OBJECTIVE:To investigate the effect and mechanism of mild moxibustion on the non-neuronal cholinergic system(NNCS) in rats with ulcerative colitis(UC).METHODS:UC rat model was established by administering 4% dextran s...OBJECTIVE:To investigate the effect and mechanism of mild moxibustion on the non-neuronal cholinergic system(NNCS) in rats with ulcerative colitis(UC).METHODS:UC rat model was established by administering 4% dextran sulfate sodium.After 7 d,mild moxibustion,α7 nicotinic acetylcholine receptors(α7nAchRs) antagonist(α-bungarotoxin,α-BGT),vesicular acetylcholine transport inhibitor(vesamicol hydrochloride,VH) and organic cation transporters inhibitor(quinine,Qu) treatments were performed once daily for 7 d.Haematoxylin and eosin staining was used for morphological evaluation of colon tissues.Enzymelinked immunosorbent assay(ELISA) was used to measure the protein expressions of interleukin-1β(IL-1β) and choline acetyltransferase(ChAT) in colon tissue.Reverse transcription quantitative real-time polymerase chain reaction(RT-q PCR) was used to detect the mRNA expressions of IL-1β,carnosine acetyltransferase(CarAT),ChAT,and nuclear factor kappa-B p65 subunit(NF-κB p65) in colon tissue.Western blot was used to detect NF-κB p65 protein expression in colon tissue.Immunofluorescence was used to detect the expressions of neuronal acetylcholine(nAch) and non-neuronal acetylcholine(nnAch,released by NNCS) in colon tissue.RESULTS:Mild moxibustion inhibited colon inflammation and repaired mucosal damage to the colon in UC rats.Meanwhile,mild moxibustion could downregulate the expressions of IL-1β,NF-κB p65 protein and mRNA(P < 0.01),and upregulate the expressions of ChAT protein and CarAT mRNA(P < 0.05,P < 0.01).The α7nAChR antagonist α-BGT can reverse the protective effect of mild moxibustion on the UC and the inhibitory effect on the inflammatory factors.VH cannot affect the effect of mild moxibustion on the expressions of IL-1β and nnAch,while Qu can reverse the effect of mild moxibustion on the expression of IL-1β and nnAch.CONCLUSIONS:Mild moxibustion can inhibite colon inflammation in UC rats,which is closely related to the release of acetylcholine by NNCS and its mediated mechanism of cholinergic anti-inflammation pathway.展开更多
With regard to brain acetylcholinesterase and acetylcholine and serum triiodothyronine(T_3) and thyroxine(T_4)profiles,a biphasic response pattern was elicited in Channa punctatus chroni- cally exposed to nonlethal do...With regard to brain acetylcholinesterase and acetylcholine and serum triiodothyronine(T_3) and thyroxine(T_4)profiles,a biphasic response pattern was elicited in Channa punctatus chroni- cally exposed to nonlethal doses of locally used pesticides,namely,Metacid-50 and Carbaryl. Data revealed that these xenobiotics caused significant inhibition of brain acetylcholinesterase activity and a decrease in thyroxine level accompanied by a concurrent increase in acetylcholine accumulation and T_3 level.It is surmised that Metacid-50 and Carbaryl influence both neural and hormonal functions.1989 Academic Press.Inc.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
Moderate one-off hypobaric hypoxia (HBH) provokes preconditioning and prolongs the resistance (T, the time before apnoea) to severe hypobaric hypoxia (SHBH). Hypoxic preconditioning has therapeutic potential;however, ...Moderate one-off hypobaric hypoxia (HBH) provokes preconditioning and prolongs the resistance (T, the time before apnoea) to severe hypobaric hypoxia (SHBH). Hypoxic preconditioning has therapeutic potential;however, the efficiency of hypoxic preconditioning varies greatly and the methods for its preliminary evaluation are absent in both animals and humans. This rodent study evaluates the dependence of SHBH resistance, initiated by HBH, on the rate of sensorimotor gating estimated in the model of the acoustic startle prepulse inhibition (PPI). A stable negative correlation was found between PPI and T. Low doses of the α7 nicotinic receptor agonist, PNU-282987 (PNU), and more pronouncedly dimethyl sulfoxide (DMSO) (a PNU solvent), inverted the correlation between PPI and T from negative to positive. The DMSO and PNU effects were reversed at PPIs of 0.36 - 0.40 (36% - 40%). DMSO increased T values by 52.2% ± 9.7% in the region of lower HBH efficiency (PPI ≥ 0.40) and reduced it by 35.2% ± 9.3% in the region of higher HBH efficiency (PPI < 0.40). PNU reduced both DMSO effects. The involvement of the central cholinergic mechanisms was substantiated in both DMSO and PNU influences on HBH. In conclusion, 1) PPI can be used to predict the efficiency of hypoxic preconditioning and to study its mechanisms, 2) two opposite cholinergic PPI-related mechanisms participate in the preconditioning effects of HBH, 3) the sensitivity of rats to DMSO and PNU diverges when the PPI is 0.36 - 0.40, and 4) DMSO can enhance resistance to severe hypoxia in the region of the lower preconditioning efficiency of HBH at PPI ≥ 0.4.展开更多
Fear memory is crucial for survival and adaptation in complex and dynamically changing environments that enables individuals to avoid or escape from potentially dangerous situations.However,excessive fear memories can...Fear memory is crucial for survival and adaptation in complex and dynamically changing environments that enables individuals to avoid or escape from potentially dangerous situations.However,excessive fear memories can significantly contribute to emotional disabilities and mental disorders,including panic disorder,phobias,social anxiety disorder,and post-traumatic stress disorder(PTSD).展开更多
The dichotomized brain system is a concept that was generalized from the‘dual syndrome hypothesis’to explain the heterogeneity of cognitive impairment,in which anterior and posterior brain systems are independent bu...The dichotomized brain system is a concept that was generalized from the‘dual syndrome hypothesis’to explain the heterogeneity of cognitive impairment,in which anterior and posterior brain systems are independent but partially overlap.The dopaminergic system acts on the anterior brain and is responsible for executive function,working memory,and planning.In contrast,the cholinergic system acts on the posterior brain and is responsible for semantic fluency and visuospatial function.Evidence from dopaminergic/cholinergic imaging or functional neuroimaging has shed significant insight relating to the involvement of the cerebellum in the cognitive process of patients with Parkinson’s disease.Previous research has reported evidence that the cerebellum receives both dopaminergic and cholinergic projections.However,whether these two neurotransmitter systems are associated with cognitive function has yet to be fully elucidated.Furthermore,the precise role of the cerebellum in patients with Parkinson’s disease and cognitive impairment remains unclear.Therefore,in this review,we summarize the cerebellar dopaminergic and cholinergic projections and their relationships with cognition,as reported by previous studies,and investigated the role of the cerebellum in patients with Parkinson’s disease and cognitive impairment,as determined by functional neuroimaging.Our findings will help us to understand the role of the cerebellum in the mechanisms underlying cognitive impairment in Parkinson’s disease.展开更多
