The Clitocybaceae is a recently established family.Currently,the infrafamilial divisions and relationships within the family are vague due to limited sampling and genes employed for phylogenetic analysis.Some mushroom...The Clitocybaceae is a recently established family.Currently,the infrafamilial divisions and relationships within the family are vague due to limited sampling and genes employed for phylogenetic analysis.Some mushrooms of the family contain the neurotoxic muscarine,which has caused many severe and even deadly poisonings worldwide.However,the taxonomic distribution and evolution of the toxin within the family is largely unknown.In this study,phylogenetic analyses based on nucleotide sequences of ITS and of six molecular loci(ITS,LSU,TEF1,RPB1,RPB2 and ATP6),plus a phylogenomic analysis based on 485 single-copy orthologous genes,were performed to reconstruct the framework of Clitocybaceae.BEAST analysis was used to estimate the divergence times within the family.Additionally,biochemical analysis for muscarine was conducted of 32 representative species.Based on these analyses,an updated classification of Clitocybaceae into six genera(Clitocybe,Collybia,Dendrocollybia,Lepista,Pseudolyophyllum,and Singerocybe)is proposed.The genus Collybia is emended to accommodate four subgenera(Collybia,Crassicybe,Leucocalocybe,and Macrosporocybe).Seventeen new Chinese species and 15 new combinations are proposed.Keys to the genera of Clitocybaceae and the subgenera of Collybia,as well as to the known species of Clitocybe and Collybia subgen.Collybia in China,are presented.In addition,muscarine was detected in 18 species,and these muscarine-containing species formed a major monophyletic clade within Collybia subgen.Collybia.Finally,our phylogenetic,phylogenomic,chemotaxonomic and molecular dating results indicate that the Clitocybaceae is a natural group estimated to have arisen some 60 million years ago,and in this family,muscarine has evolved only once circa 20 million years ago without later losses.展开更多
AIM:To investigate the effects of different light intensities and various mydriatic and miotic drugs on pupil accommodation in guinea pigs.METHODS:Forty-two-week-old guinea pigs were randomly divided into four groups ...AIM:To investigate the effects of different light intensities and various mydriatic and miotic drugs on pupil accommodation in guinea pigs.METHODS:Forty-two-week-old guinea pigs were randomly divided into four groups to assess pupillary responses under varying light intensities(100,250,500 lx)and pharmacological interventions(1%atropine,1%cyclopentolate,1%tropicamide,or 2%pilocarpine).Baseline pupil size and eccentricity were recorded using a non-contact Python-based imaging system integrating edge detection and pixel-to-distance conversion.Direct illumination effects were measured at sequential time points,followed by drug administration and longitudinal tracking of pupillary changes.The protocol was repeated at 12wk of age for developmental comparisons.Postexperiment,enucleated eyes were analyzed to evaluate in vitro vs in vivo differences.RESULTS:Significant age-dependent differences in pupil dynamics were observed.Both 2-and 12-week-old guinea pigs exhibited marked pupil constriction under direct illumination(P<0.001),with decreased eccentricity post-constriction(P<0.001).Indirect illumination caused inconsistent pupil size changes(2-week:P=0.68;12-week:P=0.49).Pharmacologically,atropine,cyclopentolate,and tropicamide induced pupil dilation(P<0.001),whereas pilocarpine caused constriction(P<0.001).All drug groups showed reduced eccentricity(P<0.001).In vivo/in vitro comparisons revealed significant structural differences.CONCLUSION:This study investigates pupillary responses in developing guinea pigs,revealing a direct pupillary light reflex(PLR)with light intensity-dependent responses,while indirect PLR was undetectable.The differential effects of muscarinic modulators on pupillary responses underscore the critical role of cholinergic signaling in ocular accommodation,with age-related variations in sensitivity.Additionally,a novel non-contact measurement methodology achieved a precision of 0.01 mm for pupillary quantification,enhancing accuracy in ocular studies.展开更多
During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their el...During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.展开更多
This minireview explores the role of acetylcholine and muscarinic receptors in the pathophysiology of schizophrenia and summarizes the latest data on xanomeline/trospium chloride,a novel antipsychotic approved by the ...This minireview explores the role of acetylcholine and muscarinic receptors in the pathophysiology of schizophrenia and summarizes the latest data on xanomeline/trospium chloride,a novel antipsychotic approved by the United States Food and Drug Administration in September 2024.Evidence suggests that cholinergic dysfunction,particularly an imbalance in the expression of the M1 and M4 muscarinic receptors,may contribute to the pathophysiology and symptoms of schizophrenia.Xanomeline/trospium chloride combines xanomeline,an M1 and M4 receptor agonist,with trospium chloride,a non-selective peripheral muscarinic receptor antagonist that reduces peripheral cholinergic side effects.Clinical trials have demonstrated significant reductions in the positive and negative symptoms of schizophrenia,with improvements in Positive and Negati-ve Syndrome Scale scores observed as early as two weeks.A post-hoc analysis of one trial revealed cognitive improvements in patients with baseline cognitive impairment.This medication was generally well-tolerated,with mild-to-moderate gastrointestinal symptoms being the most common adverse events.While these results are promising,further research is needed to better understand its effectiveness and safety in real-world clinical practice,and to define its optimal role in managing this complex psychiatric disorder.展开更多
