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Neuroinflammation is suggested as one of the potential links between CS‐induced neuronal dysfunction. Cigarette smoke (CS) is one of the significant contributors of neuroinflammation, consequently leading to cognitive impairment and neurodegeneration. Microglia are the key resident macrophage cells in the brain with cell surface TLR4 receptor for responding to various stress signals. The CS constituents promote inflammation and oxidative stress in microglia leading to cytotoxicity through the TLR4‐MK2 axis. However, the role of MK2 kinase in CS‐induced microglial inflammation is not yet clearly understood. Therefore, we have used an MK2 inhibitor, PF‐3644022 to study modulation of CS‐extract induced oxidative and inflammatory signaling in a mouse microglial cell line, Furthermore, we also evaluated the enzymatic activity of acetylcholinesterase (AChE) on a direct exposure of enzyme with CS. CS exposure led to microglial cytotoxicity and enhanced the level of oxidative stress and proinflammatory cytokine release by microglial cells. The microglial cells pretreated with MK2 inhibitor, PF‐3644022 significantly reduced the levels of oxidative stress markers, proinflammatory markers, and improved the level of antioxidant proteins in these cells. In addition, direct exposure of CS showed reduction in the enzymatic activity of AChE. [ABSTRACT FROM AUTHOR]

Abelmoschus esculentus Linn. (okra, F. Malvaceae) is a fruit widely consumed all over the world. In our study, the anti-Alzheimer's potential of A. esculentus was evaluated. An in vitro DPPH free radical assay on A. esculentus seed's total extract and AChE inhibition potential screening indicated a significant anti-Alzheimer's activity of the extract, which was confirmed through an in vivo study in an aluminum-intoxicated rat model. Additionally, in vivo results demonstrated significant improvement in Alzheimer's rats, which was confirmed by improving T-maze, beam balance tests, lower serum levels of AChE, norepinephrine, glycated end products, IL-6, and MDA. The levels of dopamine, BDNF, GSH, and TAC returned to normal values during the study. Moreover, histological investigations of brain tissue revealed that the destruction in collagen fiber nearly returns back to the normal pattern. Metabolomic analysis of the ethanolic extract of A. esculentus seeds via LC–HR-ESI-MS dereplicated ten compounds. A network pharmacology study displayed the relation between identified compounds and 136 genes, among which 84 genes related to Alzheimer's disorders, and focused on AChE, APP, BACE1, MAPT and TNF genes with interactions to all Alzheimer's disorders. Consequently, the results revealed in our study grant potential dietary elements for the management of Alzheimer's disorders. [ABSTRACT FROM AUTHOR]

Introduction: Given the severity of the condition and the increasing number of patients, developing effective therapies for Alzheimer's disease has become a significant necessity. Aggregation of Amyloid-Beta (Aβ) plaques and Tau Protein Tangles in the brain's nerve tissue are two of the most histopathological/pathophysiological symptoms. Another important element involved in the etiology of Alzheimer's disease is the reduction in acetylcholine (ACh) levels in the brain. Currently available medications for Alzheimer's disease treatment, such as cholinesterase inhibitors and an antagonist of the N-methyl-d-aspartate receptor, can temporarily reduce dementia symptoms but not stop or reverse disease development. In addition, several medicinal plants have been shown to diminish the degenerative characteristics associated with Alzheimer's disease, either in its crude form or as isolated chemicals. Aim: This review summarises the results from previous studies that reflect an array of novel therapies underway in various phases of clinical trials. Many are discontinued due to non-adherence to the designed endpoints or the surfacing of unavoidable side effects. The present piece of article focuses on the approved drugs for the treatment of Alzheimer's disease and their related mode of action as well as the promising therapies for the treatment of the said disease. Special attention has been placed on the researched herbal drugs, with the pipeline of novel therapies underway in various phases of clinical trials. Result: The current article includes a list of approved pharmaceuticals for treating Alzheimer's disease, prospective therapies for the illness's treatment, and a pipeline of novel therapies in various stages of clinical trials. Conclusion: The results suggest that the drugs under clinical trials may open new pathways for the effective treatment of patients with Alzheimer's disease while improving their quality of life.

