Design, synthesis and anticholinergic properties of novel α-benzyl dopamine, tyramine, and phenethylamine derivatives.

Due to the important biological properties of dopamine, phenethylamine, and tyramine derivatives in the central nervous system, herein the synthesis of novel α-benzyl dopamine, phenethylamine, and tyramine derivatives is described. The title compounds were synthesized starting from 3-phenylpropanoic acids and methoxybenzenes in six or seven steps. Firstly, 3-(2,3-dimethoxyphenyl)propanoic acid (11) and 3-(3,4-dimethoxyphenyl)propanoic acid (12) were selectively brominated with N-bromosuccinimide (NBS). The Friedel-Crafts acylation of methoxylated benzenes with these brominated acids or commercially available 3-phenylpropanoic acid in polyphosphoric acid gave the desired dihydrochalcones. α-Carboxylation of dihydrochalcones, reduction of benzylic carbonyl groups, hydrolysis of esters to acid derivatives, and the Curtius rearrangement reaction of acids followed by in situ synthesis of carbamates from alkyl isocyanates and hydrogenolysis of the carbamates afforded the title compounds in good total yields. Alzheimer's disease (AD) and Parkinson's disease (PD) are chronic neurodegenerative diseases that become serious over time. However, the exact pathophysiology of both diseases has not been revealed yet. There have been many different approaches to the treatment of patients for many years, especially studies on the cholinergic system cover a wide area. Within the scope of this study, the inhibition effects of dopamine-derived carbamates and amine salts on the cholinergic enzymes AChE and BChE were examined. Dopamine-derived carbamate 24a-i showed inhibition in the micro-nanomolar range; compound 24d showed a Ki value of 26.79 nM against AChE and 3.33 nM against BChE, while another molecule, 24i, showed a Ki range of 27.24 nM and 0.92 nM against AChE and BChE, respectively. AChE and BChE were effectively inhibited by dopamine-derived amine salts 25j-s, with Ki values in the range of 17.70 to 468.57 µM and 0.76-211.23 µM, respectively. Additionally, 24c, 24e and 25m were determined to be 60, 276 and 90 times more selective against BChE than AChE, respectively.

Drugs Showing Real-world Efficacy for Nocturia in Patients With Bladder Storage Symptoms.

BACKGROUND/AIM: Nocturia is defined as the symptom that an individual has to disrupt their sleep at night, for one or several times, in order to void. Nocturia is a bothersome event that markedly reduces a patient's quality of life. The aim of the study was to elucidate which drugs, prescribed to reduce nocturia, show real-world efficacy in patients with bladder storage symptoms. PATIENTS AND METHODS: One hundred consecutive patients who visited the Fukuoka University Medical Center were evaluated between May and July 2022. Anticholinergic drugs, ß3 adrenoceptor agonists, α1 blockers, desmopressin, and other medicines were prescribed for relieving nocturia. Desmopressin was used as second-line treatment of nocturia only in males with nocturnal polyuria. The association between each drug and actual decrease in nocturia was investigated using multivariate analysis. RESULTS: The number of nocturia episodes was reduced in patients using anticholinergic drugs, ß3 adrenoceptor agonists, and desmopressin (-1.4±0.9, -1.3±0.9, -2.0 ±0.8 episodes/night, respectively). Multivariate analysis for the entire cohort showed that anticholinergic drugs and ß3 adrenoceptor agonists were associated with significantly decreased nocturia episodes (p=0.01 and p=0.04, respectively). In males, only desmopressin was associated with a significant decrease in nocturia (p=0.03), and combination therapy significantly decreased the number of nocturia episodes compared to monotherapy (p=0.001). CONCLUSION: In a real-world clinical setting, anticholinergic drugs and ß3 adrenoceptor agonists were similarly effective in reducing nocturia. Administration of desmopressin combined with anticholinergic drugs and/or ß3 adrenoceptor agonists is the most effective method for reducing nocturia in male patients with both storage symptoms and nocturnal polyuria.

Nicotinic Acetylcholine Receptors in the Respiratory Tract.

