.08 and 0.12 ± 0.15 hours in the control group. No adverse effects were reported. CONCLUSION Administration of oral hyoscine in an outpatient setting was found to ripen the cervix with no clinically significant adverse drug reaction. IRANIAN REGISTRY OF CLINICAL TRIALS (IRCT20180819040830N1).

Background and purpose Alzheimer's disease (AD) is the most prevalent disease associated with cognitive dysfunction. Current AD therapeutic agents have several gastrointestinal or psychological adverse effects and therefore, novel therapeutic agents with fewer adverse effects must be developed. Previously, we demonstrated that oleanolic acid, which is similar in chemical structure to maslinic acid, ameliorates cognitive impairment through the activation of tropomyosin receptor kinase (TrkB)-ERK-cAMP response element-binding protein (CREB) phosphorylation and increased levels of brain-derived neurotrophic factor (BDNF). In the present study, we investigate the effect of maslinic acid on cholinergic blockade-induced memory impairment in mice. Methods and key results Maslinic acid reversed scopolamine-induced memory impairment, as determined by the Y-maze, passive avoidance and Morris water maze tests. In addition, we also observed that ERK-CREB, PI3K and PKB (Akt) phosphorylation levels were increased by maslinic acid administration in the mouse hippocampus. Moreover, we determined that the effects of maslinic acid on scopolamine-induced memory impairment in the passive avoidance test were abolished by a specific TrkB receptor antagonist (ANA-12). Additionally, we observed similar temporal changes in the expression levels between BDNF and tissue plasminogen activator in the hippocampus. Conclusion and implications These findings suggest that maslinic acid enhances cognitive function through the activation of BDNF and its downstream pathway signalling in the hippocampus and that it might be a potential therapeutic agent for cognitive decline, such as that observed in AD.

d-Ribose-l-cysteine (DRLC) is an analogue of cysteine that has been shown to boost cellular antioxidant capacity by enhancing intracellular biosynthesis of glutathione (GSH). Deficiency of GSH has been implicated in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder associated with loss of memory. Thus, the use of antioxidants to prevent or retard the progression of memory deteriorations in persons with AD has been the focus of intense investigations. This study was carried out to evaluate the effects of DRLC on memory and scopolamine-induced amnesia, acetyl-cholinesterase activity, and oxidative stress in mice. Male Swiss mice were given oral administration of saline (10 ml/kg), DRLC (25, 50, and 100 mg/kg) or donepezil (1 mg/kg) 30 min before testing for memory performance using Y-maze and object recognition models. Another set of mice were also pretreated orally with saline, DRLC (25, 50, and 100 mg/kg) or donepezil (1 mg/kg) but in combination with scopolamine (3 mg/kg, i.p.) daily for 7 days. Thirty minutes after treatment on Day 7, memory function was then evaluated. The brain levels of acetyl-cholinesterase and oxidative stress parameters were assayed. DRLC significantly (p < .05) enhanced memory performance and attenuated scopolamine-induced amnesia. Increased acetyl-cholinesterase activity and oxidative stress, as shown by decreased antioxidant substrates (glutathione and catalase) and elevated malondialdehyde contents in mice with scopolamine amnesia were also attenuated by DRLC. Our findings suggest that inhibition of oxidative stress and acetyl-cholinesterase activity might contribute to the potential benefit of DRLC in persons with amnesia.

Some medicinal plants of the Solanaceae produce pharmaceutical tropane alkaloids (TAs), such as hyoscyamine and scopolamine. Littorine is a key biosynthetic intermediate in the hyoscyamine and scopolamine biosynthetic pathways. However, the mechanism underlying littorine formation from the precursors phenyllactate and tropine is not completely understood. Here, we report the elucidation of littorine biosynthesis through a functional genomics approach and functional identification of two novel biosynthesis genes that encode phenyllactate UDP-glycosyltransferase (UGT1) and littorine synthase (LS). UGT1 and LS are highly and specifically expressed in Atropa belladonna secondary roots. Suppression of either UGT1 or LS disrupted the biosynthesis of littorine and its TA derivatives (hyoscyamine and scopolamine). Purified His-tagged UGT1 catalysed phenyllactate glycosylation to form phenyllactylglucose. UGT1 and LS co-expression in tobacco leaves led to littorine synthesis if tropine and phenyllactate were added. This identification of UGT1 and LS provides the missing link in littorine biosynthesis. The results pave the way for producing hyoscyamine and scopolamine for medical use by metabolic engineering or synthetic biology.

