Muscarinic control of cardiovascular function in humans: a review of current clinical evidence.

PURPOSE: To review the available evidence on the impact of muscarinic receptor modulation on cardiovascular control in humans. METHODS: In this narrative Review we summarize data on cardiovascular endpoints from clinical trials of novel subtype-selective or quasi-selective muscarinic modulators, mostly PAMs, performed in the last decade. We also review the cardiovascular phenotype in recently described human genetic and autoimmune disorders affecting muscarinic receptors. RESULTS: Recent advancements in the development of compounds that selectively target muscarinic acetylcholine receptors are expanding our knowledge about the physiological function of each muscarinic receptor subtype (M1, M2, M3, M4, M5). Among these novel compounds, positive allosteric modulators (PAMs) have emerged as the preferred therapeutic to regulate muscarinic receptor subtype function. Many muscarinic allosteric and orthosteric modulators (including but not limited to xanomeline-trospium and emraclidine) are now in clinical development and approaching regulatory approval for multiple indications, including the treatment of cognitive and psychiatric symptoms in patients with schizophrenia as well as Alzheimer's disease and other dementias. The results of these clinical trials provide an opportunity to understand the influence of muscarinic modulation on cardiovascular autonomic control in humans. While the results and the impact of each of these therapies on heart rate and blood pressure control have been variable, in part because the clinical trials were not specifically designed to measure cardiovascular endpoints, the emerging data is valuable to elucidate the relative cardiovascular contributions of each muscarinic receptor subtype. CONCLUSION: Understanding the muscarinic control of cardiovascular function is of paramount importance and may contribute to the development of novel therapeutic strategies for treating cardiovascular disease.

Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer.

Docetaxel is the most commonly used chemotherapy for advanced prostate cancer (PC), including castration-resistant disease (CRPC), but the eventual development of docetaxel resistance constitutes a major clinical challenge. Here, we demonstrate activation of the cholinergic muscarinic M1 receptor (CHRM1) in CRPC cells upon acquiring resistance to docetaxel, which is manifested in tumor tissues from PC patients post- vs. pre-docetaxel. Genetic and pharmacological inactivation of CHRM1 restores the efficacy of docetaxel in resistant cells. Mechanistically, CHRM1, via its first and third extracellular loops, interacts with the SEMA domain of cMET and forms a heteroreceptor complex with cMET, stimulating a downstream mitogen-activated protein polykinase program to confer docetaxel resistance. Dicyclomine, a clinically available CHRM1-selective antagonist, reverts resistance and restricts the growth of multiple docetaxel-resistant CRPC cell lines and patient-derived xenografts. Our study reveals a CHRM1-dictated mechanism for docetaxel resistance and identifies a CHRM1-targeted combinatorial strategy for overcoming docetaxel resistance in PC.

Management of Cholinergic Rebound After Abrupt Withdrawal of Clozapine: A Case Report and Systematic Literature Review.

BACKGROUND: Cholinergic discontinuation symptoms, also known as "cholinergic rebound," from abrupt clozapine discontinuation are characterized by a range of somatic and psychiatric symptoms. OBJECTIVE: The objective of this study was to describe the clinical features and management options for clozapine withdrawal-associated cholinergic rebound syndrome (henceforth referred to as CWCRS) and present an illustrative case report. METHODS: Based on a literature search of the databases PubMed, OVID Medline, and Embase as well as reviewing reference lists of relevant past reviews, we carried out a systematic review of case reports on the management of CWCRS from 1946 to 2023. RESULTS: We identified 10 previously published articles on the clinical management of CWCRS, with a total of 18 patients (6 female, 12 male) with an average age of 43 years (standard deviation 14). Half of the patients had a history of tardive dyskinesia. The mean dose of clozapine before discontinuation was 351 mg/day, with duration of clozapine treatment ranging from 3 weeks to 9 years. Clozapine was the most effective treatment, followed by benztropine. CONCLUSIONS: Given the small number of cases and the nonexperimental nature of the available studies, this review could not provide reliable data to guide management of CWCRS. The findings, however, suggest that clozapine may be more effective than other commonly used treatment options. With the high rates of discontinuation among patients on clozapine, there is a pressing need for further research into the epidemiology, natural history, and management of clozapine withdrawal syndromes.