Sleep deprivation has been shown to exacerbate pain sensitivity and may contribute to the onset of chronic pain,yet the precise neural mechanisms underlying this association remain elusive.In our study,we explored the...Sleep deprivation has been shown to exacerbate pain sensitivity and may contribute to the onset of chronic pain,yet the precise neural mechanisms underlying this association remain elusive.In our study,we explored the contribution of cholinergic neurons within the medial habenula(MHb)to hyperalgesia induced by sleep deprivation in rats.Our findings indicate that the activity of MHb cholinergic neurons diminishes during sleep deprivation and that chemogenetic stimulation of these neurons can mitigate the results.Interestingly,we did not find a direct response of MHb cholinergic neurons to pain stimulation.Further investigation identified the interpeduncular nucleus(IPN)and the paraventricular nucleus of the thalamus(PVT)as key players in the pro-nociceptive effect of sleep deprivation.Stimulating the pathways connecting the MHb to the IPN and PVT alleviated the hyperalgesia.These results underscore the important role of MHb cholinergic neurons in modulating pain sensitivity linked to sleep deprivation,highlighting potential neural targets for mitigating sleep deprivation-induced hyperalgesia.展开更多
The innervation of cholinergic efferent fibers in the vestibular endorgans of the rat was investigated using a modified preembedding immunostaining technique of immunoelectron microscopy. A monoclonal antibody to chol...The innervation of cholinergic efferent fibers in the vestibular endorgans of the rat was investigated using a modified preembedding immunostaining technique of immunoelectron microscopy. A monoclonal antibody to choline acetyltransferase (ChAT) was used as a marker of cholinergic fibers. It was found that there were four types of cholinergic innervation in the vestibular endorgans of the rat: (1) cholinergic nerve endings formed axo-dendritic synapses with afferent chalice surrounding the type I sensory hair cells; (2) cholinergic nerve endings formed axo-somatic synapses with type Ⅱ hair cells; (3) cholinergic fibers synapse with afferent nerve fibers and (4) a synaptic contact developed between cholinergic nerve endings. The results demonstrated that a multiform innervation of the cholinergic efferents exists in the rat vestibular periphery.展开更多
Cholinergic system associated DOPA-refractory motor and cognitive symptoms-a need for novel therapeutic approaches:Accumulating evidence points to significant motor and non-motor morbidities associated with hypocholin...Cholinergic system associated DOPA-refractory motor and cognitive symptoms-a need for novel therapeutic approaches:Accumulating evidence points to significant motor and non-motor morbidities associated with hypocholinergic deficits in central and peripheral neural systems in Parkinson’s disease(PD)(Bohnen et al.,2018,2022).This so-called“malignant”hypocholinergic disease phenotype is associated with DOPA-refractory dementia and mobility disturbances,such as falls and freezing of gait,and augur novel therapeutic approaches targeting cholinergic systems in PD.Cholinergic pharmacotherapy in PD has been an interest for a long time.However,the development of cholinergic augmentation pharmacotherapy has been hampered by limited clinical efficacy,the presumption that changes in cholinergic activity are homogeneous in the central nervous system(CNS)and peripheral nervous system,tolerance or safety of cholinesterase inhibitor drugs,low CNS penetrance,high rate of peripheral autonomic side-effects and clinical contra-indications.The development of nicotinic or muscarinic receptor modulating drugs appears more promising but is still in the development stage.Given the current unmet need for managing DOPA-refractory cognitive and mobility impairments associated with hypocholinergic neural systems,there is a need for novel and complementary therapeutic and more personalized approaches.展开更多
Chrysanthellum americanum (L.) Vatke is a medicinal plant used by the traditional healers to treat epilepsy and associated memory impairment. This work aims at evaluating the anticonvulsant effects of Chrysanthellum a...Chrysanthellum americanum (L.) Vatke is a medicinal plant used by the traditional healers to treat epilepsy and associated memory impairment. This work aims at evaluating the anticonvulsant effects of Chrysanthellum americanum aqueous extract in mice pilocarpine model of epilepsy and associated memory loss. Mice were administered orally Chrysanthellum americanum aqueous extract (27.69, 69.22, 138.45, 276.9 mg/kg, prepared from the whole part) for test groups, intraperitoneally 300 mg/kg sodium valproate for the positive control group or orally 10 mL/kg distilled water for the negative control group, respectively, during a period of seven consecutive days. On the first day, temporal lobe epilepsy was induced by intraperitoneal injection of 360 mg/kg pilocarpine one hour after the administration of different treatment to mice, and the occurrence of status epilepticus was evaluated. On the second day, the anticonvulsant property was measured after the intraperitoneal injection of a sub-convulsive dose of picrotoxin (1 mg/kg). On the seventh day, the anti-amnesic properties of the extract were evaluated in the epileptic mice using the T-maze and open field paradigms. The results show that Chrysanthellum americanum extract significantly (p Chrysanthellum americanum (276.9 mg/kg) likewise sodium valproate (300 mg/kg) significantly (p Chrysanthellum americanum aqueous extract has anticonvulsant effects against pilocarpine induced-epileptic seizures and memory impairment. These properties could be mediated by the amelioration of antioxidant defense system and cholinergic neurotransmission in epileptic mice, which could partly justify the use of Chrysanthellum americanum in the traditional medicine for the treatment of epilepsy.展开更多
Sepsis is a life-threatening inflammatory syndrome with high morbidity and mortality rates.However,options for sepsis are still limited to general treatment in intensive care units(ICUs),and effective therapies that i...Sepsis is a life-threatening inflammatory syndrome with high morbidity and mortality rates.However,options for sepsis are still limited to general treatment in intensive care units(ICUs),and effective therapies that improve sepsis survival are required.Immune disturbances play a vital role in the pathology of sepsis and are associated with protracted inflammation,susceptibility to infections,and death.Therefore,many investigators have focused on the potential benefits of immunomodulation therapy for sepsis.Electroacupuncture(EA)has been practiced in clinics for many years and has shown advantages in treating infectious diseases.Over the last few decades,our understanding of the efficacy and mechanisms of EA in sepsis has undergone considerable developments.We searched the literature regarding“CNKI,Wan Fang Data,VIP Database,PubMed,and Ingenta Connect”from 2010 to 2023,using the keywords“sepsis”“septic”and“electroacupuncture”and 336 sources were searched.Finally,we included 82 studies that targeted the immune system to determine EA’s anti-inflammatory and immunomodulatory effects on sepsis.In this review,we found that EA has clinical benefits in relieving septic inflammation,improving immune function,and attenuating related multi-organ injury through several mechanisms,such as activation of the cholinergic anti-inflammatory pathway(CAP),vagaladrenal axis,inhibition of the nuclear factor Kappa-B(NF-κB)signaling pathway,signal transducers and activators of transcription(STAT)signaling pathway,and improvement of immune cell function.Therefore,EA may be a promising complementary therapy for sepsis treatment.We also expect these data will contribute to further studies on EA in sepsis.展开更多
