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BACKGROUND: Hyposalivation is treated using oral cholinergic drugs; however, systemic side effects occasionally lead to discontinuation of treatment. We aimed to investigate the effects of transdermal pilocarpine on the salivary gland skin on saliva secretion and safety in rats. METHODS: Pilocarpine was administered to rats orally (0.5 mg/kg) or topically on the salivary gland skin (5 mg/body). Saliva volume, the number of sweat dots, and fecal weight were measured along with pilocarpine concentration in plasma and submandibular gland tissues. RESULTS: Saliva volume significantly increased 0.5 h after oral administration and 0.5, 3, and 12 h after topical administration. Fecal weight and sweat dots increased significantly 1 h after oral administration; however, no changes were observed after topical application. The pilocarpine concentration in the submandibular gland tissues of the topical group was higher than that in the oral group at 0.5, 3, and 12 h of administration. CONCLUSIONS: Pilocarpine application to salivary gland skin persistently increased salivary volume in rats without inducing sweating or diarrhea. Transdermal pilocarpine applied to the skin over the salivary glands may be an effective and safe treatment option for hyposalivation.

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Macrophages serve as vital defenders, protecting the body by exhibiting remarkable cellular adaptability in response to invading pathogens and various stimuli. These cells express nicotinic acetylcholine receptors, with the α7-nAChR being extensively studied due to its involvement in activating the cholinergic anti-inflammatory pathway. Activation of this pathway plays a crucial role in suppressing macrophages' production of proinflammatory cytokines, thus mitigating excessive inflammation and maintaining host homeostasis. Macrophage polarization, which occurs in response to specific pathogens or insults, is a process that has received limited attention concerning the activation of the cholinergic anti-inflammatory pathway and the contributions of the α7-nAChR in this context. This review aims to present evidence highlighting how the cholinergic constituents in macrophages, led by the α7-nAChR, facilitate the polarization of macrophages towards anti-inflammatory phenotypes. Additionally, we explore the influence of viral infections on macrophage inflammatory phenotypes, taking into account cholinergic mechanisms. We also review the current understanding of macrophage polarization in response to these infections. Finally, we provide insights into the relatively unexplored partial duplication of the α7-nAChR, known as dup α7, which is emerging as a significant factor in macrophage polarization and inflammation scenarios.

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Persistent neuronal firing is often observed in working memory and temporal association tasks both in humans and animals, and is believed to retain necessary information in these tasks. We have reported that hippocampal CA1 pyramidal cells are able to support persistent firing through intrinsic mechanisms in the presence of cholinergic agonists. However, it still remains largely unknown how persistent firing is affected by the development of animals and aging. Using in vitro patch-clamp recordings from CA1 pyramidal cells in rat brain slices, we first show that the cellular excitability of these aged rats was significantly lower than that of the young rats, responding with fewer spikes to current injection. In addition, we found age-dependent modulations of input resistance, membrane capacitance, and spike width. However, persistent firing in aged (approximately two-year-old) rats was as strong as that in young animals, and the properties of persistent firing were very similar among different age groups. In addition, medium spike afterhyperpolarization potential (mAHP), was not increased by aging and did not correlate with the strength of persistent firing. Lastly, we estimated the depolarization current induced by the cholinergic activation. This current was proportional to the increased membrane capacitance of the aged group and was inversely correlated with their intrinsic excitability. These observations indicate that robust persistent firing can be maintained in aged rats despite reduced excitability, because of the increased amount of cholinergically induced positive current.

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At present, Alzheimer's disease (AD) and related dementias cannot be cured. Therefore, scientists all over the world are trying to find a new approach to prolong an active life of patients with initial dementia. Both pharmacological and non-pharmacological pathways are investigated to improve the key symptom of the disease, memory loss. In this respect, influencing the neuromodulator acetylcholine via muscarinic receptors, such as cevimeline, might be one of the therapeutic alternatives. The purpose of this study is to explore the potential of cevimeline on the cognitive functions of AD patients. The methodology is based on a systematic literature review of available studies found in Web of Science, PubMed, Springer, and Scopus on the research topic. The findings indicate that cevimeline has shown an improvement in experimentally induced cognitive deficits in animal models. Furthermore, it has demonstrated to positively influence tau pathology and reduce the levels of amyloid-ß (Aß) peptide in the cerebral spinal fluid of Alzheimer's patients. Although this drug has not been approved by the FDA for its use among AD patients and there is a lack of clinical studies confirming and extending this finding, cevimeline might represent a breakthrough in the treatment of AD.

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Bladder dysfunction is associated with the overexpression of the intermediate filament (IF) proteins desmin and vimentin in obstructed bladder smooth muscle (BSM). However, the mechanisms by which these proteins contribute to BSM dysfunction are not known. Previous studies have shown that desmin and vimentin directly participate in signal transduction. In this study, we hypothesized that BSM dysfunction associated with overexpression of desmin or vimentin is mediated via c-Jun N-terminal kinase (JNK). We employed a model of murine BSM tissue in which increased expression of desmin or vimentin was induced by adenoviral transduction to examine the sufficiency of increased IF protein expression to reduce BSM contraction. Murine BSM strips overexpressing desmin or vimentin generated less force in response to KCl and carbachol relative to the levels in control murine BSM strips, an effect associated with increased JNK2 phosphorylation and reduced myosin light chain (MLC20 ) phosphorylation. Furthermore, desmin and vimentin overexpressions did not alter BSM contractility and MLC20 phosphorylation in strips isolated from JNK2 knockout mice. Pharmacological JNK2 inhibition produced results qualitatively similar to those caused by JNK2 knockout. These findings suggest that inhibition of JNK2 may improve diminished BSM contractility associated with obstructive bladder disease.