To determine: the effectiveness of three anticholinergic medications in reducing drooling in children with developmental disabilities (such as cerebral palsy, intellectual disability, and autism spectrum disorder), the frequency and nature of side effects, and their impact on treatment discontinuation.After prescription of benzhexol hydrochloride, glycopyrrolate, or scopolamine patches at a tertiary saliva control clinic, all carers of 110 consecutive, eligible patients were recruited over a 5-year period. They provided data for 52 weeks, or until drug discontinuation, on compliance, drooling, adverse effects, and reasons for cessation. We evaluated and compared best drooling response, side effects, and drug cessation rates using survival analysis, and the effect of baseline variables on the discontinuation rate using proportional hazards regression.Among 110 participants (71 males, 39 females; mean age 8y 5mo [SD 4y 3mo], range 1y 11mo-18y 11mo), benzhexol, glycopyrrolate, and scopolamine were prescribed 81, 62, and 17 times respectively, with respective response rates of 85%, 75%, and 65%. Poor head control and poor oromotor function were predictive of poor response. Side effects frequently prompted drug cessation in males more than females (hazard ratio 1.8 [95% confidence interval 1.0-3.2], p=0.048). Glycopyrrolate had the fewest side effects.Benzhexol, glycopyrrolate, and scopolamine reduce drooling, but improvement is offset by adverse side effects. Overall, glycopyrrolate performs best.In drooling, glycopyrrolate produced the greatest improvement with fewer side effects compared with benzhexol and scopolamine. Poor head control and poor oromotor function were associated with poor response. Medication side effects were common and often led to treatment discontinuation. Behavioural issues instigated cessation of benzhexol more often in males than females.MEDICAMENTOS ANTICOLINÉRGICOS PARA REDUCIR EL BABEO EN NIÑOS CON TRASTORNOS DEL DESARROLLO: OBJETIVO: Determinar: la eficacia de tres medicamentos anticolinérgicos en la reducción del babeo en niños con trastornos del desarrollo (como parálisis cerebral, discapacidad intelectual y el trastorno del espectro autista), la frecuencia y la naturaleza de los efectos secundarios y su impacto en la interrupción del tratamiento. MÉTODO: Después de la prescripción de trihexifenidilo, glicopirrolato o parches de escopolamina en una clínica terciaria de control de saliva, fueron reclutados los cuidadores de 110 pacientes elegibles durante un período de 5 años. Estos proporcionaron datos sobre el cumplimiento, babeo, efectos adversos y razones para el cese, durante 52 semanas o hasta la interrupción del medicamento. Se evaluó y comparó la mejor respuesta al babeo, efectos secundarios y tasas de cese de drogas, utilizando el análisis de supervivencia y el efecto de las variables basales en la tasa de interrupción utilizando el modelo de riesgos proporcionales. RESULTADOS: Entre 110 participantes (71 varones y 39 mujeres; edad promedio de 8 años 5 meses [DE 4 años 3 meses], con rango de 1 año 11 meses - 18 años 11 meses), se prescribió trihexifenidilo, glicopirrolato y escopolamina, 81, 62, y 17 veces respectivamente, con tasas de respuesta respectivas de 85%, 75% y 65%. El pobre control cefálico y la mala función oromotora eran predictores de una respuesta deficiente. Los efectos secundarios provocaron el cese de las drogas con más frecuencia en los varones que en las mujeres (relación de riesgo 1,8 [intervalo de confianza del 95% 1,0-3,2], p 0,048). Glicopirrolato tuvo el menor número de efectos adversos INTERPRETACIÓN: El trihexifenidilo, el glicopirrolato y la escopolamina reducen el babeo, sin embargo, la mejora se contrarresta por los efectos secundarios. En general, el glicopirrolato tiene mejores resultados.MEDICAÇÕES ANTICOLINÉRGICAS PARA REDUZIR SIALORRÉIA EM CRIANÇAS COM DEFICIÊNCIAS DESENVOLVIMENTAIS: OBJETIVO: Determinar: a efetividade de três medicações anticolinérgicas na redução da sialorréia em crianças com deficiências desenvolvimentais (como paralisia cerebral, deficiência intelectual, e transtorno do espectro autista), a frequência e natureza dos efeitos colaterais, e seu impacto na descontinuação do tratamento. MÉTODO: Após prescrição de hidroclorido benzexol, glicopirrolato, ou faixas de escopolamina em uma clínica terciária de controle da salivação, todos os cuidadores de 110 pacientes elegíveis consecutivos foram recrutados em um período de 5 anos. Eles forneceram dados de 52 semanas, ou até a descontinuação da medicação, sobre adesão, sialorréia, efeitos adversos, e razões para interrupção. Avaliamos e comparamos a melhor resposta para salivação, efeitos colaterais e interrupção da medicação usando análise de sobrevivência, e o efeito das variáveis na linha de base na taxa de descontinuação usando regressão de riscos proporcionais. RESULTADOS: Entre 110 participantes (71 do sexo masculino, 39 do sexo feminino; média de idade 8a 5m [DP 4a 3m], variação 1a 11m-18a 11m), benzexol, glicopirrolato, e escopolamina foram prescritos 81, 62, e 17 vezes respectivamente, com as respectivas taxas de resposta de 85%, 75%, and 65%. Pouco controle de cabeça e função oromotora foram preditivos de pior resposta. Efeitos colaterais mais frequentemente causaram interrupção da medicação em meninos do que em meninas (taxa de risco 1,8 [intervalo de confiança a 95% 1,0-3,2], p=0,048). Glicopirrolato teve menos efeitos colaterais. INTERPRETAÇÃO: Benzexol, glicopirrolato, ou escopolamina reduzem a sialorréia, mas as melhoras são atenuadas pelos efeitos colaterais. Em geral, glicopirrolato teve o melhor desempenho.