Alzheimer's disease is the most common type of cognitive disorder,and there is an urgent need to develop more effective,targeted and safer therapies for patients with this condition.Deep brain stimulation is an in...Alzheimer's disease is the most common type of cognitive disorder,and there is an urgent need to develop more effective,targeted and safer therapies for patients with this condition.Deep brain stimulation is an invasive surgical treatment that modulates abnormal neural activity by implanting electrodes into specific brain areas followed by electrical stimulation.As an emerging therapeutic approach,deep brain stimulation shows significant promise as a potential new therapy for Alzheimer's disease.Here,we review the potential mechanisms and therapeutic effects of deep brain stimulation in the treatment of Alzheimer's disease based on existing clinical and basic research.In clinical studies,the most commonly targeted sites include the fornix,the nucleus basalis of Meynert,and the ventral capsule/ventral striatum.Basic research has found that the most frequently targeted areas include the fornix,nucleus basalis of Meynert,hippocampus,entorhinal cortex,and rostral intralaminar thalamic nucleus.All of these individual targets exhibit therapeutic potential for patients with Alzheimer's disease and associated mechanisms of action have been investigated.Deep brain stimulation may exert therapeutic effects on Alzheimer's disease through various mechanisms,including reducing the deposition of amyloid-β,activation of the cholinergic system,increasing the levels of neurotrophic factors,enhancing synaptic activity and plasticity,promoting neurogenesis,and improving glucose metabolism.Currently,clinical trials investigating deep brain stimulation for Alzheimer's disease remain insufficient.In the future,it is essential to focus on translating preclinical mechanisms into clinical trials.Furthermore,consecutive follow-up studies are needed to evaluate the long-term safety and efficacy of deep brain stimulation for Alzheimer's disease,including cognitive function,neuropsychiatric symptoms,quality of life and changes in Alzheimer's disease biomarkers.Researchers must also prioritize the initiation of multi-center clinical trials of deep brain stimulation with large sample sizes and target earlier therapeutic windows,such as the prodromal and even the preclinical stages of Alzheimer's disease.Adopting these approaches will permit the efficient exploration of more effective and safer deep brain stimulation therapies for patients with Alzheimer's disease.展开更多
Repetitive transcranial magnetic stimulation （rTMS） is a non-invasive treatment that can enhance the recovery of neurological function after stroke. Whether it can similarly promote the recovery of cognitive functio...Repetitive transcranial magnetic stimulation （rTMS） is a non-invasive treatment that can enhance the recovery of neurological function after stroke. Whether it can similarly promote the recovery of cognitive function after vascular dementia remains unknown, In this study, a rat model for vascular dementia was established by the two-vessel occlusion method. Two days after injury, 30 pulses of rTMS were ad- ministered to each cerebral hemisphere at a frequency of 0.5 Hz and a magnetic field intensity of 1,33 T. The Morris water maze test was used to evaluate learning and memory function. The Karnovsky-Roots method was performed to determine the density of cholinergic neurons in the hippocampal CA1 region. Immunohistochemical staining was used to determine the number of brain-derived neurotroph- ic factor （BDNF）-immunoreactive cells in the hippocampal CA1 region, rTMS treatment for 30 days significantly improved learning and memory function, increased acetylcholinesterase and choline acetyltransferase activity, increased the density of cholinergic neurons, and increased the number of BDNF-immunoreactive cells. These results indicate that rTMS can ameliorate learning and memory deficiencies in rats with vascular dementia, The mechanism through which this occurs might be related to the promotion of BDNF expression and subsequent restoration of cholinergic system activity in hippocampal CA 1 region.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
Puerarin, a major isoflavonoid derived from the Chinese medical herb radix puerariae （Gegen）, has been reported to inhibit neuronal apoptosis and play an anti-inflammatory role in focal cerebral ischemia model rats....Puerarin, a major isoflavonoid derived from the Chinese medical herb radix puerariae （Gegen）, has been reported to inhibit neuronal apoptosis and play an anti-inflammatory role in focal cerebral ischemia model rats. Recent findings regarding stroke pathophysiology have recognized that anti-inflammation is an important target for the treatment of ischemic stroke. The cholinergic anti-inflammatory pathway is a highly robust neural-immune mechanism for inflammation control. This study was to investigate whether activating the cholinergic anti-inflammatory pathway can be involved in the mechanism of inhibiting the inflammatory response during puerarin-induced cerebral ischemia/reperfusion in rats. Results showed that puerarin pretreatment （intravenous injection） re- duced the ischemic infarct volume, improved neurological deficit after cerebral ischemia/reperfusion and decreased the levels of interleukin-1β, interleukin-6 and tumor necrosis factor-a in brain tissue. Pretreatment with puerarin （intravenous injection） attenuated the inflammatory response in rats, which was accompanied by janus-activated kinase 2 （JAK2） and signal transducers and activators of transcription 3 （STAT3） activation and nuclear factor kappa B （NF-KB） inhibition. These observa- tions were inhibited by the alpha7 nicotinic acetylcholine receptor （a7nAchR） antagonist a-bungarotoxin （a-BGT）. In addition, puerarin pretreatment increased the expression of a7nAchR mRNA in ischemic cerebral tissue. These data demonstrate that puerarin pretreatment strongly protects the brain against cerebral ischemia/reperfusion injury and inhibits the inflammatory re- sponse. Our results also indicated that the anti-inflammatory effect of puerarin may partly be medi- ated through the activation of the cholinergic anti-inflammatory pathway.展开更多
Objective： Acupuncture has a definite therapeutic effect on chronic obstructive pulmonary disease （COPD）, and the cholinergic anti-inflammatory pathway （CAP） has been shown to be involved in regula- tion of infla...Objective： Acupuncture has a definite therapeutic effect on chronic obstructive pulmonary disease （COPD）, and the cholinergic anti-inflammatory pathway （CAP） has been shown to be involved in regula- tion of inflammation. In this study, we investigated whether electro-acupuncture （EA） affects the CAP in COPD,Methods： Sprague-Dawley rats were induced into COPD through exposure to cigarette smoke combined with lipopolysaccharide. EA treatment was applied at Zusanli （ST36） and Feishu （BL13） points for 30 min/d for 7 d. Seventy-two rats were randomly divided into six study groups, including normal, normal ＋ EA, normal ＋ α-bungarotoxin （α-BGT） （the antagonist of the nicotinic acetylcholine receptor α7 subunit （α7nAChR）） ＋ EA, COPD, COPD ＋ EA, and COPD ＋ α-BGT ＋ EA. Lung function, pathology and vagus nerve discharge were tested. The levels of acetylcholine （ACh）, acetylcholinesterase （ACHE）, interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-ct） in bronchoalveolar lavage fluid （BALF） and lung tissue were measured by enzyme-linked immunosorbent assay. The mRNA and protein expression and immunoreac- tivity of α7nAChR and its postreceptor inflammation signal pathway, including janus kinase 2 （JAK2）, sig- nal transducers and activators of transcription 3 （STAT3）, nuclear factor-KB （NF-KB）, were observed by quantitative reverse transcription-polymerase chain reaction, Western blot and immunohistochemistry. Results： Compared with normal rats, there were a significant decline in lung function and discharge of the vagus nerve （P 〈 0.01）, a marked sign of lung inflammation and an increase of ACh, ACHE, IL-6 and TNF-α level in BALF or lung tissue （P 〈 0.05, P 〈 0.01 ） and higher expression of 0t7nAChR, JAK2, STAT3 and NF-αB （P 〈 0.05, P 〈 0.01） in the COPD rats. In rats receiving EA, the lung function and vagal discharge were enhanced （P 〈 0.01 ）, lung inflammation was improved and the levels of ACh, ACHE, IL-6 and TNF-α were decreased （P 〈 0.01）. Further, the expression of α7nAChR, JAK2, STAT3 and NF-κB was downregulated （P 〈 0.05, P 〈 0.01 ）. However, the above effects of EA were blocked in rats injected with α-BCT （P 〈 0.01 ）. Conclusion： EA treatment can reduce the lung inflammatory response and improve lung function in COPD, which may be related to its involvement in the regulation of CAP.展开更多