Extra Pyramidal Symptoms (EPS) are a group of symptoms that include dystonia, bradykinesia, tremor, akathisia, and tardive dyskinesia. They are caused by the blockage of D2 receptors in the nigro-striatal pathway and the imbalanced acetyl choline activity that results in the basal ganglia. It most likely happens when first-generation antipsychotics taken in large doses and some second-generation antipsychotics. A few tricyclic antidepressants, including amitriptyline and clomipramine, monoamine oxidase (MAO) inhibitors, such as phenelzine, and SSRIs, such as fluoxetine, may also cause EPS. Antiemetics (domperidone), antiepileptic medications like phenytoin and carbamazepine, and anti-migraine medications like sumatriptan are a few additional causes of EPS. Schizophrenia patients who have never been prescribed medication may also exhibit similar movement problems. The tricyclic antidepressant (TCA) clomipramine is a tertiary amine that has potent D2 blocking and serotonin and norepinephrine reuptake inhibitor characteristics. Constipation, dry mouth, nausea, dizziness, drowsiness, tachycardia, sweating, arrhythmia, and seizures at high doses are common side effects associated with clomipramine. In this case series, three patients from different age groups are presented, the first one being a 38-year-old female with a diagnosis of paranoid schizophrenia, the second one was a 26-year-old male with the obsessive compulsive disorder (OCD)- washer type, and the third one was a 62-year-old female with dementia all of whom developed signs of EPS like dystonia, bradykinesia and tremors following the introduction of clomipramine. In all the patients, the drug was stopped and the patients were cured. This case series stresses that a clinician should be cautious about the possibility of extrapyramidal side effects while using the TCA Clomipramine which is commonly known for its anticholinergic side effects.

Given the severity of the condition and the increasing number of patients, developing effective therapies for Alzheimer's disease has become a significant necessity. Aggregation of Amyloid-Beta (Aβ) plaques and Tau Protein Tangles in the brain's nerve tissue are two of the most histopathological/pathophysiological symptoms. Another important element involved in the etiology of Alzheimer's disease is the reduction in acetylcholine (ACh) levels in the brain. Currently available medications for Alzheimer's disease treatment, such as cholinesterase inhibitors and an antagonist of the N -methyl- d -aspartate receptor, can temporarily reduce dementia symptoms but not stop or reverse disease development. In addition, several medicinal plants have been shown to diminish the degenerative characteristics associated with Alzheimer's disease, either in its crude form or as isolated chemicals. This review summarises the results from previous studies that reflect an array of novel therapies underway in various phases of clinical trials. Many are discontinued due to non-adherence to the designed endpoints or the surfacing of unavoidable side effects. The present piece of article focuses on the approved drugs for the treatment of Alzheimer's disease and their related mode of action as well as the promising therapies for the treatment of the said disease. Special attention has been placed on the researched herbal drugs, with the pipeline of novel therapies underway in various phases of clinical trials. The current article includes a list of approved pharmaceuticals for treating Alzheimer's disease, prospective therapies for the illness's treatment, and a pipeline of novel therapies in various stages of clinical trials. The results suggest that the drugs under clinical trials may open new pathways for the effective treatment of patients with Alzheimer's disease while improving their quality of life. [ABSTRACT FROM AUTHOR]