Background Cholinergic dysfunction and oxidative stress are the crucial mechanisms of Alzheimer's disease (AD). GAPT, also called GEPT (a combination of several active components extracted from the Chinese herbs ginseng, epimedium, polygala and tuber curcumae) or Jinsiwei, is a patented Chinese herbal compound, has been clinically widely used to improve learning and memory impairment, but whether it can play a neuroprotective role by protecting cholinergic neurons and reducing oxidative stress injury remains unclear. Methods Male ICR mice were intraperitoneally injected with scopolamine (3 mg/kg) to establish a learning and memory disordered model. An LC‐MS method was established to study the chemical compounds and in vivo metabolites of GAPT. After scopolamine injection, a step‐down passive‐avoidance test (SDPA) and a Y maze test were used to estimate learning ability and cognitive function. In addition, ELISA detected the enzymatic activities of acetylcholinesterase (AChE), acetylcholine (ACh), choline acetyltransferase (ChAT), malondialdehyde (MDA), glutathione peroxidase (GPX), and total superoxide dismutase (T‐SOD). The protein expressions of AChE, ChAT, SOD1, and GPX1 were observed by western blot, and the distribution of ChAT, SOD1, and GPX1 was observed by immunohistochemical staining. Results After one‐half or 1 month of intragastric administration, GAPT can ameliorate scopolamine‐induced behavioral changes in learning and memory impaired mice. It can also decrease the activity of MDA and protein expression level of AChE, increase the activity of Ach, and increase activity and protein expression level of ChAT, SOD, and GPX in scopolamine‐treated mice. After one and a half month of intragastric administration of GAPT, echinacoside, salvianolic acid A, ginsenoside Rb1, ginsenoside Rg2, pachymic acid, and beta asarone could be absorbed into mice blood and pass through BBB. Conclusions GAPT can improve the learning and memory ability of scopolamine‐induced mice, and its mechanism may be related to protecting cholinergic neurons and reducing oxidative stress injury., GAPT can improve the learning and memory ability of scopolamine‐induced mice, and its mechanism may be related to protecting cholinergic neurons and reducing oxidative stress injury.