The tooth belongs to the trigeminal sensory pathway. Dental damage has been associated with impairments in the central nervous system that may be mediated by injury to the trigeminal nerve. In the present study, we in...The tooth belongs to the trigeminal sensory pathway. Dental damage has been associated with impairments in the central nervous system that may be mediated by injury to the trigeminal nerve. In the present study, we investigated the effects of damage to the inferior alveolar nerve, an important peripheral nerve in the trigeminal sensory pathway, on learning and memory be-haviors and structural changes in related brain regions, in a mouse model of Alzheimer’s disease. Inferior alveolar nerve transection or sham surgery was performed in middle-aged （4-month-old） or elderly （7-month-old） senescence-accelerated mouse prone 8 （SAMP8） mice. When the middle-aged mice reached 8 months （middle-aged group 1） or 11 months （middle-aged group 2）, and the elderly group reached 11 months, step-down passive avoidance and Y-maze tests of learn-ing and memory were performed, and the cholinergic system was examined in the hippocampus （Nissl staining and acetylcholinesterase histochemistry） and basal forebrain （choline acetyltrans-ferase immunohistochemistry）. In the elderly group, animals that underwent nerve transection had fewer pyramidal neurons in the hippocampal CA1 and CA3 regions, fewer cholinergic ifbers in the CA1 and dentate gyrus, and fewer cholinergic neurons in the medial septal nucleus and vertical limb of the diagonal band, compared with sham-operated animals, as well as showing impairments in learning and memory. Conversely, no signiifcant differences in histology or be-havior were observed between middle-aged group 1 or group 2 transected mice and age-matched sham-operated mice. The present ifndings suggest that trigeminal nerve damage in old age, but not middle age, can induce degeneration of the septal-hippocampal cholinergic system and loss of hippocampal pyramidal neurons, and ultimately impair learning ability. Our results highlight the importance of active treatment of trigeminal nerve damage in elderly patients and those with Alzheimer’s disease, and indicate that tooth extraction should be avoided in these populations.展开更多
The current idea behind brain pathology is that disease is initiated by mild disturbances of common physiological processes. Overtime, the disruption of the neuronal homeostasis will determine irreversible degeneratio...The current idea behind brain pathology is that disease is initiated by mild disturbances of common physiological processes. Overtime, the disruption of the neuronal homeostasis will determine irreversible degeneration and neuronal apoptosis. This could be also true in the case of nerve growth factor （NGF） al- terations in sporadic Alzheimer＇s disease （AD）, an age-related pathology characterized by cholinergic loss, amyloid plaques and neurofibrillary tangles. In fact, the pathway activated by NGF, a key neurotrophin for the metabolism of basal forebrain cholinergic neurons （BFCN）, is one of the first homeostatic systems affected in prodromal AD. NGF signaling dysfunctions have been thought for decades to occur in AD late stages, as a mere consequence of amyloid-driven disruption of the retrograde axonal transport of neuro- trophins to BFCN. Nowadays, a wealth of knowledge is potentially opening a new scenario： NGF signaling impairment occurs at the onset of AD and correlates better than amyloid load with cognitive decline. The recent acceleration in the characterization of anatomical, functional and molecular profiles of early AD is aimed at maximizing the efficacy of existing treatments and setting novel therapies. Accordingly, the elucidation of the molecular events underlying APP metabolism regulation by the NGF pathway in the sep- to-hippocampal system is crucial for the identification of new target molecules to slow and eventually halt mild cognitive impairment （MCI） and its progression toward AD.展开更多
AIM： To investigate the effects of mangiferin on gas- trointestinal transit （GIT） in normal and constipated mice, together with the possible mechanism.METHODS： Intragastrically-administered charcoal mealwas used t...AIM： To investigate the effects of mangiferin on gas- trointestinal transit （GIT） in normal and constipated mice, together with the possible mechanism.METHODS： Intragastrically-administered charcoal mealwas used to measure GIT in overnight starved Swiss mice. In the first experiments, mangiferin （3 mg/kg, 10 mg/kg, 30 mg/kg, and 100 mg/kg, po） or tegaserod （1 mg/kg, ip） were administered 30 min before the char- coal meal to study their effects on normal transit. In the second series, mangiferin （30 mg/kg） was tested on delayed GIT induced by several different pharma- cological agonists （morphine, clonidine, capsaicin） or antagonists （ondansetron, verapamil, and atropine） whereas in the third series, mangiferin （30 mg/kg, 100 mg/kg and 300 mg/kg） or tegaserod （1 mg/kg） were tested on 6 h fecal pellets outputted by freely fed mice. The ratio of wet to dry weight was calculated and used as a marker of fecal water content. RESULTS： Mangiferin administered orally significantly （P 〈 0.05） accelerated GIT at 30 mg/kg and 100 mg/kg （89% and 93%, respectively）, similarly to 5-hydroxytrypta- mine4 （5-H%） agonist tegaserod （81%） when compared to vehicle-treated control （63%）. Co-administered man- giferin （30 mg/kg） totally reversed the inhibitory effect of opioid agonist morphine, 5-HT3-receptor antagonist ondansetron and transient receptor potential vanilloid-1 receptor agonist capsaicin on GIT, but only to a partial extent with the GIT-delay induced by ~2-adrenoceptor agonist clonidine, and calcium antagonist verapamil. However, co-administered atropine completely blocked the stimulant effect of mangiferin on GIT, suggesting the involvement of muscarinic acetylcholine receptor activation. Although mangiferin significantly enhanced the 6 h fecal output at higher doses （245.5±10.43 mg vs 161.9±10.82 mg and 227.1±20.11 mg vs 161.9±10.82 mg of vehicle-treated control, at 30 and 100 mg/ kg, P 〈 0.05, respectively）, the effect of tegaserod was more potent （297.4±7.42 mg vs 161.9±10.82 mg of vehicle-treated control, P 〈 0.05）. Unlike tegaserod, which showed an enhanced water content in fecal pel- lets （59.20%±1.09% vs 51.44%±1.19% of control, P 〈 0.05）, mangiferin evidenced no such effect, indi-cating that it has only a motor and not a secretomotor effect. CONCLUSION： Our data indicate the prokinetic action of mangiferin. It can stimulate the normal GIT and also overcome the drug-induced transit delay, via a choliner- gic physiological mechanism.展开更多
The present study analyzed changes in Wnt3a expression during differentiation of adipose-derived stern cells into cholinergic neurons. Immunocytochemistry and immunofluorescence revealed significantly increased nestin...The present study analyzed changes in Wnt3a expression during differentiation of adipose-derived stern cells into cholinergic neurons. Immunocytochemistry and immunofluorescence revealed significantly increased nestin, neuron-specific enolase, microtubule-associated protein 2, and choline acetyltransferase expression in adipose-derived stem cells isolated from Sprague-Dawley rats and cultured in vitro in neural-induced medium. These expressions increased with prolonged induction time. Real-time reverse transcription-PCR and western blot assay results demonstrated significantly increased choline acetyltransferase and Wnt3a protein and mRNA expressions, respectively, in adipose-derived stem cells following induction. Choline acetyltransferase expression positively correlated with Wnt3a protein and mRNA expressions. These results demonstrated that neural-induced medium induced differentiation of adipose-derived stem cells into cholinergic neuronal-like cells, with subsequent increased Wnt3a expression.展开更多