A Recent Update on Pathophysiology and Therapeutic Interventions of Alzheimer's Disease.

AIM: Alzheimer's disease (AD) has been identified as a progressive brain disorder associated with memory dysfunction and the accumulation of ß-amyloid plaques and neurofibrillary tangles of τ protein. Mitochondria is crucial in maintaining cell survival, cell death, calcium regulation, and ATP synthesis. Mitochondrial dysfunction and linked calcium overload have been involved in the pathogenesis of AD. CRM2 (Collapsin response mediator protein-2) is involved in endosomal lysosomal trafficking as well as autophagy, and their reduced level is also a primary culprit in the progression of AD. In addition, Cholinergic neurotransmission and neuroinflammation are two other mechanisms implicated in AD onset and might be protective targets to attenuate disease progression. The microbiota-gut-brain axis (MGBA) is another crucial target for AD treatment. Crosstalk between gut microbiota and brain mutually benefitted each other, dysbiosis in gut microbiota affects the brain functions and leads to AD progression with increased AD-causing biomarkers. Despite the complexity of AD, treatment is only limited to symptomatic management. Therefore, there is an urgent demand for novel therapeutics that target associated pathways responsible for AD pathology. This review explores the role of different mechanisms involved in AD and possible therapeutic targets to protect against disease progression. BACKGROUND: Amidst various age-related diseases, AD is the most deleterious neurodegenerative disorder that affects more than 24 million people globally. Every year, approximately 7.7 million new cases of dementia have been reported. However, to date, no novel disease-modifying therapies are available to treat AD. OBJECTIVE: The aim of writing this review is to highlight the role of key biomarker proteins and possible therapeutic interventions that could play a crucial role in mitigating the ongoing prognosis of Alzheimer's disease. MATERIALS AND METHODS: The available information about the disease was collected through multiple search engines, including PubMed, Science Direct, Clinical Trials, and Google Scholar. RESULTS: Accumulated pieces of evidence reveal that extracellular aggregation of ß-amyloid plaques and intracellular tangles of τ protein are peculiar features of perpetuated Alzheimer's disease (AD). Further, the significant role of mitochondria, calcium, and cholinergic pathways in the pathogenesis of AD makes the respiratory cell organelle a crucial therapeutic target in this neurodegenerative disease. All currently available drugs either delay the clinical damage to cells or temporarily attenuate some symptoms of Alzheimer's disease. CONCLUSION: The pathological features of AD are extracellular deposition of ß-amyloid, acetylcholinesterase deregulation, and intracellular tangles of τ protein. The multifactorial heterogeneity of disease demands more research work in this field to find new therapeutic biological targets.

Suspected intermediate syndrome in a dog after organophosphate poisoning.

OBJECTIVE: To discuss the clinical presentation and successful treatment of a suspected case of intermediate syndrome due to organophosphate (OP) poisoning in a dog. CASE SUMMARY: Two dogs presented with acute cholinergic signs after ingesting an OP insecticide containing 50% acephate. Clinical signs consistent with acute cholinergic crisis resolved in both dogs within 24 hours postingestion. One dog developed an onset of neurological signs consistent with intermediate syndrome approximately 24 hours postingestion. This patient's clinical signs resolved with the use of pralidoxime chloride. NEW OR UNIQUE INFORMATION PROVIDED: OP poisoning most commonly presents as an acute cholinergic crisis, with rare instances of animals developing intermediate syndrome. Few reports of successful treatment and recovery from intermediate syndrome exist in the veterinary literature, particularly with instances in which 2 dogs within the same exposure setting were treated for acute cholinergic signs and only 1 progressed to an intermediate syndrome. This report also highlights the importance of early intervention with pralidoxime chloride prior to the onset of aging.