Objective:To observe the effect of Xipayimaizibizi oral liquid(XP)in an overactive bladder(OAB)experimental rat model and to explore its pharmacological mechanisms.Methods:Network pharmacology was used to explore the ...Objective:To observe the effect of Xipayimaizibizi oral liquid(XP)in an overactive bladder(OAB)experimental rat model and to explore its pharmacological mechanisms.Methods:Network pharmacology was used to explore the potential mechanisms of action of XP.The rats underwent bladder outlet obstruction surgery and were administered the corresponding drug concentrations by gavage for 4 weeks.The study observed the body weight,water intake,bladder and kidney indices(to evaluate their general status),urination behavior pattern(to observe frequency and urgency),and urodynamics(to measure bladder parameters).Hematoxylin and eosin and Masson's trichome staining were used to observe changes in the bladder structure.Enzyme-linked immunosorbent assay was used to measure the levels of nerve growth factor,brain-derived neurotrophic factor,and acetylcholine in the urine.The key targets involved in these mechanisms were validated using reverse transcription-quantitative polymerase chain reaction,immunohistochemistry,and western blot in vivo/vitro experiments.Result:Network pharmacological analysis predicted that XP may alleviate OAB by affecting the cholinergic synapse and calcium signaling pathways.XP treatment significantly reduced the bladder index,improved urine behavior and urodynamic parameters,decreased the neurotransmitters in urine,and reduced the thickness of the bladder wall and collagen ratio.These results indicate that XP can alleviate OAB symptoms and improve the bladder structure.In vivo/vitro experiments further demonstrated that XP can inhibit targets,such as muscarinic acetylcholine receptor 2,and participate in cholinergic synapses to further regulate the parasympathetic nervous system.It can also reduce the overexpression of Ca^(2+) caused by agonists,inhibit targets such as transient receptor potential vanilloid type 1,and participate in calcium signaling pathways to maintain Ca^(2+) homeostasis.Conclusion:These results suggest that XP inhibited bladder overactivity by maintaining Ca^(2+) homeostasis and regulating the parasympathetic nervous system.展开更多
Objective To investigate the effect of M5 muscarinic receptor subtype on the locomotor sensitization induced by heroin priming, and it＇s effect on the FosB expression in the nucleus accumbens （NAc） and the hippocam...Objective To investigate the effect of M5 muscarinic receptor subtype on the locomotor sensitization induced by heroin priming, and it＇s effect on the FosB expression in the nucleus accumbens （NAc） and the hippocampus in the heroin sensitized rats. Methods Locomotor activity was measured every 10 min for 1 h after subcutaneous injection of heroin. FosB expression was assayed by immunohistochemistry, and the antisense oligonucleotides （AS-ONs） targeting M5 muscarinic receptor was transferred with the lipofectin. Results Microinjection of AS-ONs targeting M5 muscarinic receptor in the ventral tegmental area （VTA） blocked the expression of behavioral sensitization induced by heroin priming in rats. Meanwhile, the expression of FosB-positive neurons in either the NAc or the dentate gyrus （DG） of the hippocam- pus increased in heroin-induced locomotor sensitized rats. The enhancement of FosB-positive neurons in the NAc or DG could be inhibited by microinjection of M5 muscarinic receptor AS-ONs into the VTA before the heroin-induced locomotor sensitization was performed. In contrast, microinjection of M5 muscarinic receptor sense oligonucleotide （S-ONs） into the VTA did not block the expression of behavioral sensitization or the expression of FosB in the NAc or DG in the heroin sensitized rats. Conclusion Blocking M5 muscarinic receptor in the VTA inhibits the expression of heroin-induced locomotor sensitization, which is associated with the regulation of FosB expression in the NAc and hippocampus neurons. M5 muscarinic receptor may be a useful pharmacological target for the treatment of heroin addiction.展开更多
In order to compare the potential selectivity of R-（-）-DM-phencynonate hydrochloride with its racemate （±）-DM- phencynonate hydrochloride on acetylcholine muscarinic receptor subtypes, the five human acetylch...In order to compare the potential selectivity of R-（-）-DM-phencynonate hydrochloride with its racemate （±）-DM- phencynonate hydrochloride on acetylcholine muscarinic receptor subtypes, the five human acetylcholine muscarinic receptor subtypes （M1- M5） （CHO-hml-5R） were cloned and expressed in Chinese hamster ovary （CHO-K1） cell line. The specific mRNAs of the five acetylcholine muscarinic receptor subtypes were detected by the reverse transcription-polymerase chain reaction （RT-PCR） method, demonstrating the definite expression of muscarinic receptor subtype genes （CHO-hml-5R）. The affinity and saturability of different muscarinic receptor subtypes to [^3H] N-methylscopolamine （[^3H]-NMS） were obtained by radioligand binding assay. Equilibrium binding assay revealed that the maximum binding capacity of [^3H]-NMS （Bmax value） to CHO-hml-5R were 40.22±3.23, 24.53±4.11, 29.65±2.65, 25.41±2.46, 32.78±4.81 pmol/mg·protein, respectively. Kd values of [^3H]-NMS to muscarinic receptors M1 to M5 were 0.97±0.22, 1.16±0.14, 0.99±0.06, 0.56±0.08, 1.12±0.06 nM, respectively. R-（-）-DM- phencynonate hydrochloride was found to block the M4 receptor with a much higher potency （pD2 = 7.48） than those displayed on M1 （pD2 = 6.20）, M2 （pD2 = 5.99）, M3 （pD2 = 5.99） and M5 （pD2 = 6.70） subtypes. However, for （±）-DM-phencynonate hydrochloride, no significant subtype receptor selectivity was found. Both （±）-DM- and R-（-）-DM-phencynonate hydrochloride showed allosteric effects on muscarinic receptors, the Hill coefficient （nH） of five receptor subtypes was less than 1, respectively. The results revealed that R-（-）-DM-phencynonate hydrochloride showed selectivity torwards M4 subtype, and there were allosteric effects for both R-（-）-DM-phencynonate hydrochloride and （±）-DM-phencynonate hydrochloride on muscarinic receptors.展开更多
The degeneration of cholinergic neurons and cholinergic hypofunction are pathologies associated with Alzheimer＇s disease （AD）. Muscarinic acetylcholine receptors （mAChRs） mediate acetylcholine-induced neurotransm...The degeneration of cholinergic neurons and cholinergic hypofunction are pathologies associated with Alzheimer＇s disease （AD）. Muscarinic acetylcholine receptors （mAChRs） mediate acetylcholine-induced neurotransmission and five mAChR subtypes （M1-M5） have been identified. Among them, M1 mAChR is widely expressed in the central nervous system and has been implicated in many physiological and pathological brain functions. In addition, M1 mAChR is postulated to be an important therapeutic target for AD and several other neurodegenerative diseases. In this article, we review recent progress in understanding the functional involvement of M1 mAChR in AD pathology and in developing M1 mAChR agonists forAD treatment.展开更多