Abelmoschus esculentus Linn. (okra, F. Malvaceae) is a fruit widely consumed all over the world. In our study, the anti-Alzheimer’s potential of A. esculentus was evaluated. An in vitro DPPH free radical assay on A. esculentus seed’s total extract and AChE inhibition potential screening indicated a significant anti-Alzheimer’s activity of the extract, which was confirmed through an in vivo study in an aluminum-intoxicated rat model. Additionally, in vivo results demonstrated significant improvement in Alzheimer’s rats, which was confirmed by improving T-maze, beam balance tests, lower serum levels of AChE, norepinephrine, glycated end products, IL-6, and MDA. The levels of dopamine, BDNF, GSH, and TAC returned to normal values during the study. Moreover, histological investigations of brain tissue revealed that the destruction in collagen fiber nearly returns back to the normal pattern. Metabolomic analysis of the ethanolic extract of A. esculentus seeds via LC–HR-ESI-MS dereplicated ten compounds. A network pharmacology study displayed the relation between identified compounds and 136 genes, among which 84 genes related to Alzheimer’s disorders, and focused on AChE, APP, BACE1, MAPT and TNF genes with interactions to all Alzheimer’s disorders. Consequently, the results revealed in our study grant potential dietary elements for the management of Alzheimer’s disorders.

Background: Despite exhaustive research, melanocyte disappearance and the evolution of vitiligo remain enigmatic, and although multi‐factorial, oxidative stress appears as a major player. The role of cutaneous cholinergic system in vitiligo pathogenesis has also been reported in some studies. Objective: To evaluate and correlate the influence of phototherapy on cutaneous cholinergic system and oxidative stress in vitiligo. Methods: Acetyl choline (ACh), its receptors; nicotinic (nAChR) and muscarinic (mAChR); acetylcholine esterase (AChE) and H2O2 levels were estimated in de‐pigmented and re‐pigmented lesions of 30 vitiligo patients before and after NB‐UVB phototherapy and in 30 controls. ACh and H2O2 levels were measured by colorimetry. AChE and acetylcholine receptors expression were measured by quantitative real‐time PCR. Results: Mean ACh and H2O2 levels were significantly higher in vitiligo lesions before NB‐UVB (P <.001) whereas AChE enzyme level was significantly lower (P <.001) compared to both re‐pigmented and control skin. Additionally, mean mAChR was significantly higher and mean nAChR was significantly lower in vitiligo lesions before NB‐UVB versus controls and re‐pigmented skin (P <.001). Also, H2O2 and AChE showed negative correlation whereas ACh and mAChR showed significant positive correlation. Although all the studied parameters showed significant changes after treatment and subsequent re‐pigmentation, a significant difference continued to exist between all vitiligo skin and controls. Conclusion: Cholinergic system is strongly involved in vitiligo pathogenesis through H2O2 inhibition of AChE which could be reversed by NB‐UVB. Moreover, the strong activation of mAChRs may reflect genetic and/or acquired errors, direct up‐regulation by ACh and H2O2 or both. [ABSTRACT FROM AUTHOR]

Cognitive function relies on the dynamic cooperation of specialized regions of the brain; however, the elements of the system responsible for coordinating this interaction remain poorly understood. In this Opinion article I argue that this capacity is mediated in part by competitive and cooperative dynamic interactions between two prominent metabotropic neuromodulatory systems – the cholinergic basal forebrain and the noradrenergic locus coeruleus (LC). I assert that activity in these projection nuclei regulates the amount of segregation and integration within the whole brain network by modulating the activity of a diverse set of specialized regions of the brain on a timescale relevant for cognition and attention. The dynamic balance between segregation and integration in the brain is crucial for cognitive function. The ascending arousal system is ideally placed to modulate dynamic network topology over time. The cholinergic basal forebrain facilitates segregation through the targeted alteration of multiplicative gain. The noradrenergic LC facilitates integration through the diffuse alteration of response gain. Coordinated activity between the cholinergic and noradrenergic system sets the balance between segregation and integration in the brain. [ABSTRACT FROM AUTHOR]

The effects of Piracetam against Acetyl Choline (Ach) in adult mice. The Medium Lethal Dose LD50 of Piracetam was 455.5mg/kg B.W. orally and Ach 7.25 mg/kg B.W i.p, then an animal’s are divided to 4 groups First group serves as control group given normal saline, a second 400 mg /kg B.W. o.p. of Piracetam and third group 5 mg/kg B.W. i.p. Ach. Forth group 400 mg /kg B.W. o.p. of Piracetam and 5 mg/kg B.W. i.p. Ach. The behavioral changes, the Run time, swimming, Time on glass, and biochemical parameters in Ach and Piracetam pretreatment significantly (P