Gelatin/polyethylene glycol-loaded magnesium hydroxide nanocomposite to attenuate acetylcholinesterase, neurotoxicity, and activation of GPR55 protein in rat models of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease marked by mitochondrial dysfunction, amyloid-ß (Aß) aggregation, and neuronal cell loss. G-protein-coupled receptor 55 (GPR55) has been used as a promising target for insulin receptors in diabetes therapy, but GPR55's role in AD is still unidentified. Gelatin (GE) and polyethylene glycol (PEG) polymeric hydrogels are commonly used in the drug delivery system. Therefore, the aim of the present study was the preparation of magnesium hydroxide nanocomposite using Clitoria ternatea (CT) flower extract, GE, and PEG (GE/PEG/Mg(OH)2NCs) by the green precipitation method. The synthesized GE/PEG/Mg(OH)2NCs were used to determine the effect of GPR55 activation of intracerebroventricular administration on streptozotocin (ICV-STC)-induced cholinergic dysfunction, oxidative stress, neuroinflammation, and cognitive deficits. The GE/PEG/Mg(OH)2NCs were administered following bilateral ICV-STC administration (3 mg/kg) in experimental rats. Neurobehavioral assessments were performed using a Morris water maze (MWM) and a passive avoidance test (PA). Cholinergic and antioxidant activity, oxidative stress, and mitochondrial complex activity were estimated in the cortex and hippocampus through biochemical analysis. Inflammatory markers (TNF-α, IL-6, and IL-1ß) were determined using the ELISA method. Our study results demonstrated that the GE/PEG/Mg(OH)2NCs treatment significantly improved spatial and non-spatial memory functions in behavioral studies. Moreover, the treatment with GE/PEG/Mg(OH)2NCs group significantly attenuated cholinergic dysfunction, oxidative stress, and inflammatory markers, and also highly improved anti-oxidant activity (GSH, SOD, CAT, and GPx) in the cortex and hippocampus regions. The western blot results suggest the activation of the GPR55 protein expression through GE/PEG/Mg(OH)2NCs. The histopathological studies showed clear cytoplasm and healthy neurons, effectively promoting neuronal activity. Furthermore, the molecular docking results demonstrated the binding affinity and potential interactions of the compounds with the AChE enzyme. In conclusion, the GE/PEG/Mg(OH)2NCs treated groups showed reduced neurotoxicity and have the potential as a therapeutic agent to effectively target AD.

Non-Psychosis Symptoms of Clozapine Withdrawal: a Systematic Review.

OBJECTIVE: Clozapine is a potent antipsychotic medication with a complex receptor profile. It is reserved for treatment-resistant schizophrenia. We systematically reviewed studies of non-psychosis symptoms of clozapine withdrawal. METHODS: CINAHL, Medline, PsycINFO, PubMed, and the Cochrane Database of Systematic Reviews were searched using the keywords 'clozapine,' and 'withdrawal,' or 'supersensitivity,' 'cessation,' 'rebound,' or 'discontinuation'. Studies related to non-psychosis symptoms after clozapine withdrawal were included. RESULTS: Five original studies and 63 case reports / series were included in analysis. In 195 patients included in the five original studies, approximately 20% experienced non-psychosis symptoms following discontinuation of clozapine. In 89 patients in four of the studies, 27 experienced cholinergic rebound, 13 exhibited extrapyramidal symptoms (including tardive dyskinesia), and three had catatonia. In 63 case reports / series included, 72 patients with non-psychosis symptoms were reported, which were catatonia (n=30), dystonia or dyskinesia (n=17), cholinergic rebound (n=11), serotonin syndrome (n=4), mania (n=3), insomnia (n=3), neuroleptic malignant syndrome (NMS) [n=3, one of them had both catatonia and NMS], and de novo obsessive compulsive symptoms (n=2). Restarting clozapine appeared to be the most effective treatment. CONCLUSIONS: Non-psychosis symptoms following clozapine withdrawal have important clinical implications. Clinicians should be aware of the possible presentations of symptoms to ensure early recognition and management. Further research is warranted to better characterise the prevalence, risk factors, prognosis, and optimal drug dosing for each withdrawal symptom.

Turning the Spotlight to Cholinergic Pharmacotherapy of the Human Language System.