AIM:To investigate the pathway(s)mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent,bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction...AIM:To investigate the pathway(s)mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent,bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction. METHODS:Circular smooth muscle strips from the antrum of Sprague-Dawley rats were mounted in muscle baths in Krebs buffer.Isometric tension was recorded.Cumulative concentration-response curves were obtained for(+)-cis- dioxolane(cD),a nonspecific muscarinic agonist,at 10^(-8)- 10^(-4)mol/L,in the presence of tetrodotoxin(TTX,10^(-7)mol/L). Results were normalized to cross sectional area.A repeat concentration-response curve was obtained after incubation of the muscle for 90 min with antagonists for M1(pirenzepine), M2(methoctramine)and M3(darifenadn)muscarinic receptor subtypes.The sensitivity to PTX was tested by the ip injection of 100 mg/kg of PTX 5 d before the experiment.The antral circular smooth muscles were removed from PTX-treated and non-treated rats as strips and dispersed smooth muscle cells to identify whether PTX-linked pathway mediated the contractility to bethanechol. RESULTS:A dose-dependent contractile response observed with bethanechol,was not affected by TTx.The pretreatment of rats with pertussis toxin decreased the contraction induced by bethanechol.Lack of calcium as well as the presence of the L-type calcium channel blocker,nifedipine,also inhibited the cholinergic contraction,with a reduction in response from 2.5±0.4 g/mm^2 to 1.2±0.4 g/mm^2(P<0.05).The dose- response curves were shifted to the right by muscarinic antagonists in the following order of affinity:darifenacin (M_3)>methocramine(M_2)>pirenzepine(M_1). CONCLUSION:The muscarinic receptors-dependent contraction of rat antral circular smooth muscles was linked to the signal transduction pathway(s)involving pertussis-toxin sensitive GTP-binding proteins and to extracellular calcium via L-type voltage gated calcium channels.The presence of the residual contractile response after the treatment with nifedipine,suggests that an additional pathway could mediate the cholinergic contraction.The involvement of more than one muscarinic receptor(functionally predominant type 3 over type 2)also suggests more than one pathway mediating the cholinergic contraction in rat antrum.展开更多
Cardiovascular diseases are life-threatening illnesses with high morbidity and mortality. Suppressed vagal(parasympathetic) activity and increased sympathetic activity are involved in these diseases. Currently, pharma...Cardiovascular diseases are life-threatening illnesses with high morbidity and mortality. Suppressed vagal(parasympathetic) activity and increased sympathetic activity are involved in these diseases. Currently, pharmacological interventions primarily aim to inhibit overexcitation of sympathetic nerves, while vagal modulation has been largely neglected. Many studies have demonstrated that increased vagal activity reduces cardiovascular risk factors in both animal models and human patients.Therefore, the improvement of vagal activity may be an alternate approach for the treatment of cardiovascular diseases. However, drugs used for vagus nerve activation in cardiovascular diseases are limited in the clinic. In this review, we provide an overview of the potential drug targets for modulating vagal nerve activation, including muscarinic, and b-adrenergic receptors. In addition,vagomimetic drugs(such as choline, acetylcholine, and pyridostigmine) and the mechanism underlying their cardiovascular protective effects are also discussed.展开更多
The autonomic nervous system contributes to prostate cancer proliferation and metastasis. However, the exact molecular mechanism remains unclear. In this study, muscarinic acetylcholine receptor M1 （CHRM1） expressio...The autonomic nervous system contributes to prostate cancer proliferation and metastasis. However, the exact molecular mechanism remains unclear. In this study, muscarinic acetylcholine receptor M1 （CHRM1） expression was measured via immunohistochemical analysis in human prostate cancer tissue array slides. PC-3, LNCaP, and A549 cells were treated with pirenzepine or carbachol, and the cell migration and invasion abilities were evaluated. Western blotting and quantitative real-time PCR were performed to measure GLI family zinc finger 1 （GLI1）, patched 1 （PTCH1）, and sonic hedgehog （SHH） expression levels. High expression of CHRM1 was found in early-stage human prostate cancer tissues. In addition, the selective CHRM1 antagonist pirenzepine inhibited PC-3, LNCaP, and A549 cell migration and invasion, but the agonist carbachol promoted the migration and invasion of these three cell lines. Muscarinic signaling can be relayed by hedgehog signaling. These data show that CHRM1 is involved in the regulation of prostate cancer migration and invasion through the hed^eho~ si^nalin~ ~athwav.展开更多
Objective:To evaluate pharmacological mimetic action of herbal extract Desmodium gangeticum (DC) roots on ischemia reperfusion injury.Methods:With the help of Langendroff perfusion technique,ischemic post condition(PO...Objective:To evaluate pharmacological mimetic action of herbal extract Desmodium gangeticum (DC) roots on ischemia reperfusion injury.Methods:With the help of Langendroff perfusion technique,ischemic post condition(POC) mimetic action of DG methanol root extract was evaluated and compared by using standard drugs that acts as muscarinic receptor agonist and antagonist,namely acetylcholine(Ach) and atropine(Atr) respectively in an isolated rat heart. Results:The physiological parameters like left ventricular developed pressure,end diastolic pressure and working index of isolated rat heart showed significant recovery in DG root extract administrated rat heart,similar to the recovery by POC.Kymogram results showed muscarinic receptor agonist like action for DG methanol root extract,confirmed in rat heart by muscarnic receptor agonist(acetylcholine) and anatoginst(atropine).Administration of DC root extract prior to reperfusion showed better antioxidant status in myocardial tissue homogenate and mitochondrial,complemented by the levels of cardiac specific marker proteins in myocardial tissue and perfusate.Even though DG methanol root extract mimics its action similar to that of Ach,the myocardial protection mediated by the extract was superior to Ach,due to the presence of antioxidants in the crude extract.Conclusions:DG methanol root extract provides myocardial protection towards IRI by stimulating muscarinic receptors.展开更多
This paper is aimed to study the effect of ADL on expression of ~z-AR and Mz-AchR in myocardial cells of rats exposed to microwave radiation. Immunohistochemistry, Western blot and image analysis were used to detect t...This paper is aimed to study the effect of ADL on expression of ~z-AR and Mz-AchR in myocardial cells of rats exposed to microwave radiation. Immunohistochemistry, Western blot and image analysis were used to detect the expression of ~I-AR and Mz-AchR in myocardial cells at 7 and 14 d after microwave exposure. The results show that the expression level was higher in microwave exposure group and 0.75 g/（kg.d） ADL group than in sham operation group and significantly lower in 1.5 and 3.0 g/（kg.d） ADL groups than in microwave group. So we have a conclusion that the expression of I^z-AR and Mz-AchR is down-regulated in myocardial cells of rats exposed to microwave radiation. ADL can protect rats against microwave-induced heart tissue injury.展开更多