Nicotinic acetylcholine receptors (nAChR) are widely distributed in neuronal and non-neuronal tissues, where they play diverse physiological roles. In this review, we highlight the recent findings regarding the role of nAChR in the respiratory tract with a special focus on the involvement of nAChR in the regulation of multiple processes in health and disease. We discuss the role of nAChR in mucociliary clearance, inflammation, and infection and in airway diseases such as asthma, chronic obstructive pulmonary disease, and cancer. The subtype diversity of nAChR enables differential regulation, making them a suitable pharmaceutical target in many diseases. The stimulation of the α3ß4 nAChR could be beneficial in diseases accompanied by impaired mucociliary clearance, and the anti-inflammatory effect due to an α7 nAChR stimulation could alleviate symptoms in diseases with chronic inflammation such as chronic obstructive pulmonary disease and asthma, while the inhibition of the α5 nAChR could potentially be applied in non-small cell lung cancer treatment. However, while clinical studies targeting nAChR in the airways are still lacking, we suggest that more detailed research into this topic and possible pharmaceutical applications could represent a valuable tool to alleviate the symptoms of diverse airway diseases.

Urinary reabsorption in the rat kidney by anticholinergics.

Anticholinergics, therapeutic agents for overactive bladder, are clinically suggested to reduce urine output. We investigated whether this effect is due to bladder or kidney urine reabsorption. Various solutions were injected into the bladder of urethane-anesthetized SD rats. The absorption rate for 2 h was examined following the intravenous administration of the anticholinergics imidafenacin (IM), atropine (AT), and tolterodine (TO). The bilateral ureter was then canulated and saline was administered to obtain a diuretic state. Anticholinergics or 1-deamino-[8-D-arginine]-vasopressin (dDAVP) were intravenously administered. After the IM and dDAVP administrations, the rat kidneys were immunostained with AQP2 antibody, and intracellular cAMP was measured. The absorption rate was ~ 10% of the saline injected into the bladder and constant even when anticholinergics were administered. The renal urine among peaked 2 h after the saline administration. Each of the anticholinergics significantly suppressed the urine production in a dose-dependent manner, as did dDAVP. IM and dDAVP increased the intracellular cAMP levels and caused the AQP2 molecule to localize to the collecting duct cells' luminal side. The urinary reabsorption mechanism through the bladder epithelium was not activated by anticholinergic administration. Thus, anticholinergics suppress urine production via an increase in urine reabsorption in the kidneys' collecting duct cells via AQP2.

Prepulse inhibition based grouping of rats and assessing differences in response to pharmacological agents.

Schizophrenia modeling by disrupting prepulse inhibition (PPI) is one of the most frequently used psycho-pharmacological methods by administering pharmacological agents to stimulate disruption. However, since PPI is also a biological indicator of schizophrenia, it is possible to classify subjects based on their basal PPI values and group them as "low inhibition" and "high inhibition without taking any pharmacological agent. Therefore this study was conducted to show that rats can be divided into groups in terms of susceptibility to schizophrenia according to basal PPI values. It was also observed that these groups might give different responses to different pharmacological agents (apomorphine, amphetamine, MK-801, scopolamine, nicotine, caffeine). Male Sprague Dawley rats (250-350 g) were used in the study. To examine the effects of different pharmacological agents on the groups, apomorphine (0.5 mg/kg and 1 mg/kg), amphetamine (4 mg/kg), MK-801 (0.05 mg/kg and 0.15 mg/kg), scopolamine (0.4 mg/kg), nicotine (1 mg/kg) and caffeine (10 mg/kg and 30 mg/kg) were used. Amphetamine showed a disruptive effect on PPI in both low and high inhibitory groups, while apomorphine, MK-801, scopolamine, and nicotine showed PPI decrease only in the high inhibitory group. Besides, caffeine decreased PPI levels at two doses in the high inhibitory group; however, 10 mg/kg dose caffeine was increased only in the low inhibitory group. According to the data obtained from this study, rats can be grouped with baseline inhibition values by using PPI, and response differences of pharmacological agents to groups may vary.

Clinical outcomes associated with anticholinergic burden in older hospitalized patients with advanced cancer: a single-center database study.