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Objective · To study the electrophysiological effect of (S)-OTS·HCl on the heart. Methods · The conventional intracellular recording, electrocardiograph (ECG) and Langendorff cardiac perfusion technique were employed to investigate the effect of (S)-OTS·HCl on in-vivo and in-vitro hearts of guinea pigs and rabbits. Results · (S)-OTS·HCl could bind to M2 muscarinic receptors and dose-dependently prolong the RR intervals significantly in vivo. It had no effect on resting potential (RP), action potential amplitude (APA), and maximum upstroke velocity of phase 0 (Vmax) of ventricular myocytes. Instead, 1×10-5 mol/L (S)-OTS·HCl could shorten the action potential duration at 50 percent repolarization (APD50) and APD90 to 91.6% and 90.9%, respectively. And the spontaneous depolarization rate of phase 4 (SDR) of sinus nodes was reduced to its 13.7% when rabbit sinus nodes were exposed to 1×10-7 mol/L (S)-OTS·HCl. (S)-OTS·HCl could inhibit Ca2+channel effectively. It decreased APA and Vmax of sinus nodes and attenuated the cardiac contractility in vitro. Conclusion · (S)-OTS·HCl is a potent cholinergic agonist and has negative chronotropic, dromotropic, and inotropic effects on hearts via binding to M2 muscarinic receptors.

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BACKGROUND: The cholinergic anti-inflammatory pathway (CAP) modulates inflammatory responses through the vagus nerve and the α-7-nicotinic acetylcholine receptor (α7nAChR) on macrophages and immune cells. Sympathetic/parasympathetic imbalance and chronic inflammation are both linked to poor outcome in dialysis patients. The aim of this study was to investigate CAP activity in these patients. METHODS: Twenty dialysis patients, 12 hemodialysis (HD) and 8 peritoneal dialysis (PD) patients (12 male, 8 female; age range 47-83 years) and 8 controls (5 male, 3 female; age range 31-52 years) were analyzed for C-reactive protein (CRP), tumor necrosis factor (TNF), interleukin-1b (IL-1b), IL-6 and IL-10 at baseline. The cytokines were then assessed after whole blood stimulation ex vivo with lipopolysaccharide (LPS) (10 and 100 ng/mL) and again in the presence of 45 and 90 µmol/L GTS-21, a cholinergic α7nAChR agonist. RESULTS: CRP, TNF, IL-1 and IL-6 were significantly higher, whereas IL-10 was significantly lower at baseline in patients compared with controls. After LPS stimulation, TNF increased significantly more in patients than in controls but decreased to similar levels in both groups after addition of GTS-21. IL-6 attenuation was comparable with TNF and the IL-1b pattern was similar but remained significantly higher in patients. Interestingly, IL-10 increased after GTS-21 in a dose-dependent manner, but only in patients. Results in HD and PD patients did not differ. CONCLUSIONS: The response of immune cells after LPS exposure and cholinergic stimulation suggests a functional CAP in dialysis patients. It may thus be possible to target the α7nAChR control of cytokine release as an anti-inflammatory strategy and thereby improve outcome in these patients.

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BACKGROUND: After peripheral nerve injury in human, a syndrome of events (spontaneous pain, allodynia and hyperalgesia) may be observed that includes no response of morphine and dependency of this pain state on intact sympathetic function. Spinally delivered 2-adrenoceptor agonist and cholinergic agonist or cholinesterase inhibitors have been shown to have actions attenuating the hyperalgesia in rat models of nerve injury-induced pain. Using a fixed-dose analysis and an isobolographic paradigm, the spinal interaction between the 2-adrenoreceptor agonist, clonidine and cholinergic agonist, carbachol is characterized in rat model of nerve injury-induced tactile hyperalgesia. METHODS: Male Sprague Dawely rats were anesthetized with halothane, and the left L5 and L6 spinal nerve were ligated (Chung model). After recovery, a polyethylene tubing catheter was implanted into lumbar intrathecal space. After recovery from catheter implantation, intrathecal dose-response curves were established for the antiallodynic effect of carbachol (0.1, 0.3, 1.0, 3.0 microgram) and clonidine (0.3, 1.0, 3.0, 10 microgram) alone to obtain the ED50 for each agent. ED50 fractions (1/2, 1/4, 1/8, 1/16) of drug combinations of carbachol-clonidine were administered and thresholds for left hind limb paw withdrawal to von Frey hair application were assessed. The ED50 of carbachol-clonidine combination was established and isobolographic analysis of the drug interactions was carried out.c RESULTS: Intrathecal carbachol and clonidine alone produced dose-dependent reductions of tactile allodynia: ED50 of 66 ng (12~367 ng) and 39 ng (1~1452 ng), respectively. With the fixed dose analysis, the log dose-response curves showed a left shift that considerably exceeds the theoretical curves made by a simple sum of the effects of carbachol alone and clonidine. With the isobolographic analysis, ED50 of mixture was found to be statistically less than the theoretical additive ED50 of mixture. CONCLUSION: The experiments suggest that intrathecal carbachol and clonidine alone produce a dose dependent antagonism on touch evoked allodynia and intrathecal carbachol is synergistic when combined with intrathecal clonidine.

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