AIM： To investigate the effects of green flickering light on refractive development and expression of muscarinic acetylcholine receptor（mAChR） M1 in the eyes of guinea pigs.METHODS： Thirty guinea pigs（15-20 days ...AIM： To investigate the effects of green flickering light on refractive development and expression of muscarinic acetylcholine receptor（mAChR） M1 in the eyes of guinea pigs.METHODS： Thirty guinea pigs（15-20 days old） were randomly divided into three groups（n=10/group）. Animals in group I were raised in a completely closed carton with green flickering light illumination. Those in group II were kept in the open top closed carton under normal natural light. Guinea pigs were raised in a sight-widen cage under normal natural light in group III. The refractive status and axial length were measured before and after 8 weeks＇ illumination. Moreover, total RNA extracted from retinal, choroidal, and scleral tissues were determined by real-time reverse transcription polymerase chain reaction（RT-PCR）. The expressions of the receptor M1 were also explored in the retina, choroid, and sclera using immunohistochemistry.RESULTS： There was a remarkable reduction in refractive error and increase in axial length after 8-weeks＇ green flickering light stimulation（P〈0.001）. The expression of M1 receptor mRNA in sclera and retina in myopia group were remarkably lower than that in group II and III（P〈0.01）. Significant reduced expression of M1 receptor stimulated by green flickering light in retina and sclera tissues were also observed（P〈0.05）. However, there was no M1 receptor expression in choroid in 3 groups.CONCLUSION： Myopia can be induced by 8 weeks＇ green flickering light exposure in the animal model. M1 receptor may be involved causally or protectively in myopia development.展开更多
Tropane alkaloids(TAs)are among the most valued chemical compounds known since pre-historic times.Poisonous plants from Solanaceae family(Hyoscyamus niger,Datura,Atropa belladonna,Scopolia lurida,Mandragora officinaru...Tropane alkaloids(TAs)are among the most valued chemical compounds known since pre-historic times.Poisonous plants from Solanaceae family(Hyoscyamus niger,Datura,Atropa belladonna,Scopolia lurida,Mandragora officinarum,Duboisia)and Erythroxylaceae(Erythroxylum coca)are rich sources of tropane alkaloids.These compounds possess the anticholinergic properties as they could block the neurotransmitter acetylcholine action in the central and peripheral nervous system by binding at either muscarinic and/or nicotinic receptors.Hence,they are of great clinical impor-tance and are used as antiemetics,anesthetics,antispasmodics,bronchodilator and mydriatics.They also serve as the lead compounds to generate more effective drugs.Due to the important pharmacological action they are listed in the WHO list of essential medicines and are available in market with FDA approval.However,being anticholinergic in action,TA medication are under the suspicion of causing dementia and cognitive decline like other medications with anticholinergic action,interestingly which is incorrect.There are published reviews on chemistry,biosynthesis,phar-macology,safety concerns,biotechnological aspects of TAs but the detailed information on anticholinergic mecha-nism of action,clinical pharmacology,FDA approval and anticholinergic burden is lacking.Hence the present review tries to fill this lacuna by critically summarizing and discussing the above mentioned aspects.展开更多
The changes in density of M-cholinergic receptors in different areas of senile rats and the regulatory action of Huang Qi ([symbol: see text] Radix Astragali, a drug for warming yang and replenishing qi) were observed...The changes in density of M-cholinergic receptors in different areas of senile rats and the regulatory action of Huang Qi ([symbol: see text] Radix Astragali, a drug for warming yang and replenishing qi) were observed by autoradiography. The results showed that the gray scale displayed in brain sections was clear and mainly distributed in the cortex, hippocampus and striate body, while that due to nonspecific combination was negligible. The gray scale in the cortex, hippocampus and striate body of the experimental group was markedly lower than that in the young control rats, decreased respectively by 24.87%, 14.12% and 12.76% (all P展开更多
Schizophrenia is a psychiatric disorder affecting approximately 1% of the population worldwide and is characterised by the presence of positive and negative symptoms and cognitive deficits. Whilst current therapeutics...Schizophrenia is a psychiatric disorder affecting approximately 1% of the population worldwide and is characterised by the presence of positive and negative symptoms and cognitive deficits. Whilst current therapeutics ameliorate positive symptoms, they are largely ineffective in improving negative symptoms and cognitive deficits. The cholinergic neurotransmitter system heavily influences cognitive function and there is evidence that implicates disruption of the central cholinergic system in schizophrenia. Historically, targeting the cholinergic system has been impeded by poor selectivity leading to intolerable side effects warranting the need to develop more targeted therapeutic compounds. In this review we will summarise evidence supporting the roles of the cholinergic system, particularly the muscarinic M1 receptor, in the pathophysiology of schizophrenia and discuss the potential of a promising new class of candidate compounds, allosteric ligands, for addressing the difficulties involved in targeting this system. The body of evidence presented here highlights the dysfunction of the cholinergic system in schizophrenia and that targeting this system by taking advantage of allosteric ligands is having clinically meaningful effect on cognitive deficits.展开更多
Besides the mainstay of α-blockers and 5α-reductase inhibitors,other forms of medical therapy complete the armamentarium in the treatment of lower urinary tract symptoms(LUTS)in men.These treatments can target speci...Besides the mainstay of α-blockers and 5α-reductase inhibitors,other forms of medical therapy complete the armamentarium in the treatment of lower urinary tract symptoms(LUTS)in men.These treatments can target specific symptoms as well as associated symptoms that would affect the quality of life of the patients.Many patients are bothered by storage symptoms,more so than the voiding symptoms.Antimuscarinics are efficacious and safe,provided the patients do not have high post void residual urine.Many patients with LUTS also have erectile dysfunction,and phosphodiesterase type Ⅴ inhibitors are effective in relieving both LUTS as well as erectile dysfunction for such patients.Phytotherapy provides a popular and safe treatment for LUTS,however,the efficacy of the treatment has not been proven in well conducted prospective randomized controlled studies.展开更多
基金This study was supported by Yunnan Xingdian Talents Support Plan-Science and Technology Leading Talents Program(202305AB350004)Yunnan Ten-Thousand-Talents Plan-Yunling Scholar Project(YNWR-YLXZ-2018-011)Postdoctoral Directional Training Foundation of Yunnan Province.