PURPOSE: Although anticholinergic burden has been known to be associated with adverse outcomes in older adults, its clinical importance has been less studied in patients with advanced cancer. We aimed to assess clinical impacts of using anticholinergic medications in older patients with cancer. METHODS: This is a single-center retrospective database study. This study included patients with stage IV solid cancer aged 65 years or older who were hospitalized in a hospitalist-operated medical unit of a tertiary hospital. We calculated anticholinergic cognitive burden (ACB) scores on admission and during hospitalization by reviewing all medications during hospital stays and collected the following data: demographic, medical history and clinical severity, occurrence of delirium, location of discharge, in-hospital mortality, and after discharge mortality data. RESULTS: When we divided the patients into two groups based on the change in ACB during hospitalization, the in-hospital mortality rate, incidence of delirium, frequency of transfers to long-term care hospitals, and length of hospital stay were higher in the ACB-increased group than those in the non-increased group. Even after excluding patients with clinically detected delirium, increased ACB were associated with increased in-hospital mortality. Patients in the ACB-increased group showed higher mortality risk after discharge than those in the non-increased group based on the Cox proportional hazard model. CONCLUSION: Increased ACB during hospitalization is a predictor of worsening clinical features and higher mortality in older patients with cancer. Further studies investigating causal relationship between an increased ACB and poor prognosis are warranted.

The effects of anticholinergic medications on cognition in children: a systematic review and meta-analysis.

Cognitive side effects of anticholinergic medications in older adults are well documented. Whether these poor cognitive outcomes are observed in children has not been systematically investigated. We aimed to conduct a systematic review and meta-analysis on the associations between anticholinergic medication use and cognitive performance in children. Systematic review was conducted using Medline, PsychInfo, and Embase, identifying studies testing cognitive performance relative to the presence versus absence of anticholinergic medication(s) in children. We assessed effects overall, as well as relative to drug class, potency (low and high), cognitive domain, and duration of administration. The systematic search identified 46 articles suitable for meta-analysis. For the most part, random effects meta-analyses did not identify statistically significant associations between anticholinergic exposure and cognitive performance in children; the one exception was a small effect of anticholinergic anti-depressants being associated with better cognitive function (Hedges' g = 0.24, 95% CI 0.06-0.42, p = 0.01). Anticholinergic medications do not appear to be associated with poor cognitive outcomes in children, as they do in older adults. The discrepancy in findings with older adults may be due to shorter durations of exposure in children, differences in study design (predominantly experimental studies in children rather than predominantly epidemiological in older adults), biological ageing (e.g. blood brain barrier integrity), along with less residual confounding due to minimal polypharmacy and comorbidity in children.

Elimination of the Causes of Poor Sleep Underlying Delirium is a Basic Strategy to Prevent Delirium.

Delirium is a very common but annoying clinical state that interferes with the treatment of background disease and delays recovery. Delirium is a troublesome condition that exhausts not only the patient but also his/her family and healthcare professionals. Since aging is a risk factor for delirium, how to control delirium is an extremely important issue in an aging society. Phenotype of delirium is so diverse that it is difficult to elucidate the mechanism of individual symptoms, but it is clinically well known that maintaining sleep quality is important in preventing and improving delirium. Drugs and factors that are known to disrupt the sleep-wake cycle also overlap with the risk factors for delirium, indicating the close connection between delirium and sleep. Although the sleep-wake cycle is tightly regulated by many neurotransmitters and hormones, the role of each substance in this cycle is being elucidated in detail. It is well known that acetylcholine is one of the most important neurotransmitters involved in wakefulness, and anticholinergic drugs reduce rapid eye movement sleep. Anticholinergic drugs are also the major drug causing drug-induced delirium. Several clinical studies have reported that melatonin receptor agonists reduce delirium. Some clinical studies have examined the relationship between delirium and environmental factors that interfere with sleep, such as noise and brightness. The purpose of this review is to organize the cause of poor sleep underlying delirium and propose strategies to prevent delirium, based on rich neurological and pharmacological findings of sleep. We consider that elimination of causes of sleep deprivation underlying delirium is one of the most effective prevention strategies for delirium.

The impact of high-pressure processing on the polyphenol profile and anti-glycaemic, anti-hypertensive and anti-cholinergic activities of extracts obtained from kiwiberry (Actinidia arguta) fruits.