Scopolamine is an antiemetic agent used for postoperative nausea and vomiting prevention; however, it has anticholinergic effects (eg, bradycardia, dry mouth, dizziness, visual disturbances). Avoiding scopolamine use in specific populations is crucial to prevent adverse effects and harm to patients. This systematic review describes the anticholinergic effects of scopolamine in perioperative patient populations. After searching the available literature, we reviewed the eligible articles to determine whether they met the inclusion criteria (eg, full text, English language, included a discussion of scopolamine's anticholinergic effects in perioperative patients). Twenty-six articles were included in this review. We used The Johns Hopkins Research Evidence Appraisal Tool to appraise the literature. The results of this literature review reveal that clinicians should avoid administering scopolamine to certain perioperative patient populations (ie, pediatric, older adult).

Homeopathic products are still a controversial issue in modern medicine, understood as complementary or alternative medicine (CAM). In this particular case, homeopathic products prepared from Atropa belladonna extracts may present specific problems due to the effects derived from its components. This article applies a simple, rapid, reliable method to the analysis of different homeopathic products obtained from Atropa belladonna; drugs containing high concentration of plant extracts; and Atropa belladonna seeds. The method was based on a simple solid-phase preconcentration method followed by ultra-high pressure liquid chromatography (UHPLC) coupled to high resolution mass spectrometry using Exactive-Orbitrap as an analyser. An in-house database was set and atropine and scopolamine were the compounds detected at highest concentrations in homeopathic products from Atropa belladonna extracts (4.57 and 2.56 μg/kg, respectively), in Belladonna ointment (4007 and 1139 μg/kg, respectively) and Belladonna seeds (338 and 32.1 mg/kg, respectively). Other tropane alkaloids such as tropine, apoatropine, aposcopolamine, tropinone, homatropine, and anisodamine were detected at lower concentrations (0.04-1.36 μg/kg). When untargeted analysis was performed, other tropane alkaloids were identified in the tested samples, such as ecgonine (0.003 μg/kg), benzoylecgonine (0.56 μg/kg), calystegines A (19.6 μg/kg), B (33.1 μg/kg), and C (1.01 μg/kg). Finally other compounds present in the homeopathic products, such as sugars (fructose, glucose, and lactose) or amino acids (valine, ornithine, leucine, and phenylalanine), were identified.

There is a well-known relationship between the cholinergic system and learning, memory, and other common cognitive processes. The process for researching and developing new drugs has lead researchers to repurpose older ones. This study investigated the effects of ebselen on the activity of acethylcholinesterase (AChE) isoforms in vitro and in an amnesia model induced by scopolamine in Swiss mice. In vitro, ebselen at concentrations equal or higher than 10 μM inhibited the activity of cortical and hippocampal G4/AChE, but not G1/AChE isoform. Treatment of mice with ebselen (50 mg/kg, i.p.) was effective against impairment of spatial recognition memory in both Y-maze and novel object recognition tests induced by scopolamine (1 mg/kg, i.p.). Ebselen (50 mg/kg) inhibited hippocampal AChE activity in mice. The present study demonstrates that ebselen inhibited the G4/AChE isoform in vitro and elicited an anti-amnesic effect in a mouse model induced by scopolamine. These findings reveal ebselen as a potential compound in terms of opening up valid therapeutic avenues for the treatment of memory impairment diseases.

Paracetamol is an active ingredient commonly found in pharmaceutical formulations in combination with one of the following compounds: codeine, orphenadrine, promethazine, scopolamine, and tramadol. In this work, we propose a unique analytical method for determination of these active ingredients in pharmaceutical samples. The method is based on capillary electrophoresis with capacitively coupled contactless conductivity detection. The separation was achieved on a fused silica capillary (50 cm total length, 40 cm effective length, and 50 μm id) using an optimized background electrolyte composed of 20 mmol/L β-alanine/4 mmol/L sodium chloride/4 μmol/L sodium hydroxide (pH 9.6). Each sample can be analyzed in a single run (≤2 min) and the limits of detection were 2.5, 0.62, 0.63, 2.5, 15, and 1.6 μmol/L for scopolamine, tramadol, orphenadrine, promethazine, codeine, and paracetamol, respectively. Recovery values for spiked samples were between 94 and 104%.