文摘The Clitocybaceae is a recently established family.Currently,the infrafamilial divisions and relationships within the family are vague due to limited sampling and genes employed for phylogenetic analysis.Some mushrooms of the family contain the neurotoxic muscarine,which has caused many severe and even deadly poisonings worldwide.However,the taxonomic distribution and evolution of the toxin within the family is largely unknown.In this study,phylogenetic analyses based on nucleotide sequences of ITS and of six molecular loci(ITS,LSU,TEF1,RPB1,RPB2 and ATP6),plus a phylogenomic analysis based on 485 single-copy orthologous genes,were performed to reconstruct the framework of Clitocybaceae.BEAST analysis was used to estimate the divergence times within the family.Additionally,biochemical analysis for muscarine was conducted of 32 representative species.Based on these analyses,an updated classification of Clitocybaceae into six genera(Clitocybe,Collybia,Dendrocollybia,Lepista,Pseudolyophyllum,and Singerocybe)is proposed.The genus Collybia is emended to accommodate four subgenera(Collybia,Crassicybe,Leucocalocybe,and Macrosporocybe).Seventeen new Chinese species and 15 new combinations are proposed.Keys to the genera of Clitocybaceae and the subgenera of Collybia,as well as to the known species of Clitocybe and Collybia subgen.Collybia in China,are presented.In addition,muscarine was detected in 18 species,and these muscarine-containing species formed a major monophyletic clade within Collybia subgen.Collybia.Finally,our phylogenetic,phylogenomic,chemotaxonomic and molecular dating results indicate that the Clitocybaceae is a natural group estimated to have arisen some 60 million years ago,and in this family,muscarine has evolved only once circa 20 million years ago without later losses.
文摘AIM:To investigate the effects of different light intensities and various mydriatic and miotic drugs on pupil accommodation in guinea pigs.METHODS:Forty-two-week-old guinea pigs were randomly divided into four groups to assess pupillary responses under varying light intensities(100,250,500 lx)and pharmacological interventions(1%atropine,1%cyclopentolate,1%tropicamide,or 2%pilocarpine).Baseline pupil size and eccentricity were recorded using a non-contact Python-based imaging system integrating edge detection and pixel-to-distance conversion.Direct illumination effects were measured at sequential time points,followed by drug administration and longitudinal tracking of pupillary changes.The protocol was repeated at 12wk of age for developmental comparisons.Postexperiment,enucleated eyes were analyzed to evaluate in vitro vs in vivo differences.RESULTS:Significant age-dependent differences in pupil dynamics were observed.Both 2-and 12-week-old guinea pigs exhibited marked pupil constriction under direct illumination(P<0.001),with decreased eccentricity post-constriction(P<0.001).Indirect illumination caused inconsistent pupil size changes(2-week:P=0.68;12-week:P=0.49).Pharmacologically,atropine,cyclopentolate,and tropicamide induced pupil dilation(P<0.001),whereas pilocarpine caused constriction(P<0.001).All drug groups showed reduced eccentricity(P<0.001).In vivo/in vitro comparisons revealed significant structural differences.CONCLUSION:This study investigates pupillary responses in developing guinea pigs,revealing a direct pupillary light reflex(PLR)with light intensity-dependent responses,while indirect PLR was undetectable.The differential effects of muscarinic modulators on pupillary responses underscore the critical role of cholinergic signaling in ocular accommodation,with age-related variations in sensitivity.Additionally,a novel non-contact measurement methodology achieved a precision of 0.01 mm for pupillary quantification,enhancing accuracy in ocular studies.
基金supported by Catalan Government,Nos.2014SGR344(to JT),2017SGR704(to JT),2021SGR01214(to MAL)MCIN/AEI/10.13039/501100011033/by“ERDF A way of making Europe,”Nos.SAF2015-67143(to JT),PID2019-106332GB-I00(to JT and MAL)and PID2022-141252NB-I00(to MAL).
文摘During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.
文摘This minireview explores the role of acetylcholine and muscarinic receptors in the pathophysiology of schizophrenia and summarizes the latest data on xanomeline/trospium chloride,a novel antipsychotic approved by the United States Food and Drug Administration in September 2024.Evidence suggests that cholinergic dysfunction,particularly an imbalance in the expression of the M1 and M4 muscarinic receptors,may contribute to the pathophysiology and symptoms of schizophrenia.Xanomeline/trospium chloride combines xanomeline,an M1 and M4 receptor agonist,with trospium chloride,a non-selective peripheral muscarinic receptor antagonist that reduces peripheral cholinergic side effects.Clinical trials have demonstrated significant reductions in the positive and negative symptoms of schizophrenia,with improvements in Positive and Negati-ve Syndrome Scale scores observed as early as two weeks.A post-hoc analysis of one trial revealed cognitive improvements in patients with baseline cognitive impairment.This medication was generally well-tolerated,with mild-to-moderate gastrointestinal symptoms being the most common adverse events.While these results are promising,further research is needed to better understand its effectiveness and safety in real-world clinical practice,and to define its optimal role in managing this complex psychiatric disorder.
基金supported by the Natural Science Foundation in Xinjiang Uygur Autonomous Region(Urumqi,China,2023D01F38).