Even though language is essential in human communication, research on pharmacological therapies for language deficits in highly prevalent neurodegenerative and vascular brain diseases has received little attention. Emerging scientific evidence suggests that disruption of the cholinergic system may play an essential role in language deficits associated with Alzheimer's disease and vascular cognitive impairment, including post-stroke aphasia. Therefore, current models of cognitive processing are beginning to appraise the implications of the brain modulator acetylcholine in human language functions. Future work should be directed further to analyze the interplay between the cholinergic system and language, focusing on identifying brain regions receiving cholinergic innervation susceptible to modulation with pharmacotherapy to improve affected language domains. The evaluation of language deficits in pharmacological cholinergic trials for Alzheimer's disease and vascular cognitive impairment has thus far been limited to coarse-grained methods. More precise, fine-grained language testing is needed to refine patient selection for pharmacotherapy to detect subtle deficits in the initial phases of cognitive decline. Additionally, noninvasive biomarkers can help identify cholinergic depletion. However, despite the investigation of cholinergic treatment for language deficits in Alzheimer's disease and vascular cognitive impairment, data on its effectiveness are insufficient and controversial. In the case of post-stroke aphasia, cholinergic agents are showing promise, particularly when combined with speech-language therapy to promote trained-dependent neural plasticity. Future research should explore the potential benefits of cholinergic pharmacotherapy in language deficits and investigate optimal strategies for combining these agents with other therapeutic approaches.

Cognitive Enhancer Donepezil Attenuates Heroin-Seeking Behavior Induced by Cues in Rats.

PURPOSE: Opioid use disorder is a significant global problem. Chronic heroin use is associated with impairment of cognitive function and conscious control ability. The cholinergic system can be disrupted following heroin administration, indicating that activation of the cholinergic system may prevent chronic heroin misuse. Donepezil as an inhibitor of cholinesterase has been reported to clinically improve cognition and attention. In this study, the inhibition of heroin self-administration and heroin-seeking behaviours by donepezil were evaluated in rats. METHODS: Rats were trained to self-administer heroin every four hours for 14 consecutive days under a fixed ratio 1 (FR1) reinforcement schedule, then underwent withdrawal for two weeks. A progressive ratio schedule was then used to evaluate the relative motivational value of heroin reinforcement. After withdrawal, a conditioned cue was introduced for the reinstatement of heroin-seeking behaviour. Donepezil (0.3-3 mg/kg, i.p.) was used during both the FR1 heroin self-administration and progressive ratio schedules. Immunohistochemistry was used to investigate the mechanism of action of donepezil in the rat brain. RESULTS: Pre-treatment with high dose donepezil (3 mg/kg) but not low doses (0.3-1 mg/kg) significantly inhibited heroin self-administration under the FR1 schedule. Donepezil decreased motivation values under the progressive ratio schedule in a dose-dependent manner. All doses of donepezil (1-3 mg/kg) decreased the reinstatement of heroin seeking induced by cues. Correlation analysis indicated that the inhibition of donepezil on heroin-seeking behaviour was positively correlated with an increased expression of dopamine receptor 1 (D1R) and dopamine receptor 2 (D2R) in the nucleus accumbens (NAc) and increased expression of choline acetyltransferase (ChAT) in the ventral tegmental area (VTA). CONCLUSIONS: The present study demonstrated that donepezil could inhibit heroin intake and heroin-seeking behaviour. Further, donepezil could regulate dopamine receptors in the NAc via an increase of acetylcholine. These results suggested that donepezil could be developed as a potential approach for the treatment of heroin misuse.

Neuroprotective effects of photobiomodulation by hormesis on scopolamine induced neurodegenerative diseases of memory disorders in rats a paradigm shift.