This study analysed the impact of high pressure processing (HHP) on the inhibitory effects (IC50) of kiwiberries (cv. 'Weiki'), on the formation of advanced glycation end-products (AGEs) and the activity of angiotenisn-converting enzyme (ACE) and the enzyme acetylcholinesterase (AChE). The polyphenol profile (HPLC-MS/MS) and antioxidant capacity (PCLACW, ABTS, FRAP) were also studied. HHP-treated 'Weiki' (450 MPa/5 min and 650 MPa/5 min) was the most potent inhibitor of AGEs in the BSA-GLU model (6.52 mg/mL on average) relative to other materials (12.09-7.21 mg/mL). Among all samples assayed in the BSA-MGO model (61.97-14.48 mg/mL), HHP-treated 'Weiki' (450 MPa/5 min) showed the highest anti-AGE activity (12.37 mg/mL). Pressurization (450 MPa/5 min) significantly enhanced the anti-ACE (14.09 mg/mL) and anti-AChE (16.95 mg/mL) potentials of the tested extract relative to the other materials (23.75-14.50 mg/mL and 37.88-19.69 mg/mL, respectively). Pressurization increased polyphenol content and antioxidant capacity of the samples analysed.

The Effect of Cardiovascular Morbidity on Clinical Responsiveness to Anticholinergics in Postmenopausal Women With Urge Urinary Incontinence.

OBJECTIVE: To evaluate whether there is an association between severity of cardiovascular morbidity and urge urinary incontinence (UUI), and to assess the clinical responses of postmenopausal female patients in different cardiovascular risk groups to anticholinergics. METHODS: A total of 220 postmenopausal female patients aged 43-70 years old with overactive bladder with UUI between December 2019 and July 2020 were included. They were divided into 3 groups according to the Framingham risk score that calculates the 10-year risk of cardiovascular disease development: low-risk (n: 90, 40.9%), intermediate-risk (n: 47, 21.3%), and high-risk (n: 83, 37.8%).Their demographic and clinical data were recorded. The intensity of UUI and its effect on quality of life (QoL) were evaluated at admission, 8th week and 16th week of anticholinergic therapy. RESULTS: At admission attendance, BMI, smoking rate, presence of hypertension and diabetes mellitus, total cholesterol level and severity of UUI were higher in the high-risk group, whereas HDL level was lower and the effect of UUI on QoL was worse (P< .001). At the 16-week follow-up the improvement of UUI severity and QoL was significantly more pronounced in the low-risk and intermediate-risk groups (P< .001).The highest daily-dryness rates were observed in the low-risk group (65.6%), while the highest rates for refractory overactive bladder (OAB) were seen in the high-risk group (19.3%). CONCLUSION: Our findings show that more severe UUI and more impaired QoL is observed in high-risk patients for cardiovascular morbidity. Individualized treatment may be important in the high-risk group since they may benefit less from anticholinergics and refractory OAB can be more common.

An acetylcholine-dopamine interaction in the nucleus accumbens and its involvement in ethanol's dopamine-releasing effect.

Alcohol use disorder is a chronic, relapsing brain disorder causing substantial morbidity and mortality. Cholinergic interneurons (CIN) within the nucleus accumbens (nAc) have been suggested to exert a regulatory impact on dopamine (DA) neurotransmission locally, and defects in CIN have been implied in several psychiatric disorders. The aim of this study was to investigate the role of CIN in regulation of basal extracellular levels of DA and in modulation of nAc DA release following ethanol administration locally within the nAc of male Wistar rats. Using reversed in vivo microdialysis, the acetylcholinesterase inhibitor physostigmine was administered locally in the nAc followed by addition of either the muscarinic acetylcholine (ACh) receptor antagonist scopolamine or the nicotinic ACh receptor antagonist mecamylamine. Further, ethanol was locally perfused in the nAc following pretreatment with scopolamine and/or mecamylamine. Lastly, ethanol was administered locally into the nAc of animals with accumbal CIN-ablation induced by anticholine acetyl transferase-saporin. Physostigmine increased accumbal DA levels via activation of muscarinic ACh receptors. Neither scopolamine and/or mecamylamine nor CIN-ablation altered basal DA levels, suggesting that extracellular DA levels are not tonically controlled by ACh in the nAc. In contrast, ethanol-induced DA elevation was prevented following coadministration of scopolamine and mecamylamine and blunted in CIN-ablated animals, suggesting involvement of CIN-ACh in ethanol-mediated DA signaling. The data presented in this study suggest that basal extracellular levels of DA within the nAc are not sustained by ACh, whereas accumbal CIN-ACh is involved in mediating ethanol-induced DA release.

An insight into medicinal attributes of dithiocarbamates: Bird's eye view.