文摘Objective:To observe the effect of Xipayimaizibizi oral liquid(XP)in an overactive bladder(OAB)experimental rat model and to explore its pharmacological mechanisms.Methods:Network pharmacology was used to explore the potential mechanisms of action of XP.The rats underwent bladder outlet obstruction surgery and were administered the corresponding drug concentrations by gavage for 4 weeks.The study observed the body weight,water intake,bladder and kidney indices(to evaluate their general status),urination behavior pattern(to observe frequency and urgency),and urodynamics(to measure bladder parameters).Hematoxylin and eosin and Masson's trichome staining were used to observe changes in the bladder structure.Enzyme-linked immunosorbent assay was used to measure the levels of nerve growth factor,brain-derived neurotrophic factor,and acetylcholine in the urine.The key targets involved in these mechanisms were validated using reverse transcription-quantitative polymerase chain reaction,immunohistochemistry,and western blot in vivo/vitro experiments.Result:Network pharmacological analysis predicted that XP may alleviate OAB by affecting the cholinergic synapse and calcium signaling pathways.XP treatment significantly reduced the bladder index,improved urine behavior and urodynamic parameters,decreased the neurotransmitters in urine,and reduced the thickness of the bladder wall and collagen ratio.These results indicate that XP can alleviate OAB symptoms and improve the bladder structure.In vivo/vitro experiments further demonstrated that XP can inhibit targets,such as muscarinic acetylcholine receptor 2,and participate in cholinergic synapses to further regulate the parasympathetic nervous system.It can also reduce the overexpression of Ca^(2+) caused by agonists,inhibit targets such as transient receptor potential vanilloid type 1,and participate in calcium signaling pathways to maintain Ca^(2+) homeostasis.Conclusion:These results suggest that XP inhibited bladder overactivity by maintaining Ca^(2+) homeostasis and regulating the parasympathetic nervous system.
基金This work was supported by the National Nature Science Foundation of China （No.30470554）the National Basic Research Development Program of China（No.2003CB515404）.
文摘Objective To investigate the effect of M5 muscarinic receptor subtype on the locomotor sensitization induced by heroin priming, and it＇s effect on the FosB expression in the nucleus accumbens （NAc） and the hippocampus in the heroin sensitized rats. Methods Locomotor activity was measured every 10 min for 1 h after subcutaneous injection of heroin. FosB expression was assayed by immunohistochemistry, and the antisense oligonucleotides （AS-ONs） targeting M5 muscarinic receptor was transferred with the lipofectin. Results Microinjection of AS-ONs targeting M5 muscarinic receptor in the ventral tegmental area （VTA） blocked the expression of behavioral sensitization induced by heroin priming in rats. Meanwhile, the expression of FosB-positive neurons in either the NAc or the dentate gyrus （DG） of the hippocam- pus increased in heroin-induced locomotor sensitized rats. The enhancement of FosB-positive neurons in the NAc or DG could be inhibited by microinjection of M5 muscarinic receptor AS-ONs into the VTA before the heroin-induced locomotor sensitization was performed. In contrast, microinjection of M5 muscarinic receptor sense oligonucleotide （S-ONs） into the VTA did not block the expression of behavioral sensitization or the expression of FosB in the NAc or DG in the heroin sensitized rats. Conclusion Blocking M5 muscarinic receptor in the VTA inhibits the expression of heroin-induced locomotor sensitization, which is associated with the regulation of FosB expression in the NAc and hippocampus neurons. M5 muscarinic receptor may be a useful pharmacological target for the treatment of heroin addiction.
基金National Natural Science Foundation of China (Grant No. 30672445)
文摘In order to compare the potential selectivity of R-（-）-DM-phencynonate hydrochloride with its racemate （±）-DM- phencynonate hydrochloride on acetylcholine muscarinic receptor subtypes, the five human acetylcholine muscarinic receptor subtypes （M1- M5） （CHO-hml-5R） were cloned and expressed in Chinese hamster ovary （CHO-K1） cell line. The specific mRNAs of the five acetylcholine muscarinic receptor subtypes were detected by the reverse transcription-polymerase chain reaction （RT-PCR） method, demonstrating the definite expression of muscarinic receptor subtype genes （CHO-hml-5R）. The affinity and saturability of different muscarinic receptor subtypes to [^3H] N-methylscopolamine （[^3H]-NMS） were obtained by radioligand binding assay. Equilibrium binding assay revealed that the maximum binding capacity of [^3H]-NMS （Bmax value） to CHO-hml-5R were 40.22±3.23, 24.53±4.11, 29.65±2.65, 25.41±2.46, 32.78±4.81 pmol/mg·protein, respectively. Kd values of [^3H]-NMS to muscarinic receptors M1 to M5 were 0.97±0.22, 1.16±0.14, 0.99±0.06, 0.56±0.08, 1.12±0.06 nM, respectively. R-（-）-DM- phencynonate hydrochloride was found to block the M4 receptor with a much higher potency （pD2 = 7.48） than those displayed on M1 （pD2 = 6.20）, M2 （pD2 = 5.99）, M3 （pD2 = 5.99） and M5 （pD2 = 6.70） subtypes. However, for （±）-DM-phencynonate hydrochloride, no significant subtype receptor selectivity was found. Both （±）-DM- and R-（-）-DM-phencynonate hydrochloride showed allosteric effects on muscarinic receptors, the Hill coefficient （nH） of five receptor subtypes was less than 1, respectively. The results revealed that R-（-）-DM-phencynonate hydrochloride showed selectivity torwards M4 subtype, and there were allosteric effects for both R-（-）-DM-phencynonate hydrochloride and （±）-DM-phencynonate hydrochloride on muscarinic receptors.
基金Supported by National Basic Research Program of China grant(to Zhu B),No.2011CB505201National Natural Science Foundation of China No.81130063 and No.81173345(to Zhu B and Gao X)
文摘AIM: To investigate the effect and mechanism of acupuncture at heterotopic acupoints on jejunal motility, particularly in pathological conditions.