The release of adrenocorticotropin (ACTH) from the corticotrophs is controlled principally by vasopressin and corticotropin-releasing hormone (CRH). Oxytocin may augment the release of ACTH under certain conditions, whereas atrial natriuretic peptide acts as a corticotropin release-inhibiting factor to inhibit ACTH release by direct action on the pituitary. Glucocorticoids act on their receptors within the hypothalamus and anterior pituitary gland to suppress the release of vasopressin and CRH and the release of ACTH in response to these neuropeptides. CRH neurons in the paraventricular nucleus also project to the cerebral cortex and subcortical regions and to the locus ceruleus (LC) in the brain stem. Cortical influences via the limbic system and possibly the LC augment CRH release during emotional stress, whereas peripheral input by pain and other sensory impulses to the LC causes stimulation of the noradrenergic neurons located there that project their axons to the CRH neurons stimulating them by alpha-adrenergic receptors. A muscarinic cholinergic receptor is interposed between the alpha-receptors and nitric oxidergic interneurons which release nitric oxide that activates CRH release by activation of cyclic guanosine monophosphate, cyclooxygenase, lipoxygenase and epoxygenase. Vasopressin release during stress may be similarly mediated. Vasopressin augments the release of CRH from the hypothalamus and also augments the action of CRH on the pituitary. CRH exerts a positive ultrashort loop feedback to stimulate its own release during stress, possibly by stimulating the LC noradrenergic neurons whose axons project to the paraventricular nucleus to augment the release of CRH.

Objective: Analysis of red blood cell acetyl cholinesterase (AChE) in a familial Alzheimer's diseases (AD) Parkinson's disease dementia (PDD) and their first generation. Setting: General hospital, Mahad district, Raigad. Patients and Methods: Clinically diagnosed patients of AD and PDD and their asymptomatic relatives. Their blood was collected in EDTA tube and transferred to laboratory at Mumbai. Result: Median red blood cell (RBC) cholinesterase levels amongst PDD, their first generation asymptomatic relatives, familial AD, asymptomatic relatives of AD, healthy controls, farmers exposed to pesticides (positive control) and other neurological condition without dementia (hypertension with TIA 1, sub-dural hematoma 2, hypothyroid 1, non-familial unilateral parkinsonism without dementia 3, writers cramps 2, hyponitremia 1 and cerebral palsy with non-fluent aphasia 1). Median values of RBC AChE were 19086.78 U/L, 15666.05 U/L, 9013.11 U/L, 7806.19 U/L, 14334.57 U/L, 9785.05 U/L and 13162.60 U/L, respectively. As compared to controls, RBC AChE levels were statistically significant among PDD (P = 0.004) and significantly lowered among familial AD patients (P = 0.010), relatives of patients (P = 0.010). Interpretations: Below the normal RBC AChE level is a potential biomarker in asymptomatic relatives of familial AD patients. RBC AChE is raised than normal level in patients suffering from PDD, where AChE inhibitors are helpful. However, RBC AChE level below the normal where AChE inhibitor may not be effective. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate pharmacological mimetic action of herbal extract Desmodium gangeticum (DG) 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 DG 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. [Copyright &y& Elsevier]

In this study, we have assessed the impact of vitamin E and exercise on acquisition and retention of spatial memory for a given task in aging rats, using a T-maze. Acetylcholine esterase (AChE) and cholineacetyl transferase (ChAT) activities and acetylcholine (ACh) were measured in the cerebral cortex (CC) of male Wistar rats of 4- (adult), 12- (middle-aged) and 18-months (old) of age. Animals were categorized into sedentary [(SEC (N)], sedentary supplemented [SEC (+E)], swim trained [SWT (N)] and swim trained supplemented [SWT (+E)]. In the old, ChAT activity increased in the SEC (+E). AChE activity was highest in the adults, irrespective of training or supplementation. By contrast, ACh concentration remained unaltered with age, exercise and supplementation. Middle-aged and old rats were benefited in terms of a better acquisition and retention in the case of those that were trained and supplemented with Vitamin E. Adults showed better retention in all the groups after 7 and 15 days, while in the middle-aged, training was beneficial after 15 days. We observed decreased AChE activity when old rats were trained with the supplement. Our results also suggest that this regimen may be analogous to the AChE inhibitors that are widely advocated to derive positive benefits in up-regulating the possible reduction in ACh and in turn age-associated memory deficits. [ABSTRACT FROM AUTHOR]