基金National Natural Science Foundation of China:Study for the Mechanism of Moxibustion in Ulcerative Colitis based on the α7 Nicotinic Acetylcholine Receptor Mediated Cholinergic Antiinflammatory Pathway (No.82205293)National Natural Science Foundation of China:Study of the Central Nervous System Regulatory Mechanism of Moxibustion Repair of Ulcerative Colitis Gut Vascular Barrier Based on Ubiquitin Specific Peptidase 14 Deubiquitination (No.82274641)+3 种基金National Natural Science Foundation of China:Moxibustion Regulates P300-mediated Histone H3K27 Acetylation Modification in the Treatment of Crohn's Disease (No.82205262)National Natural Science Foundation of China:Study on the Protective Mechanism of Moxibustion on Intestinal Mucosal Barrier in Ulcerative Colitis based on GABAergic System (No.82105012)Shanghai Sailing Program:to Study the Protective Effect of Moxibustion on Intestinal Mucosal Barrier in Crohn's Disease Based on Histone H3 Acetylation Modification (No.22YF1444100)State Administration of Traditional Chinese Medicine High-level Key Discipline Construction Project (No.zyyzdxk-2023068)。
文摘OBJECTIVE:To investigate the effect and mechanism of mild moxibustion on the non-neuronal cholinergic system(NNCS) in rats with ulcerative colitis(UC).METHODS:UC rat model was established by administering 4% dextran sulfate sodium.After 7 d,mild moxibustion,α7 nicotinic acetylcholine receptors(α7nAchRs) antagonist(α-bungarotoxin,α-BGT),vesicular acetylcholine transport inhibitor(vesamicol hydrochloride,VH) and organic cation transporters inhibitor(quinine,Qu) treatments were performed once daily for 7 d.Haematoxylin and eosin staining was used for morphological evaluation of colon tissues.Enzymelinked immunosorbent assay(ELISA) was used to measure the protein expressions of interleukin-1β(IL-1β) and choline acetyltransferase(ChAT) in colon tissue.Reverse transcription quantitative real-time polymerase chain reaction(RT-q PCR) was used to detect the mRNA expressions of IL-1β,carnosine acetyltransferase(CarAT),ChAT,and nuclear factor kappa-B p65 subunit(NF-κB p65) in colon tissue.Western blot was used to detect NF-κB p65 protein expression in colon tissue.Immunofluorescence was used to detect the expressions of neuronal acetylcholine(nAch) and non-neuronal acetylcholine(nnAch,released by NNCS) in colon tissue.RESULTS:Mild moxibustion inhibited colon inflammation and repaired mucosal damage to the colon in UC rats.Meanwhile,mild moxibustion could downregulate the expressions of IL-1β,NF-κB p65 protein and mRNA(P < 0.01),and upregulate the expressions of ChAT protein and CarAT mRNA(P < 0.05,P < 0.01).The α7nAChR antagonist α-BGT can reverse the protective effect of mild moxibustion on the UC and the inhibitory effect on the inflammatory factors.VH cannot affect the effect of mild moxibustion on the expressions of IL-1β and nnAch,while Qu can reverse the effect of mild moxibustion on the expression of IL-1β and nnAch.CONCLUSIONS:Mild moxibustion can inhibite colon inflammation in UC rats,which is closely related to the release of acetylcholine by NNCS and its mediated mechanism of cholinergic anti-inflammation pathway.
文摘With regard to brain acetylcholinesterase and acetylcholine and serum triiodothyronine(T_3) and thyroxine(T_4)profiles,a biphasic response pattern was elicited in Channa punctatus chroni- cally exposed to nonlethal doses of locally used pesticides,namely,Metacid-50 and Carbaryl. Data revealed that these xenobiotics caused significant inhibition of brain acetylcholinesterase activity and a decrease in thyroxine level accompanied by a concurrent increase in acetylcholine accumulation and T_3 level.It is surmised that Metacid-50 and Carbaryl influence both neural and hormonal functions.1989 Academic Press.Inc.
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Moderate one-off hypobaric hypoxia (HBH) provokes preconditioning and prolongs the resistance (T, the time before apnoea) to severe hypobaric hypoxia (SHBH). Hypoxic preconditioning has therapeutic potential;however, the efficiency of hypoxic preconditioning varies greatly and the methods for its preliminary evaluation are absent in both animals and humans. This rodent study evaluates the dependence of SHBH resistance, initiated by HBH, on the rate of sensorimotor gating estimated in the model of the acoustic startle prepulse inhibition (PPI). A stable negative correlation was found between PPI and T. Low doses of the α7 nicotinic receptor agonist, PNU-282987 (PNU), and more pronouncedly dimethyl sulfoxide (DMSO) (a PNU solvent), inverted the correlation between PPI and T from negative to positive. The DMSO and PNU effects were reversed at PPIs of 0.36 - 0.40 (36% - 40%). DMSO increased T values by 52.2% ± 9.7% in the region of lower HBH efficiency (PPI ≥ 0.40) and reduced it by 35.2% ± 9.3% in the region of higher HBH efficiency (PPI < 0.40). PNU reduced both DMSO effects. The involvement of the central cholinergic mechanisms was substantiated in both DMSO and PNU influences on HBH. In conclusion, 1) PPI can be used to predict the efficiency of hypoxic preconditioning and to study its mechanisms, 2) two opposite cholinergic PPI-related mechanisms participate in the preconditioning effects of HBH, 3) the sensitivity of rats to DMSO and PNU diverges when the PPI is 0.36 - 0.40, and 4) DMSO can enhance resistance to severe hypoxia in the region of the lower preconditioning efficiency of HBH at PPI ≥ 0.4.
文摘Fear memory is crucial for survival and adaptation in complex and dynamically changing environments that enables individuals to avoid or escape from potentially dangerous situations.However,excessive fear memories can significantly contribute to emotional disabilities and mental disorders,including panic disorder,phobias,social anxiety disorder,and post-traumatic stress disorder(PTSD).
基金supported by the National Natural Science Foundation of China,No.82071419Key Research and Development Program of Guangzhou,No.202206010086+1 种基金High-level Hospital Construction Project,No.DFJH201907Supporting Research Funds for Outstanding Young Medical Talents in Guangdong Province,No.KJ012019442(all to YZ)。
文摘The dichotomized brain system is a concept that was generalized from the‘dual syndrome hypothesis’to explain the heterogeneity of cognitive impairment,in which anterior and posterior brain systems are independent but partially overlap.The dopaminergic system acts on the anterior brain and is responsible for executive function,working memory,and planning.In contrast,the cholinergic system acts on the posterior brain and is responsible for semantic fluency and visuospatial function.Evidence from dopaminergic/cholinergic imaging or functional neuroimaging has shed significant insight relating to the involvement of the cerebellum in the cognitive process of patients with Parkinson’s disease.Previous research has reported evidence that the cerebellum receives both dopaminergic and cholinergic projections.However,whether these two neurotransmitter systems are associated with cognitive function has yet to be fully elucidated.Furthermore,the precise role of the cerebellum in patients with Parkinson’s disease and cognitive impairment remains unclear.Therefore,in this review,we summarize the cerebellar dopaminergic and cholinergic projections and their relationships with cognition,as reported by previous studies,and investigated the role of the cerebellum in patients with Parkinson’s disease and cognitive impairment,as determined by functional neuroimaging.Our findings will help us to understand the role of the cerebellum in the mechanisms underlying cognitive impairment in Parkinson’s disease.