基金supported by grants from the National Institutes of Health,USA(R01AG038710,R01AG021173,R01AG044420 and R01NS046673)the Alzheimer’s Association,the National Natural Science Foundation of China(91332112,81225008 and 81161120496)+1 种基金Fundamental Research Funds for the Central Universities of Chinathe Fok Ying Tung Education Foundation
文摘The degeneration of cholinergic neurons and cholinergic hypofunction are pathologies associated with Alzheimer＇s disease （AD）. Muscarinic acetylcholine receptors （mAChRs） mediate acetylcholine-induced neurotransmission and five mAChR subtypes （M1-M5） have been identified. Among them, M1 mAChR is widely expressed in the central nervous system and has been implicated in many physiological and pathological brain functions. In addition, M1 mAChR is postulated to be an important therapeutic target for AD and several other neurodegenerative diseases. In this article, we review recent progress in understanding the functional involvement of M1 mAChR in AD pathology and in developing M1 mAChR agonists forAD treatment.
文摘AIM:To investigate the pathway(s)mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent,bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction. METHODS:Circular smooth muscle strips from the antrum of Sprague-Dawley rats were mounted in muscle baths in Krebs buffer.Isometric tension was recorded.Cumulative concentration-response curves were obtained for(+)-cis- dioxolane(cD),a nonspecific muscarinic agonist,at 10^(-8)- 10^(-4)mol/L,in the presence of tetrodotoxin(TTX,10^(-7)mol/L). Results were normalized to cross sectional area.A repeat concentration-response curve was obtained after incubation of the muscle for 90 min with antagonists for M1(pirenzepine), M2(methoctramine)and M3(darifenadn)muscarinic receptor subtypes.The sensitivity to PTX was tested by the ip injection of 100 mg/kg of PTX 5 d before the experiment.The antral circular smooth muscles were removed from PTX-treated and non-treated rats as strips and dispersed smooth muscle cells to identify whether PTX-linked pathway mediated the contractility to bethanechol. RESULTS:A dose-dependent contractile response observed with bethanechol,was not affected by TTx.The pretreatment of rats with pertussis toxin decreased the contraction induced by bethanechol.Lack of calcium as well as the presence of the L-type calcium channel blocker,nifedipine,also inhibited the cholinergic contraction,with a reduction in response from 2.5±0.4 g/mm^2 to 1.2±0.4 g/mm^2(P<0.05).The dose- response curves were shifted to the right by muscarinic antagonists in the following order of affinity:darifenacin (M_3)>methocramine(M_2)>pirenzepine(M_1). CONCLUSION:The muscarinic receptors-dependent contraction of rat antral circular smooth muscles was linked to the signal transduction pathway(s)involving pertussis-toxin sensitive GTP-binding proteins and to extracellular calcium via L-type voltage gated calcium channels.The presence of the residual contractile response after the treatment with nifedipine,suggests that an additional pathway could mediate the cholinergic contraction.The involvement of more than one muscarinic receptor(functionally predominant type 3 over type 2)also suggests more than one pathway mediating the cholinergic contraction in rat antrum.
基金supported by grants from the National Natural Science Foundation of China(81770293 and 81473203)
文摘Cardiovascular diseases are life-threatening illnesses with high morbidity and mortality. Suppressed vagal(parasympathetic) activity and increased sympathetic activity are involved in these diseases. Currently, pharmacological interventions primarily aim to inhibit overexcitation of sympathetic nerves, while vagal modulation has been largely neglected. Many studies have demonstrated that increased vagal activity reduces cardiovascular risk factors in both animal models and human patients.Therefore, the improvement of vagal activity may be an alternate approach for the treatment of cardiovascular diseases. However, drugs used for vagus nerve activation in cardiovascular diseases are limited in the clinic. In this review, we provide an overview of the potential drug targets for modulating vagal nerve activation, including muscarinic, and b-adrenergic receptors. In addition,vagomimetic drugs(such as choline, acetylcholine, and pyridostigmine) and the mechanism underlying their cardiovascular protective effects are also discussed.
基金Tnis workwas supportedby the Natural Science Foundation of Chongqing （CSTC, 2009BA5081）.
文摘The autonomic nervous system contributes to prostate cancer proliferation and metastasis. However, the exact molecular mechanism remains unclear. In this study, muscarinic acetylcholine receptor M1 （CHRM1） expression was measured via immunohistochemical analysis in human prostate cancer tissue array slides. PC-3, LNCaP, and A549 cells were treated with pirenzepine or carbachol, and the cell migration and invasion abilities were evaluated. Western blotting and quantitative real-time PCR were performed to measure GLI family zinc finger 1 （GLI1）, patched 1 （PTCH1）, and sonic hedgehog （SHH） expression levels. High expression of CHRM1 was found in early-stage human prostate cancer tissues. In addition, the selective CHRM1 antagonist pirenzepine inhibited PC-3, LNCaP, and A549 cell migration and invasion, but the agonist carbachol promoted the migration and invasion of these three cell lines. Muscarinic signaling can be relayed by hedgehog signaling. These data show that CHRM1 is involved in the regulation of prostate cancer migration and invasion through the hed^eho~ si^nalin~ ~athwav.
文摘Objective:To evaluate pharmacological mimetic action of herbal extract Desmodium gangeticum (DC) roots on ischemia reperfusion injury.Methods:With the help of Langendroff perfusion technique,ischemic post condition(POC) mimetic action of DG methanol root extract was evaluated and compared by using standard drugs that acts as muscarinic receptor agonist and antagonist,namely acetylcholine(Ach) and atropine(Atr) respectively in an isolated rat heart. Results:The physiological parameters like left ventricular developed pressure,end diastolic pressure and working index of isolated rat heart showed significant recovery in DG root extract administrated rat heart,similar to the recovery by POC.Kymogram results showed muscarinic receptor agonist like action for DG methanol root extract,confirmed in rat heart by muscarnic receptor agonist(acetylcholine) and anatoginst(atropine).Administration of DC root extract prior to reperfusion showed better antioxidant status in myocardial tissue homogenate and mitochondrial,complemented by the levels of cardiac specific marker proteins in myocardial tissue and perfusate.Even though DG methanol root extract mimics its action similar to that of Ach,the myocardial protection mediated by the extract was superior to Ach,due to the presence of antioxidants in the crude extract.Conclusions:DG methanol root extract provides myocardial protection towards IRI by stimulating muscarinic receptors.