Dithiocarbamates are considered as an important motif owing to its extensive biological applications in medicinal chemistry. The synthesis of this framework can easily be achieved via a one-pot reaction of primary/secondary amines, CS2, and alkyl halides under catalyst-free conditions or sometimes in the presence of a base. By virtue of its colossal pharmacological scope, it has been an evolving subject of interest for many researchers around the world. The present review aims to highlight various synthetic approaches for dithiocarbamates with the major emphasis on medicinal attributes of these architectures as leads in the drug discovery of small molecules such as HDAC inhibitor, lysine-specific demethylase 1 (LSD1) down-regulator, kinase inhibitor (focal adhesion kinase, pyruvate kinase, Bruton's tyrosine kinase), carbonic anhydrase inhibitor, DNA intercalators, and apoptosis-inducing agents. Moreover, recent medicinal advancements in the synthesis of dithiocarbamate derivatives as anticancer, antifungal, antibacterial, anti-Alzheimer, antitubercular, anti-glaucoma, anti-cholinergic, antihyperglycemic, anti-inflammatory activities have been elaborated with notable examples.

The effect of desloratadine on ischemia reperfusion induced oxidative and inflammatory renal injury in rats.

Purpose: To examine the effect of desloratadine on kidney ischemia-reperfusion (I/R) injury in albino Wistar male rats using biochemical and histopathological methods.Methods: The treated with ischemia-reperfusion + 5 mg/kg desloratadine (IRD) group (n-6) was given 5 mg/kg desloratadine by gavage orally, and applied renal ischemia-reperfusion (BIR) group (n-6) and control (SG) group undergoing Sham operation (n-6) rats were given distilled water as solvent one hour before ketamine anesthesia. During the anesthesia period, ischemia was induced for 2 h unilaterally in the left kidney of all rats followed by reperfusion for 6 h. The kidneys of the SG group had sham operation without any intervention.Results: Our biochemical test results showed that malondialdehyde (MDA), nuclear factor kappa (NF-κB), tumor necrosis factor alpha (TNF-α), interleukin one beta (IL-1ß), creatinine, and blood urea nitrogen (BUN) levels were significantly increased in the BIR group compared to the healthy control and IRD groups treated with desloratadine. Histopathological results were revealed tubular dilatation, tubular necrosis, loss of brushy margins, cast formation, and apoptotic bodies in tubular epithelial cells in the BIR group. There were no histopathological findings except for the swelling of tubule epithelial cells and the accumulation of proteinous material in some tubule lumens in renal tissue of desloratadine-treated rats.Conclusions: Experimental results suggested that desloratadine may be useful in the treatment of renal I/R injury.

Desloratadine, a Novel Antigrowth Reagent for Bladder Cancer.

Desloratadine, a potent antagonist for human histamine H1 receptor, has been revealed to exhibit antihistaminic activity and anti-inflammatory activity. However, it is not yet known whether desloratadine has any effect on the biological behaviors of tumor cells. In this study, we aimed to investigate the effects of desloratadine on cell growth and invasion in bladder cancer EJ and SW780 cells in vitro. We observed that desloratadine inhibited cell viability of EJ and SW780 cells in a dose- and time-dependent manner. Desloratadine treatment was also revealed to suppress colony-formation ability and induce cell cycle arrest at G1 phase in EJ cells. Desloratadine promoted cell apoptosis via modulating the expression of Bcl-2, Bax, cleaved caspase 3, and cleaved caspase 9 in EJ and SW780 cells. Western blot resulted showed that desloratadine also impaired the expression of autophagy-related proteins, such as Beclin 1, P62, and LC3I/II in EJ and SW780 cells; while autophagy inhibitor LY294002 reversed the effects of desloratadine on these proteins. Moreover, desloratadine remarkably attenuated cell migration and invasion. Furthermore, we illustrated that desloratadine downregulated the expression of N-cadherin, Vimentin, Snail1, and Snail2, while upregulated the expression of E-cadherin in EJ and SW780 cells in vitro. The level of interleukin 6 was reduced in desloratadine-treated cells, while upregulation of interleukin 6 significantly abolished the anticancer activity of desloratadine in cell invasion and Bcl-2, Bax, Beclin1, LC3-I/II, N-cadherin, and E-cadherin expression in EJ cells. Taken together, our data suggest a potential anticancer activity of desloratadine on cell growth and invasion for bladder cancer, which may be mediated by diminishing the epithelial-to-mesenchymal transition and interleukin 6.

The non-receptor tyrosine kinase Pyk2 modulates acute locomotor effects of cocaine in D1 receptor-expressing neurons of the nucleus accumbens.