基金supported by grants from the Ministry of Science and Technology of China(2021ZD0203204)the National Natural Science Foundation of China(32030052 and 31530028).
文摘Sleep deprivation has been shown to exacerbate pain sensitivity and may contribute to the onset of chronic pain,yet the precise neural mechanisms underlying this association remain elusive.In our study,we explored the contribution of cholinergic neurons within the medial habenula(MHb)to hyperalgesia induced by sleep deprivation in rats.Our findings indicate that the activity of MHb cholinergic neurons diminishes during sleep deprivation and that chemogenetic stimulation of these neurons can mitigate the results.Interestingly,we did not find a direct response of MHb cholinergic neurons to pain stimulation.Further investigation identified the interpeduncular nucleus(IPN)and the paraventricular nucleus of the thalamus(PVT)as key players in the pro-nociceptive effect of sleep deprivation.Stimulating the pathways connecting the MHb to the IPN and PVT alleviated the hyperalgesia.These results underscore the important role of MHb cholinergic neurons in modulating pain sensitivity linked to sleep deprivation,highlighting potential neural targets for mitigating sleep deprivation-induced hyperalgesia.
文摘The innervation of cholinergic efferent fibers in the vestibular endorgans of the rat was investigated using a modified preembedding immunostaining technique of immunoelectron microscopy. A monoclonal antibody to choline acetyltransferase (ChAT) was used as a marker of cholinergic fibers. It was found that there were four types of cholinergic innervation in the vestibular endorgans of the rat: (1) cholinergic nerve endings formed axo-dendritic synapses with afferent chalice surrounding the type I sensory hair cells; (2) cholinergic nerve endings formed axo-somatic synapses with type Ⅱ hair cells; (3) cholinergic fibers synapse with afferent nerve fibers and (4) a synaptic contact developed between cholinergic nerve endings. The results demonstrated that a multiform innervation of the cholinergic efferents exists in the rat vestibular periphery.
基金supported by the National Institute of Health,No.P50 NS123067The Farmer Family Foundation+2 种基金supported by the NIHR Newcastle Biomedical Research Centre(BRC)The NIHR BRC is a partnership between Newcastle Hospitals NHS Foundation Trust and Newcastle Universityfunded by the National Institute for Health and Care Research(NIHR)。
文摘Cholinergic system associated DOPA-refractory motor and cognitive symptoms-a need for novel therapeutic approaches:Accumulating evidence points to significant motor and non-motor morbidities associated with hypocholinergic deficits in central and peripheral neural systems in Parkinson’s disease(PD)(Bohnen et al.,2018,2022).This so-called“malignant”hypocholinergic disease phenotype is associated with DOPA-refractory dementia and mobility disturbances,such as falls and freezing of gait,and augur novel therapeutic approaches targeting cholinergic systems in PD.Cholinergic pharmacotherapy in PD has been an interest for a long time.However,the development of cholinergic augmentation pharmacotherapy has been hampered by limited clinical efficacy,the presumption that changes in cholinergic activity are homogeneous in the central nervous system(CNS)and peripheral nervous system,tolerance or safety of cholinesterase inhibitor drugs,low CNS penetrance,high rate of peripheral autonomic side-effects and clinical contra-indications.The development of nicotinic or muscarinic receptor modulating drugs appears more promising but is still in the development stage.Given the current unmet need for managing DOPA-refractory cognitive and mobility impairments associated with hypocholinergic neural systems,there is a need for novel and complementary therapeutic and more personalized approaches.
文摘Chrysanthellum americanum (L.) Vatke is a medicinal plant used by the traditional healers to treat epilepsy and associated memory impairment. This work aims at evaluating the anticonvulsant effects of Chrysanthellum americanum aqueous extract in mice pilocarpine model of epilepsy and associated memory loss. Mice were administered orally Chrysanthellum americanum aqueous extract (27.69, 69.22, 138.45, 276.9 mg/kg, prepared from the whole part) for test groups, intraperitoneally 300 mg/kg sodium valproate for the positive control group or orally 10 mL/kg distilled water for the negative control group, respectively, during a period of seven consecutive days. On the first day, temporal lobe epilepsy was induced by intraperitoneal injection of 360 mg/kg pilocarpine one hour after the administration of different treatment to mice, and the occurrence of status epilepticus was evaluated. On the second day, the anticonvulsant property was measured after the intraperitoneal injection of a sub-convulsive dose of picrotoxin (1 mg/kg). On the seventh day, the anti-amnesic properties of the extract were evaluated in the epileptic mice using the T-maze and open field paradigms. The results show that Chrysanthellum americanum extract significantly (p Chrysanthellum americanum (276.9 mg/kg) likewise sodium valproate (300 mg/kg) significantly (p Chrysanthellum americanum aqueous extract has anticonvulsant effects against pilocarpine induced-epileptic seizures and memory impairment. These properties could be mediated by the amelioration of antioxidant defense system and cholinergic neurotransmission in epileptic mice, which could partly justify the use of Chrysanthellum americanum in the traditional medicine for the treatment of epilepsy.
基金funded by the National Key Research and Development Program(2022YFC3500704)the National Natural Science Foundation of China(82174500,82004491).
文摘Sepsis is a life-threatening inflammatory syndrome with high morbidity and mortality rates.However,options for sepsis are still limited to general treatment in intensive care units(ICUs),and effective therapies that improve sepsis survival are required.Immune disturbances play a vital role in the pathology of sepsis and are associated with protracted inflammation,susceptibility to infections,and death.Therefore,many investigators have focused on the potential benefits of immunomodulation therapy for sepsis.Electroacupuncture(EA)has been practiced in clinics for many years and has shown advantages in treating infectious diseases.Over the last few decades,our understanding of the efficacy and mechanisms of EA in sepsis has undergone considerable developments.We searched the literature regarding“CNKI,Wan Fang Data,VIP Database,PubMed,and Ingenta Connect”from 2010 to 2023,using the keywords“sepsis”“septic”and“electroacupuncture”and 336 sources were searched.Finally,we included 82 studies that targeted the immune system to determine EA’s anti-inflammatory and immunomodulatory effects on sepsis.In this review,we found that EA has clinical benefits in relieving septic inflammation,improving immune function,and attenuating related multi-organ injury through several mechanisms,such as activation of the cholinergic anti-inflammatory pathway(CAP),vagaladrenal axis,inhibition of the nuclear factor Kappa-B(NF-κB)signaling pathway,signal transducers and activators of transcription(STAT)signaling pathway,and improvement of immune cell function.Therefore,EA may be a promising complementary therapy for sepsis treatment.We also expect these data will contribute to further studies on EA in sepsis.