Some 3-phenyl-quinazolin-4(3H)-one-2-thioethers (3a-e, 5a,b, 7a-e, 9a-d, 10a-d, and 12) along with 2-aminoquinazoline derivatives 13a-c were prepared and screened for their in vitro phosphodiesterase (PDE) inhibitory activity. Some compounds such as 7d,e, 9a,b,d, 10a,d, and 13b exhibited promising activity as compared with the non-selective PDE inhibitor IBMX. This inhibitory activity was validated by molecular docking in the active site of PDE7A and PDE4 to investigate their selectivity. Furthermore, the most active compound 10d (IC50 = 1.15 μM) was tested in vivo using behavioral tests. Compound 10d was able to pass the blood-brain barrier and improve scopolamine-induced cognitive deficits. Therefore, this core can be considered as a promising scaffold for further optimization to obtain new compounds with better PDE7A selective inhibition.

Summary Background and aims Severe motion sickness is a huge obstacle for people conducting precise aviation, marine or emergency service tasks. The combination of scopolamine and d-amphetamine is most effective in preventing severe motion sickness. However, this combination is not included in any present pharmacopoeia due to the abuse liability of d-amphetamine. We wanted to find a combination to replace it for the treatment of severe motion sickness. Methods and results We compared the efficacy of scopolamine, diphenhydramine, and granisetron (representing three classes of drugs) with different doses, and found that scopolamine was the most effective one. We also found scopolamine inhibited central nervous system at therapeutic doses and caused anxiety. Then, we combined it with different doses of psychostimulants (d-amphetamine, modafinil, caffeine) to find the best combination for motion sickness. The efficacy of scopolamine with modafinil (1 + 10 mg/kg) was equivalent to that of scopolamine with d-amphetamine (1 + 1 mg/kg); This combination also excited central nervous system and abolished the anxiety caused by scopolamine. Conclusions The optimal dose ratio of scopolamine and modafinil is 1:10. This combination is beneficial for motion sickness and can abolish the side effects of scopolamine. So, it might be a good replacement of scopolamine and d-amphetamine for severe motion sickness.

Scopolamine was synthesized using 6,7-dehydrotropine as a key intermediate. Rhodium-catalyzed [4 + 3] cycloaddition chemistry and a modified Robinson–Schopf reaction were each independently evaluated for their utility in constructing the tropane core. Both synthetic approaches gave comparable overall yields.

Trace conditioning is impaired by lesions to dorsal hippocampus, as well as by treatment with the muscarinic acetylcholine antagonist scopolamine. However, the role of muscarinic receptors within hippocampus has received little attention. The present study examined the effects of intra-hippocampal infusion of scopolamine (30?g/side) in an appetitive trace conditioning procedure using sucrose pellets as the unconditioned stimulus (US). This treatment resulted in reduced responding to a trace conditioned stimulus (CS), an effect most clearly seen when the US was presented at a 2s trace (inter-stimulus-interval, ISI). Intra-hippocampal scopolamine similarly depressed responding within the ISI (at both 2 and 10s trace intervals), but there was no such effect in the inter-trial-interval (ITI). There was also some overall reduction in responding when the US was delivered; significant at the 10s but not at the 2s trace interval. A similar pattern of results to that seen in response to the CS during acquisition was shown drug-free (in the 5s post-CS) in the extinction tests of conditioned responding. Moreover, in a different apparatus, locomotor activity was increased under scopolamine. Thus the results suggest that non-specific changes in activity or motivation to respond for the US cannot explain the reduction in trace conditioning as measured by reduced CS responding and in the ISI. Rather the findings of the present study point to the importance of associative aspects of the task in determining its sensitivity to the effects of scopolamine, suggesting that muscarinic receptors in the hippocampus are important modulators of short-term working memory.

Banisteriopsis caapi, a liana indigenous to the Amazon basin with metagnomigenic properties and possible anti‐depressant effects is one of the natural sources of harmala alkaloids. A summary of early trials with extracts of Banisteriopsis caapi and Peganum harmala (from which harmine was first isolated) in the 1920s and 1930s on various forms of parkinsonism is given as well as a brief overview of the known pharmacological properties of harmine. Despite its earlier abandonment because of perceived weaker efficacy than solanaceous alkaloids like scopolamine and hyoscine we propose that harmine should be reconsidered as a potential rapidly acting anti‐Parkinsonian agent.