The striatum is critical for cocaine-induced locomotor responses. Although the role of D1 receptor-expressing neurons is established, underlying molecular pathways are not fully understood. We studied the role of Pyk2, a non-receptor, calcium-dependent protein-tyrosine kinase. The locomotor coordination and basal activity of Pyk2 knock-out mice were not altered and major striatal protein markers were normal. Cocaine injection increased Pyk2 tyrosine phosphorylation in mouse striatum. Pyk2-deficient mice displayed decreased locomotor response to acute cocaine injection. In contrast, locomotor sensitization and conditioned place preference were normal. Cocaine-activated ERK phosphorylation, a signaling pathway essential for these late responses, was unaltered. Conditional deletion of Pyk2 in the nucleus accumbens or in D1 neurons reproduced decreased locomotor response to cocaine, whereas deletion of Pyk2 in the dorsal striatum or in A2A receptor-expressing neurons did not. In mice lacking Pyk2 in D1-neurons locomotor response to D1 agonist SKF-81297, but not to an anticholinergic drug, was blunted. Our results identify Pyk2 as a regulator of acute locomotor responses to psychostimulants. They highlight the role of tyrosine phosphorylation pathways in striatal neurons and suggest that changes in Pyk2 expression or activation may alter specific responses to drugs of abuse, or possibly other behavioral responses linked to dopamine action.

Deferiprone ameliorates memory impairment in Scopolamine-treated rats: The impact of its iron-chelating effect on ß-amyloid disposition.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive and memory problems. Scopolamine (SCOP) is a natural anticholinergic drug that was proven to cause memory impairment in rats. Chelating agents are potential neuroprotective and memory enhancing agents as they can trap iron that enters in pathological deposition of ß-amyloid (Aß) which is a hallmark in AD and memory disorders. This study investigated the potential neuroprotective and memory enhancing effects of the iron chelating drug, Deferiprone. Three doses (5, 10, and 20 mg/kg) were administered to rats treated with SCOP (1.14 mg/kg/day). Systemic administration of SCOP for seven days caused memory impairment which manifested as decreased time spent in platform quadrant in Morris water maze test, decreased retention latencies in passive avoidance test, and increased acetylcholinesterase (AChE) activity, Aß, and free iron deposition. It was observed that pretreatment with Deferiprone increased platform quadrant time in Morris water maze and increased retention latencies in the passive avoidance test. It also attenuated the increase in AChE activity and decreased Aß and iron deposition. Overall, Deferiprone (10 mg/kg) was determined as the most effective dose. Therefore, this study suggests neuroprotective and memory enhancing effects for Deferiprone in SCOP-treated rats which might be attributed to its iron chelating action and anti-oxidative effect.

High cortical delta power correlates with aggravated allodynia by activating anterior cingulate cortex GABAergic neurons in neuropathic pain mice.

Patients with chronic pain often report being sensitive to pain at night before falling asleep, a time when the synchronization of cortical activity is initiated. However, how cortical activity relates to pain sensitivity is still unclear. Because sleep is characterized by enhanced cortical delta power, we hypothesized that enhanced cortical delta power may be an indicator of intensified pain. To test this hypothesis, we used pain thresholds tests, EEG/electromyogram recordings, c-Fos staining, and chemogenetic and pharmacological techniques in mice. We found that sleep deprivation or pharmacologic enhancement of EEG delta power by reserpine and scopolamine dramatically decreased mechanical pain thresholds, but not thermal withdrawal latency, in a partial sciatic nerve ligation model of neuropathic pain mice. On the contrary, suppression of EEG delta power using a wake-promoting agent modafinil significantly attenuated mechanical allodynia. Moreover, when EEG delta power was enhanced, c-Fos expression decreased in most regions of the cortex, except the anterior cingulate cortex (ACC), where c-Fos was increased in the somatostatin- and parvalbumin-positive GABAergic neurons. Chemogenetic activation of GABAergic neurons in ACC enhanced EEG delta power and lowered mechanical pain thresholds simultaneously in naive mice. However, chemogenetic inhibition of ACC GABAergic neurons could not block mechanical allodynia. These results provided compelling evidence that elevated EEG delta power is accompanied with aggravated neuropathic pain, whereas decreased delta power attenuated it, suggesting that enhanced delta power can be a specific marker of rising chronic neuropathic pain and that wake-promoting compounds could be used as analgesics in the clinic.