基金supported by the Capital Fund for Health Improvement and Research,No.2022-2-2048(to WZ)the National Natural Science Foundation of China,No.81970992(to WZ)+3 种基金Capital Clinical Characteristic Application Research,No.Z121107001012161(to WZ)the Natural Science Foundation of Beijing,No.7082032(to WZ)the Key Technology R&D Program of Beijing Municipal Education Commission,No.KZ201610025030(to WZ)Project of Scientific and Technological Development of Traditional Chinese Medicine in Beijing,No.JJ2018-48(to WZ)。
文摘Alzheimer's disease is the most common type of cognitive disorder,and there is an urgent need to develop more effective,targeted and safer therapies for patients with this condition.Deep brain stimulation is an invasive surgical treatment that modulates abnormal neural activity by implanting electrodes into specific brain areas followed by electrical stimulation.As an emerging therapeutic approach,deep brain stimulation shows significant promise as a potential new therapy for Alzheimer's disease.Here,we review the potential mechanisms and therapeutic effects of deep brain stimulation in the treatment of Alzheimer's disease based on existing clinical and basic research.In clinical studies,the most commonly targeted sites include the fornix,the nucleus basalis of Meynert,and the ventral capsule/ventral striatum.Basic research has found that the most frequently targeted areas include the fornix,nucleus basalis of Meynert,hippocampus,entorhinal cortex,and rostral intralaminar thalamic nucleus.All of these individual targets exhibit therapeutic potential for patients with Alzheimer's disease and associated mechanisms of action have been investigated.Deep brain stimulation may exert therapeutic effects on Alzheimer's disease through various mechanisms,including reducing the deposition of amyloid-β,activation of the cholinergic system,increasing the levels of neurotrophic factors,enhancing synaptic activity and plasticity,promoting neurogenesis,and improving glucose metabolism.Currently,clinical trials investigating deep brain stimulation for Alzheimer's disease remain insufficient.In the future,it is essential to focus on translating preclinical mechanisms into clinical trials.Furthermore,consecutive follow-up studies are needed to evaluate the long-term safety and efficacy of deep brain stimulation for Alzheimer's disease,including cognitive function,neuropsychiatric symptoms,quality of life and changes in Alzheimer's disease biomarkers.Researchers must also prioritize the initiation of multi-center clinical trials of deep brain stimulation with large sample sizes and target earlier therapeutic windows,such as the prodromal and even the preclinical stages of Alzheimer's disease.Adopting these approaches will permit the efficient exploration of more effective and safer deep brain stimulation therapies for patients with Alzheimer's disease.
基金supported by a grant from the Major Project of Educational Commission of Hubei Province of China,No.D20152101
文摘Repetitive transcranial magnetic stimulation （rTMS） is a non-invasive treatment that can enhance the recovery of neurological function after stroke. Whether it can similarly promote the recovery of cognitive function after vascular dementia remains unknown, In this study, a rat model for vascular dementia was established by the two-vessel occlusion method. Two days after injury, 30 pulses of rTMS were ad- ministered to each cerebral hemisphere at a frequency of 0.5 Hz and a magnetic field intensity of 1,33 T. The Morris water maze test was used to evaluate learning and memory function. The Karnovsky-Roots method was performed to determine the density of cholinergic neurons in the hippocampal CA1 region. Immunohistochemical staining was used to determine the number of brain-derived neurotroph- ic factor （BDNF）-immunoreactive cells in the hippocampal CA1 region, rTMS treatment for 30 days significantly improved learning and memory function, increased acetylcholinesterase and choline acetyltransferase activity, increased the density of cholinergic neurons, and increased the number of BDNF-immunoreactive cells. These results indicate that rTMS can ameliorate learning and memory deficiencies in rats with vascular dementia, The mechanism through which this occurs might be related to the promotion of BDNF expression and subsequent restoration of cholinergic system activity in hippocampal CA 1 region.
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supported by the Young Scientists Foundation of Hubei Provincial Health Department,No.QJX2012-16
文摘Puerarin, a major isoflavonoid derived from the Chinese medical herb radix puerariae （Gegen）, has been reported to inhibit neuronal apoptosis and play an anti-inflammatory role in focal cerebral ischemia model rats. Recent findings regarding stroke pathophysiology have recognized that anti-inflammation is an important target for the treatment of ischemic stroke. The cholinergic anti-inflammatory pathway is a highly robust neural-immune mechanism for inflammation control. This study was to investigate whether activating the cholinergic anti-inflammatory pathway can be involved in the mechanism of inhibiting the inflammatory response during puerarin-induced cerebral ischemia/reperfusion in rats. Results showed that puerarin pretreatment （intravenous injection） re- duced the ischemic infarct volume, improved neurological deficit after cerebral ischemia/reperfusion and decreased the levels of interleukin-1β, interleukin-6 and tumor necrosis factor-a in brain tissue. Pretreatment with puerarin （intravenous injection） attenuated the inflammatory response in rats, which was accompanied by janus-activated kinase 2 （JAK2） and signal transducers and activators of transcription 3 （STAT3） activation and nuclear factor kappa B （NF-KB） inhibition. These observa- tions were inhibited by the alpha7 nicotinic acetylcholine receptor （a7nAchR） antagonist a-bungarotoxin （a-BGT）. In addition, puerarin pretreatment increased the expression of a7nAchR mRNA in ischemic cerebral tissue. These data demonstrate that puerarin pretreatment strongly protects the brain against cerebral ischemia/reperfusion injury and inhibits the inflammatory re- sponse. Our results also indicated that the anti-inflammatory effect of puerarin may partly be medi- ated through the activation of the cholinergic anti-inflammatory pathway.
基金supported by grants from the National Natural Science Foundation of China(No. 81373743)Outstanding Young Talents Support Program of Anhui(No. 20140181)
文摘Objective： Acupuncture has a definite therapeutic effect on chronic obstructive pulmonary disease （COPD）, and the cholinergic anti-inflammatory pathway （CAP） has been shown to be involved in regula- tion of inflammation. In this study, we investigated whether electro-acupuncture （EA） affects the CAP in COPD,Methods： Sprague-Dawley rats were induced into COPD through exposure to cigarette smoke combined with lipopolysaccharide. EA treatment was applied at Zusanli （ST36） and Feishu （BL13） points for 30 min/d for 7 d. Seventy-two rats were randomly divided into six study groups, including normal, normal ＋ EA, normal ＋ α-bungarotoxin （α-BGT） （the antagonist of the nicotinic acetylcholine receptor α7 subunit （α7nAChR）） ＋ EA, COPD, COPD ＋ EA, and COPD ＋ α-BGT ＋ EA. Lung function, pathology and vagus nerve discharge were tested. The levels of acetylcholine （ACh）, acetylcholinesterase （ACHE）, interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-ct） in bronchoalveolar lavage fluid （BALF） and lung tissue were measured by enzyme-linked immunosorbent assay. The mRNA and protein expression and immunoreac- tivity of α7nAChR and its postreceptor inflammation signal pathway, including janus kinase 2 （JAK2）, sig- nal transducers and activators of transcription 3 （STAT3）, nuclear factor-KB （NF-KB）, were observed by quantitative reverse transcription-polymerase chain reaction, Western blot and immunohistochemistry. Results： Compared with normal rats, there were a significant decline in lung function and discharge of the vagus nerve （P 〈 0.01）, a marked sign of lung inflammation and an increase of ACh, ACHE, IL-6 and TNF-α level in BALF or lung tissue （P 〈 0.05, P 〈 0.01 ） and higher expression of 0t7nAChR, JAK2, STAT3 and NF-αB （P 〈 0.05, P 〈 0.01） in the COPD rats. In rats receiving EA, the lung function and vagal discharge were enhanced （P 〈 0.01 ）, lung inflammation was improved and the levels of ACh, ACHE, IL-6 and TNF-α were decreased （P 〈 0.01）. Further, the expression of α7nAChR, JAK2, STAT3 and NF-κB was downregulated （P 〈 0.05, P 〈 0.01 ）. However, the above effects of EA were blocked in rats injected with α-BCT （P 〈 0.01 ）. Conclusion： EA treatment can reduce the lung inflammatory response and improve lung function in COPD, which may be related to its involvement in the regulation of CAP.