Astronauts experience Space Motion Sickness requiring treatment with an anti-motion sickness medication, scopolamine during space missions. Bioavailability after oral administration of scopolamine is low and variable, and absorption form transdermal patch is slow and prolonged. Intranasal administration achieves faster absorption and higher bioavailability of drugs that are subject to extrahepatic, first pass metabolism after oral dosing. We examined pharmacokinetics of 0.1, 0.2, and 0.4 mg doses of the Investigational New Drug formulation of intranasal scopolamine gel (INSCOP) in 12 healthy subjects using a randomized, double-blind cross-over study design. Subjects received one squirt of 0.1 g of gel containing either 0.1 mg or 0.2 mg/0.1 mL scopolamine or placebo in each nostril. Serial blood samples and total urine voids were collected after dosing and drug concentrations were determined using a modified LC-MS-MS method. Results indicate dose-linear pharmacokinetics of scopolamine with linear increases in Cmax and AUC within the dose range tested. Plasma drug concentrations were significantly lower in females than in males after administration of 0.4 dose. All three doses were well tolerated with no unexpected or serious adverse side effects reported. These results suggest that intranasal scopolamine gel formulation (INSCOP) offers a fast, reliable, and safe alternative for the treatment of motion sickness.

Anthocyanins are a group of natural phenolic compounds responsible for the color to plants and fruits. These compounds might have beneficial effects on memory and have antioxidant properties. In the present study we have investigated the therapeutic efficacy of anthocyanins in an animal model of cognitive deficits, associated to Alzheimer's disease, induced by scopolamine. We evaluated whether anthocyanins protect the effects caused by SCO on nitrite/nitrate (NOx) levels and Na(+),K(+)-ATPase and Ca(2+)-ATPase and acetylcholinesterase (AChE) activities in the cerebral cortex and hippocampus (of rats. We used 4 different groups of animals: control (CTRL), anthocyanins treated (ANT), scopolamine-challenged (SCO), and scopolamine+anthocyanins (SCO+ANT). After seven days of treatment with ANT (200mgkg(-1); oral), the animals were SCO injected (1mgkg(-1); IP) and were performed the behavior tests, and submitted to euthanasia. A memory deficit was found in SCO group, but ANT treatment prevented this impairment of memory (P0.05). The ANT treatment per se had an anxiolytic effect. AChE activity was increased in both in cortex and hippocampus of SCO group, this effect was significantly attenuated by ANT (P0.05). SCO decreased Na(+),K(+)-ATPase and Ca(2+)-ATPase activities in hippocampus, and ANT was able to significantly (P0.05) prevent these effects. No significant alteration was found on NOx levels among the groups. In conclusion, the ANT is able to regulate cholinergic neurotransmission and restore the Na(+),K(+)-ATPase and Ca(2+)-ATPase activities, and also prevented memory deficits caused by scopolamine administration.

Summary Aims To investigate whether Meserine, a novel phenylcarbamate derivative of (−)-meptazinol, possesses beneficial activities against cholinergic deficiency and amyloidogenesis, the two major pathological characteristics of Alzheimer's disease (AD). Methods Ellman's assay and Morris water maze were used to detect acetylcholinesterase (AChE) activity and evaluate spatial learning and memory ability, respectively. Both high content screening and Western blotting were carried out to detect β-amyloid precursor protein (APP), while RT-PCR and ELISA were conducted to detect APP-mRNA and β-amyloid peptide (Aβ). Results In scopolamine-induced dementia mice, Meserine (1 mg/kg, i.p.) significantly ameliorated spatial learning and memory deficits, which was consistent with its in vitro inhibitory ability against AChE (recombinant human AChE, IC50 = 274 ± 49 nM). Furthermore, Meserine (7.5 mg/kg) injected intraperitoneally once daily for 3 weeks lowered APP level by 28% and Aβ42 level by 42% in APP/PS1 transgenic mouse cerebrum. This APP modulation action might be posttranscriptional, as Meserine reduced APP by about 30% in SH-SY5Y-APP695 cells but did not alter APP-mRNA level. And both APP and Aβ42 lowering action of Meserine maintained longer than that of rivastigmine. Conclusion Meserine executes dual actions against cholinergic deficiency and amyloidogenesis and provides a promising lead compound for symptomatic and modifying therapy of AD.

Scopolamine was synthesized using 6,7-dehydrotropine as a key intermediate. Rhodium-catalyzed [4 + 3] cycloaddition chemistry and a modified Robinson–Schopf reaction were each independently evaluated for their utility in constructing the tropane core. Both synthetic approaches gave comparable overall yields.