Effects of Anticholinergic Drugs Used for the Therapy of Overactive Bladder on P-Glycoprotein Activity.

We evaluated the effects of anticholinergic drugs principally used for the therapy of overactive bladder (OAB) on the activity of P-glycoprotein, an efflux transport protein, in Caco-2 cells. The time-dependent changes in the fluorescence of residual rhodamine 123, a P-glycoprotein activity marker, in the apical region of Caco-2 cells were measured in the presence of anticholinergic drugs using time-lapse confocal laser scanning microscopy. The effect of anticholinergic drugs on human P-glycoprotein ATPase activity was also measured. The fluorescence of residual rhodamine 123 in untreated Caco-2 cells decreased over time. The gradual decrease in the fluorescence was significantly inhibited by treatment with cyclosporine A, darifenacin, and trospium. In contrast, oxybutynin, N-desethyl-oxybutynin (DEOB), propiverine, and its active metabolites (M-1, M-2), imidafenacin, solifenacin, or tolterodine had little effect on the efflux of rhodamine 123. P-Glycoprotein ATPase activity was increased by darifenacin. Darifenacin and trospium reduced the rhodamine 123 transfer across the apical cell membrane. These data suggest that darifenacin and trospium interact with P-glycoprotein. Additionally, darifenacin influenced P-glycoprotein ATPase activity. These results suggest that darifenacin may be a substrate of P-glycoprotein. This study is the first paper to test simultaneously the effects of 10 anticholinergic drugs used currently for the therapy of OAB, on the P-glycoprotein.

Effect of Tiotropium Bromide on Airway Inflammation and Programmed Cell Death 5 in a Mouse Model of Ovalbumin-Induced Allergic Asthma.

Rationale: We previously demonstrated increased expression of programmed cell death 5 (PDCD5) in asthmatic patients and ovalbumin-induced allergic asthma. International guidelines (GINA 2019) have included the use of tiotropium bromide for chronic treatment of the most severe and frequently exacerbated asthma in patients ≥6 years old, who do not have good response to inhaled corticosteroids. Objective: To explore the role of tiotropium and its effect on PDCD5 level in a mouse model of chronic asthma. Methods: We divided 12 female mice into 2 groups: untreated asthma (n = 6) and tiotropium-treated asthma (n = 6). The impact of tiotropium was assessed by histology of lung tissue and morphometry. Pulmonary function was tested by using pressure sensors. The number of cells in bronchoalveolar lavage fluid (BALF) was detected. Levels of PDCD5, active caspase-3, and muscarinic acetylcholine receptors M2 (ChRM2) and M3 (ChRM3) were examined. Results: Tiotropium treatment significantly reduced airway inflammation and remodeling in asthmatic mice and intensified the lung function. PDCD5 level was reduced with tiotropium (p < 0.05). Moreover, active caspase-3 level was decreased with tiotropium (p < 0.001), and ChRM3 level was increased. Conclusions: Tiotropium treatment may alleviate the pathological changes with asthma by regulating apoptosis.

Novel tribenzylaminobenzolsulphonylimine based on their pyrazine and pyridazines: Synthesis, characterization, antidiabetic, anticancer, anticholinergic, and molecular docking studies.

A new method of obtaining multifunctional pyrazoles by the reaction of 1,3-dipolar addition of tribenzylsulfonyliminochloride to polarophiles has been developed. This imine is obtained by reacting tribenzylamine with N-chlorobenzene sulfamide (chloramine-B). Regardless of the structure and composition of polarophiles, the cyclization reaction takes place in the presence of alkali in 6-8 h of boiling, which proves the activation of the methylene groups of tribenzylamine using the electron-withdrawing sulfonamide group. These novel derivatives were effective inhibitors of the α-glycosidase, butyrylcholinesterase (BChE), and acetylcholinesterase enzymes (AChE) with Ki values in the range of 0.45 ±â€¯0.08-1.24 ±â€¯0.27 µM for α-glycosidase, 6.04 ±â€¯0.95-11.61 ±â€¯2.84 µM for BChE, and 2.04 ±â€¯0.24-4.23 ±â€¯1.02 µM for AChE, respectively. The biological activities of the studied molecules against enzyme molecules were investigated by molecular docking calculations. The enzymes studied were AChE for ID 4M0E, BChE for ID 5NN0 BChE, and α-Glycosidase for ID 1XSI (α-Gly) respectively.