MKC-231, a putative cholinergic activity, is reported to improve learning and memory impaired in AF64A-treated animals. MKC-231 enhances high-affinity choline uptake (HACU) known as the rate-limiting step of acetylcholine (ACh) synthesis. We investigated the mode of action (MOA) of HACU enhancement by MKC-231. Intracerebroventricular (i.c.v.) injections of AF64A (3 nmol/brain) resulted in significant HACU reduction in hippocampal synaptosomes. Treatment with MKC-231 increased V max of HACU and B max of [3H]-HC-3 binding 1.6 and 1.7-fold, respectively. In studies of [3H]-MKC-231 binding and Biacore analysis, MKC-231 showed noticeable affinity for cloned high-affinity choline transporters (CHT1). The present study suggests that MKC-231 directly affects trafficking of CHT1 and increases the numbers of transporter, working for HACU, at the synaptic membrane. [ABSTRACT FROM AUTHOR]

The way a rabbit moves its eyes in response to a stimulus consisting of two moving random dot patterns largely depends on the relative luminances of the two patterns. Concurrent rotation of the animal enhances the response to the visual pattern that represents the same head movement as the vestibular stimulation. In this paper we investigate the role that the flocculus plays in this behaviour. We injected the non-selective acetylcholine agonist carbachol into the flocculus. These injections are known to increase the gain of the optokinetic reflex, but have a smaller effect on the vestibulo-ocular reflex. We investigated the effect on the oculomotor response to (vestibulo-) transparent stimuli, where one pattern oscillated sinusoidally and the other pattern was stable with respect to the head. We found that the injections caused a higher response gain at a lower luminance of the oscillating pattern. Furthermore the influence of concurrent vestibular stimulation decreased. These findings agree with a role of the flocculus that is downstream of the visual normalisation, but upstream of the visual-vestibular interaction. [ABSTRACT FROM AUTHOR]

The release of pancreatic polypeptide (PP) by gut hormones, acetyl choline and adrenaline was investigated in an isolated perfused pancreas preparation. PP was potently released by 1 nmol/l caerulein (186±12%, p<0.001) and gastric inhibitory peptide (GIP) (211±31%, p<0.005) as well as by 1 [νmol/l acetyl choline (1097±59%, p<0.001). A significant two-fold release of PP was also evoked by 1 nmol/l vasoactive intestinal peptide (VIP) (129±38%, p<0.02 and gastrin (108±25% p<0.01). Insulin release, induced by high glucose concentration was enhanced by both GIP (210 ±38%, p<(0.01) and VIP (48±5%, p<0.001). In addition GIP enhanced the release of glucagon by 179±18% (p<0.001) at 1.4 mmol/l glucose and by 127±24% (p<0.005) at 8.3 mmol/l glucose. Thus no simple inter-relationship appears to exist between the control of the three circulating islet hormones. [ABSTRACT FROM AUTHOR]

Abstract: This patient presented with progressive eating difficulties, having been originally investigated for mechanical gastroenterological problems. Fruitless examinations led to referral to a tertiary oral medicine unit and a detailed review of his history, where the significance of progressive fatiguability during and after mastication became apparent in his dysphagia. The insidious onset contrasted with his more rapid decline in function between the initial examination and specialist electromyographic investigations, neurological admission and management. The dangers of fatigue and pharyngeal incompetence are of particular relevance to oral and maxillofacial clinicians. [Copyright &y& Elsevier]

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