The loss and progressive dysfunction of neurons are hallmarks of neurodegenerative diseases. The aim of the current study is to explore the effects of photobiomodulation at 460-660 nm (100-1000 lux units) on the progression of scopolamine-induced cognitive dysfunctions in Wistar male rats. Photobiomodulation (PBM) is defined as "the use of monochromatic or quasi-monochromatic light from a low-power laser or light-emitting diode (LED) source to modify or modulate biological functions." Neuroprotective activity was assessed by in vivo models such as the Morris water maze, the elevated plus maze (EPM), and the T-maze. After using scopolamine (1 mg/kg/day) as a dementia induction model for 21 days, the induction was primarily due to impairments in cholinergic transmission, oxidative stress, and inflammation. The in vitro determinations, including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), reduced glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-α), Interleukin 1 beta (IL-1ß), and alkaline phosphatase (ALP), were assessed biochemicals and biomarkers. The structural and morphological integrity of the cortex and hippocampus was investigated through histopathology. In vivo studies of exteroceptive behavior models such as the Morris water maze, the EPM, and the T-maze revealed that administration of scopolamine resulted in enhanced escape latency time (ELT), transfer latency (TL), and decreased percentage alternation, respectively. The levels of AChE, BChE, reduced, GSH, SOD, TNF-α, IL-1ß and ALP were increased, while MDA level was decreased. In contrast to normal and control groups with treatment groups, histopathology of the cortex and hippocampus examination revealed the maintenance of structural integrity and densities of CA1 and CA3 neuronal cells. However, network pharmacology predicted Ca+2 modulation of various pathways, among the treatments with red LED light showed highly significant amelioration compared with normal and control groups. Photobiomodulation by hormesis, chromophores in cells, and tissues excitation can influence neuroprotective effect mainly by scavenging of ROS, variation in the level of GSH MDA and SOD mitochondrial electron transfer, the improved abscopal effects on improved in gut microbiome by resembles the of fecal ALP level correlation of intestinal microbiome, cholinergic neurotransmissions, anti-inflammatory, and antioxidant activities.

Caffeic acid attenuates neuroinflammation and cognitive impairment in streptozotocin-induced diabetic rats: Pivotal role of the cholinergic and purinergic signaling pathways.

The present study evaluated the effect of caffeic acid (CA) on behavioral learning and memory tasks in the diabetic state. We also evaluated the effect of this phenolic acid on the enzymatic activities of acetylcholinesterase, ecto-nucleoside triphosphate diphosphohydrolase, ecto-5-nucleotidase and adenosine deaminase as well as on the density of M1R, α7nAChR, P2×7R, A1R, A2AR, and inflammatory parameters in the cortex and hippocampus of diabetic rats. Diabetes was induced by a single intraperitoneal dose of streptozotocin (55 mg/kg). The animals were divided into six groups: control/vehicle; control/CA 10 and 50 mg/kg; diabetic/vehicle; diabetic/CA 10 and 50 mg/kg, treated by gavage. The results showed that CA improved learning and memory deficits in diabetic rats. Also, CA reversed the increase in acetylcholinesterase and adenosine deaminase activities and reduced ATP and ADP hydrolysis. Moreover, CA increased the density of M1R, α7nAChR, and A1R receptors and reversed the increase in P2×7R and A2AR density in both evaluated structures. In addition, CA treatment attenuated the increase in NLRP3, caspase 1, and interleukin 1ß density in the diabetic state; moreover, it increased the density of interleukin-10 in the diabetic/CA 10 mg/kg group. The results indicated that CA treatment positively modified the activities of cholinergic and purinergic enzymes and the density of receptors, and improved the inflammatory parameters of diabetic animals. Thus, the outcomes suggest that this phenolic acid could improve the cognitive deficit linked to cholinergic and purinergic signaling in the diabetic state.

M1/M4-Preferring Muscarinic Cholinergic Receptor Agonist Xanomeline Reverses Wake and Arousal Deficits in Nonpathologically Aged Mice.