基金supported by the National Natural Science Foundation of China,No.81371107,81470760the Natural Science Foundation of Guangdong Province in China,No.S2013010015888+1 种基金the Foundation of Open Laboratory of Sun Yat-sen University in China,No.KF201312a grant from Translational Medicine Center,Guangdong Department of Science&Technology,No.2011A080300002
文摘The tooth belongs to the trigeminal sensory pathway. Dental damage has been associated with impairments in the central nervous system that may be mediated by injury to the trigeminal nerve. In the present study, we investigated the effects of damage to the inferior alveolar nerve, an important peripheral nerve in the trigeminal sensory pathway, on learning and memory be-haviors and structural changes in related brain regions, in a mouse model of Alzheimer’s disease. Inferior alveolar nerve transection or sham surgery was performed in middle-aged （4-month-old） or elderly （7-month-old） senescence-accelerated mouse prone 8 （SAMP8） mice. When the middle-aged mice reached 8 months （middle-aged group 1） or 11 months （middle-aged group 2）, and the elderly group reached 11 months, step-down passive avoidance and Y-maze tests of learn-ing and memory were performed, and the cholinergic system was examined in the hippocampus （Nissl staining and acetylcholinesterase histochemistry） and basal forebrain （choline acetyltrans-ferase immunohistochemistry）. In the elderly group, animals that underwent nerve transection had fewer pyramidal neurons in the hippocampal CA1 and CA3 regions, fewer cholinergic ifbers in the CA1 and dentate gyrus, and fewer cholinergic neurons in the medial septal nucleus and vertical limb of the diagonal band, compared with sham-operated animals, as well as showing impairments in learning and memory. Conversely, no signiifcant differences in histology or be-havior were observed between middle-aged group 1 or group 2 transected mice and age-matched sham-operated mice. The present ifndings suggest that trigeminal nerve damage in old age, but not middle age, can induce degeneration of the septal-hippocampal cholinergic system and loss of hippocampal pyramidal neurons, and ultimately impair learning ability. Our results highlight the importance of active treatment of trigeminal nerve damage in elderly patients and those with Alzheimer’s disease, and indicate that tooth extraction should be avoided in these populations.
基金supported by Ministry of Education,Universities and Research(MIUR/FIRB)funding to PC
文摘The current idea behind brain pathology is that disease is initiated by mild disturbances of common physiological processes. Overtime, the disruption of the neuronal homeostasis will determine irreversible degeneration and neuronal apoptosis. This could be also true in the case of nerve growth factor （NGF） al- terations in sporadic Alzheimer＇s disease （AD）, an age-related pathology characterized by cholinergic loss, amyloid plaques and neurofibrillary tangles. In fact, the pathway activated by NGF, a key neurotrophin for the metabolism of basal forebrain cholinergic neurons （BFCN）, is one of the first homeostatic systems affected in prodromal AD. NGF signaling dysfunctions have been thought for decades to occur in AD late stages, as a mere consequence of amyloid-driven disruption of the retrograde axonal transport of neuro- trophins to BFCN. Nowadays, a wealth of knowledge is potentially opening a new scenario： NGF signaling impairment occurs at the onset of AD and correlates better than amyloid load with cognitive decline. The recent acceleration in the characterization of anatomical, functional and molecular profiles of early AD is aimed at maximizing the efficacy of existing treatments and setting novel therapies. Accordingly, the elucidation of the molecular events underlying APP metabolism regulation by the NGF pathway in the sep- to-hippocampal system is crucial for the identification of new target molecules to slow and eventually halt mild cognitive impairment （MCI） and its progression toward AD.
基金Supported by National Council of Technological and Scientific Development (CNPq)Ceará Foundation for the Support of Scientific and Technological Development of the Ceará State(FUNCAP),Brazil
文摘AIM： To investigate the effects of mangiferin on gas- trointestinal transit （GIT） in normal and constipated mice, together with the possible mechanism.METHODS： Intragastrically-administered charcoal mealwas used to measure GIT in overnight starved Swiss mice. In the first experiments, mangiferin （3 mg/kg, 10 mg/kg, 30 mg/kg, and 100 mg/kg, po） or tegaserod （1 mg/kg, ip） were administered 30 min before the char- coal meal to study their effects on normal transit. In the second series, mangiferin （30 mg/kg） was tested on delayed GIT induced by several different pharma- cological agonists （morphine, clonidine, capsaicin） or antagonists （ondansetron, verapamil, and atropine） whereas in the third series, mangiferin （30 mg/kg, 100 mg/kg and 300 mg/kg） or tegaserod （1 mg/kg） were tested on 6 h fecal pellets outputted by freely fed mice. The ratio of wet to dry weight was calculated and used as a marker of fecal water content. RESULTS： Mangiferin administered orally significantly （P 〈 0.05） accelerated GIT at 30 mg/kg and 100 mg/kg （89% and 93%, respectively）, similarly to 5-hydroxytrypta- mine4 （5-H%） agonist tegaserod （81%） when compared to vehicle-treated control （63%）. Co-administered man- giferin （30 mg/kg） totally reversed the inhibitory effect of opioid agonist morphine, 5-HT3-receptor antagonist ondansetron and transient receptor potential vanilloid-1 receptor agonist capsaicin on GIT, but only to a partial extent with the GIT-delay induced by ~2-adrenoceptor agonist clonidine, and calcium antagonist verapamil. However, co-administered atropine completely blocked the stimulant effect of mangiferin on GIT, suggesting the involvement of muscarinic acetylcholine receptor activation. Although mangiferin significantly enhanced the 6 h fecal output at higher doses （245.5±10.43 mg vs 161.9±10.82 mg and 227.1±20.11 mg vs 161.9±10.82 mg of vehicle-treated control, at 30 and 100 mg/ kg, P 〈 0.05, respectively）, the effect of tegaserod was more potent （297.4±7.42 mg vs 161.9±10.82 mg of vehicle-treated control, P 〈 0.05）. Unlike tegaserod, which showed an enhanced water content in fecal pel- lets （59.20%±1.09% vs 51.44%±1.19% of control, P 〈 0.05）, mangiferin evidenced no such effect, indi-cating that it has only a motor and not a secretomotor effect. CONCLUSION： Our data indicate the prokinetic action of mangiferin. It can stimulate the normal GIT and also overcome the drug-induced transit delay, via a choliner- gic physiological mechanism.
文摘The present study analyzed changes in Wnt3a expression during differentiation of adipose-derived stern cells into cholinergic neurons. Immunocytochemistry and immunofluorescence revealed significantly increased nestin, neuron-specific enolase, microtubule-associated protein 2, and choline acetyltransferase expression in adipose-derived stem cells isolated from Sprague-Dawley rats and cultured in vitro in neural-induced medium. These expressions increased with prolonged induction time. Real-time reverse transcription-PCR and western blot assay results demonstrated significantly increased choline acetyltransferase and Wnt3a protein and mRNA expressions, respectively, in adipose-derived stem cells following induction. Choline acetyltransferase expression positively correlated with Wnt3a protein and mRNA expressions. These results demonstrated that neural-induced medium induced differentiation of adipose-derived stem cells into cholinergic neuronal-like cells, with subsequent increased Wnt3a expression.