文摘This paper is aimed to study the effect of ADL on expression of ~z-AR and Mz-AchR in myocardial cells of rats exposed to microwave radiation. Immunohistochemistry, Western blot and image analysis were used to detect the expression of ~I-AR and Mz-AchR in myocardial cells at 7 and 14 d after microwave exposure. The results show that the expression level was higher in microwave exposure group and 0.75 g/（kg.d） ADL group than in sham operation group and significantly lower in 1.5 and 3.0 g/（kg.d） ADL groups than in microwave group. So we have a conclusion that the expression of I^z-AR and Mz-AchR is down-regulated in myocardial cells of rats exposed to microwave radiation. ADL can protect rats against microwave-induced heart tissue injury.
基金Supported by Qilu Hospital of Shandong University (No.201805049)
文摘AIM： To investigate the effects of green flickering light on refractive development and expression of muscarinic acetylcholine receptor（mAChR） M1 in the eyes of guinea pigs.METHODS： Thirty guinea pigs（15-20 days old） were randomly divided into three groups（n=10/group）. Animals in group I were raised in a completely closed carton with green flickering light illumination. Those in group II were kept in the open top closed carton under normal natural light. Guinea pigs were raised in a sight-widen cage under normal natural light in group III. The refractive status and axial length were measured before and after 8 weeks＇ illumination. Moreover, total RNA extracted from retinal, choroidal, and scleral tissues were determined by real-time reverse transcription polymerase chain reaction（RT-PCR）. The expressions of the receptor M1 were also explored in the retina, choroid, and sclera using immunohistochemistry.RESULTS： There was a remarkable reduction in refractive error and increase in axial length after 8-weeks＇ green flickering light stimulation（P〈0.001）. The expression of M1 receptor mRNA in sclera and retina in myopia group were remarkably lower than that in group II and III（P〈0.01）. Significant reduced expression of M1 receptor stimulated by green flickering light in retina and sclera tissues were also observed（P〈0.05）. However, there was no M1 receptor expression in choroid in 3 groups.CONCLUSION： Myopia can be induced by 8 weeks＇ green flickering light exposure in the animal model. M1 receptor may be involved causally or protectively in myopia development.
基金funded by the National Research Foundation of Korea and by the Korean Government (2020R1A2B5B01002463 and 2021R1A6A1A03038996).
文摘Tropane alkaloids(TAs)are among the most valued chemical compounds known since pre-historic times.Poisonous plants from Solanaceae family(Hyoscyamus niger,Datura,Atropa belladonna,Scopolia lurida,Mandragora officinarum,Duboisia)and Erythroxylaceae(Erythroxylum coca)are rich sources of tropane alkaloids.These compounds possess the anticholinergic properties as they could block the neurotransmitter acetylcholine action in the central and peripheral nervous system by binding at either muscarinic and/or nicotinic receptors.Hence,they are of great clinical impor-tance and are used as antiemetics,anesthetics,antispasmodics,bronchodilator and mydriatics.They also serve as the lead compounds to generate more effective drugs.Due to the important pharmacological action they are listed in the WHO list of essential medicines and are available in market with FDA approval.However,being anticholinergic in action,TA medication are under the suspicion of causing dementia and cognitive decline like other medications with anticholinergic action,interestingly which is incorrect.There are published reviews on chemistry,biosynthesis,phar-macology,safety concerns,biotechnological aspects of TAs but the detailed information on anticholinergic mecha-nism of action,clinical pharmacology,FDA approval and anticholinergic burden is lacking.Hence the present review tries to fill this lacuna by critically summarizing and discussing the above mentioned aspects.
文摘The changes in density of M-cholinergic receptors in different areas of senile rats and the regulatory action of Huang Qi ([symbol: see text] Radix Astragali, a drug for warming yang and replenishing qi) were observed by autoradiography. The results showed that the gray scale displayed in brain sections was clear and mainly distributed in the cortex, hippocampus and striate body, while that due to nonspecific combination was negligible. The gray scale in the cortex, hippocampus and striate body of the experimental group was markedly lower than that in the young control rats, decreased respectively by 24.87%, 14.12% and 12.76% (all P
文摘Schizophrenia is a psychiatric disorder affecting approximately 1% of the population worldwide and is characterised by the presence of positive and negative symptoms and cognitive deficits. Whilst current therapeutics ameliorate positive symptoms, they are largely ineffective in improving negative symptoms and cognitive deficits. The cholinergic neurotransmitter system heavily influences cognitive function and there is evidence that implicates disruption of the central cholinergic system in schizophrenia. Historically, targeting the cholinergic system has been impeded by poor selectivity leading to intolerable side effects warranting the need to develop more targeted therapeutic compounds. In this review we will summarise evidence supporting the roles of the cholinergic system, particularly the muscarinic M1 receptor, in the pathophysiology of schizophrenia and discuss the potential of a promising new class of candidate compounds, allosteric ligands, for addressing the difficulties involved in targeting this system. The body of evidence presented here highlights the dysfunction of the cholinergic system in schizophrenia and that targeting this system by taking advantage of allosteric ligands is having clinically meaningful effect on cognitive deficits.
文摘Besides the mainstay of α-blockers and 5α-reductase inhibitors,other forms of medical therapy complete the armamentarium in the treatment of lower urinary tract symptoms(LUTS)in men.These treatments can target specific symptoms as well as associated symptoms that would affect the quality of life of the patients.Many patients are bothered by storage symptoms,more so than the voiding symptoms.Antimuscarinics are efficacious and safe,provided the patients do not have high post void residual urine.Many patients with LUTS also have erectile dysfunction,and phosphodiesterase type Ⅴ inhibitors are effective in relieving both LUTS as well as erectile dysfunction for such patients.Phytotherapy provides a popular and safe treatment for LUTS,however,the efficacy of the treatment has not been proven in well conducted prospective randomized controlled studies.