Degeneration of the cholinergic basal forebrain is implicated in the development of cognitive deficits and sleep/wake architecture disturbances in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Indirect-acting muscarinic cholinergic receptor agonists, such as acetylcholinesterase inhibitors (AChEIs), remain the only FDA-approved treatments for the cognitive impairments observed in AD that target the cholinergic system. Novel direct-acting muscarinic cholinergic receptor agonists also improve cognitive performance in young and aged preclinical species and are currently under clinical development for AD. However, little is known about the effects of direct-acting muscarinic cholinergic receptor agonists on disruptions of sleep/wake architecture and arousal observed in nonpathologically aged rodents, nonhuman primates, and clinical populations. The purpose of the present study was to provide the first assessment of the effects of the direct-acting M1/M4-preferring muscarinic cholinergic receptor agonist xanomeline on sleep/wake architecture and arousal in young and nonpathologically aged mice, in comparison with the AChEI donepezil, when dosed in either the active or inactive phase of the circadian cycle. Xanomeline produced a robust reversal of both wake fragmentation and disruptions in arousal when dosed in the active phase of nonpathologically aged mice. In contrast, donepezil had no effect on either age-related wake fragmentation or arousal deficits when dosed during the active phase. When dosed in the inactive phase, both xanomeline and donepezil produced increases in wake and arousal and decreases in nonrapid eye movement sleep quality and quantity in nonpathologically aged mice. Collectively, these novel findings suggest that direct-acting muscarinic cholinergic agonists such as xanomeline may provide enhanced wakefulness and arousal in nonpathological aging, MCI, and AD patient populations.

Current Status of Alzheimer's Disease and Pathological Mechanisms Investigating the Therapeutic Molecular Targets.

Alzheimer's disease (AD) is a psychological, biological, or developmental disorder that affects basic mental functioning. AD is generally affiliated with marked discomfort and impaired social, professional, or other crucial aspects of life. AD is predominant worldwide, but a disparity in prevalence is observed amongst nations. Around 3/4 of people with Alzheimer's disease are from underdeveloped nations, which receive only 1/10th of global mental health resources. Residents of each community and age category share their presence in the overall load of AD. AD is a multifactorial disease impacted by numerous environmental, genetic, and endogenous elements. Heteromorphic interactive downstream cascades, networks, and molecular mechanisms (inflammation and immune network, cholinergic deficit, lipid transit, endocytosis, excitotoxicity, oxidative stress, amyloid and tau pathology, energy metabolism, neuron and synapse loss, and cell death) have been isolated, imparting a non-dissociative contribution in pathogenesis of AD. In the CNS, the structural organization of cholinergic neurons can give a novel insight into the mechanism of new learning. The alleviation of central cholinergic transposal following destruction in the basal forebrain cholinergic neurons precipitates a decline in neurocognitive symptoms visible in AD patients. The brain of patients suffering from AD exhibits plaques of aggregated amyloid-ß and neurofibrillary tangles containing hyperphosphorylated tau protein. Amyloid-ß triggers cholinergic loss by modulation of calcium and generation of cell-damaging molecules such as nitric oxide and reactive oxygen species intermediates. The present review focuses on the pathogenic mechanisms related to stages, diagnosis, and therapeutic approaches involved in AD.

Donepezil treatment is associated with improved outcomes in critically ill dementia patients via a reduction in delirium.

INTRODUCTION: During hospital admissions, patients with dementia are at risk for developing delirium, an acute state of brain failure associated with significant morbidity. There are currently no pharmacologic tools to treat or prevent delirium. Decreased cholinergic signaling plays a role in the pathophysiology of both disorders. Whether enhanced pre-hospital cholinergic signaling in patients with dementia improves outcomes during critical illness remains unknown. METHODS: We utilized the Medical Information Mart for Intensive Care III (MIMIC-III) database to determine whether pre-hospital donepezil use was associated with improved outcomes during critical illness in dementia patients. RESULTS: We identified 2734 subjects with dementia admitted to the intensive care unit (ICU; 447 received donepezil). After adjusting for confounders, patients with dementia who were receiving donepezil had a significantly reduced in-hospital and 90-day mortality, ICU length of stay, and duration of mechanical ventilation. Donepezil use was associated with, and its benefit was mediated by, reduced delirium. DISCUSSION: Patients with dementia who are treated with donepezil have improved outcomes during critical illness and reductions in delirium. HIGHLIGHTS: No pharmacologic treatments exist to reduce delirium in patients with dementia. Donepezil improves outcomes during critical illness in patients with dementia. Improved outcomes are mediated by a reduction in hospital delirium. Future studies in patients with dementia should prospectively evaluate donepezil in the prevention of delirium.

Gelatin/polyvinyl alcohol loaded magnesium hydroxide nanocomposite attenuates neurotoxicity and oxidative stress in Alzheimer's disease induced rats.

Amyloid-ß (Aß) plaque formation, neuronal cell death, mitochondrial and cholinergic dysfunction are key indicators of Alzheimer's disease (AD). In this study, gelatin and polyvinyl alcohol (PVA) were tethered with magnesium hydroxide (Mg(OH)2) to synthesize nanocomposite (Ge/PVA/Mg(OH)2) through alkali co-precipitation. The characterization studies using FT-IR, XRD, DLS, and SEM-EDX confirmed the successful formation of Ge/PVA/Mg(OH)2 nanocomposite. Further, in vitro study it clearly demonstrated the impact of Ge/PVA/Mg(OH)2 nanocomposite on biocompatibility, cellular uptake, reduced Aß protein expression and protection of neuronal cell death. The confocal study further confirmed the down-regulation of Aß expression. The subsequent in vivo analysis witnessed the protective effect of Ge/PVA/Mg(OH)2 nanocomposites on the cognitive and synaptic impairments of AD in intraceribroventricular streptozotocin (ICV-STZ) treated rats. Oxidative stress, antioxidant enzymes, cholinergic and mitochondrial complex activity were conducted and revealed that the Acetylcholineesterase (AChE) and Malondialdehyde (MDA) activities were significantly decreased by contrast the antioxidant enzyme activities were found to be increased in the cortex and hippocampus regions of the brain. Thus, the present investigation recommends Ge/PVA/Mg(OH)2 nanocomposite to target AD and clinical translation.

Proteomics Evidence of the Role of TDMQ20 in the Cholinergic System and Synaptic Transmission in a Mouse Model of Alzheimer's Disease.

The interaction between copper ions and amyloid peptide Aß has been reported to be involved in Alzheimer's disease (AD) pathology. Based on copper coordination biochemistry, we designed specific copper chelators [tetradentate monoquinolines (TDMQs)] in order to regulate copper homeostasis in the AD brain and inhibit the deleterious oxidative stress catalyzed by copper-Aß complexes. We previously reported that TDMQ20, a highly selective copper chelator selected as a drug candidate, was able to extract copper from the Cu-Aß1-16 complex and restore cognitive and behavioral deficits in AD mouse models. For a better understanding of the mechanism of action of TDMQ20, we decided to investigate the change of profile of proteins expressed in 5xFAD mice after an oral treatment of TDMQ20 (dose = 10 mg/kg, once every two days for 3 months, in total 45 times). Clioquinol (CQ), a non-specific chelator, has been used as a comparator. Here, we report the proteomic alterations in the cortex of 5xFAD mice using iTRAQ (isobaric tags for relative and absolute quantification) proteomics technology. The results indicated that 178 differentially expressed proteins (DEPs) have been identified in the AD mouse group with respect to wild type (WT) animals (AD/WT). After treatment by TDMQ20, 35 DEPs were found common in AD/WT and TDMQ20/AD groups in an opposite change manner (up- or down-regulated, respectively). In addition, among the 35 DEPs mentioned above, 10 common target proteins have been identified in AD/WT, TDMQ20/AD, and CQ/AD groups, among which 3 target proteins were successfully validated by western blot analysis. In particular, the expression levels of ChAT and CHRM4 are significantly increased upon TDMQ20 treatment with respect to 5xFAD mice, while CQ did not significantly change the expression of these proteins. Our study suggests the involvement of the copper chelator TDMQ20 on the cholinergic system, a feature that may explain the improved cognitive and behavioral performance in AD mice upon oral treatment of TDMQ20.

Kaempferol as a potential neuroprotector in Alzheimer's disease.

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, is largely associated with cognitive disability, amnesia, and abnormal behavior, which accounts for about two third of people with dementia worldwide. A growing body of research demonstrates that AD is connected to several factors, such as aberrant accumulation of amyloid-beta (Aß), increase in the hyperphosphorylation of Tau protein, and the formation of neurofibrillary tangles, mitochondrial dysfunction, and inordinate production of reactive oxygen species (ROS). Despite remarkable efforts to realize the etiology and pathophysiology of AD, until now, scientists have not developed and introduced medications that can permanently cease the progression of AD. Thus, nowadays, research on the role of natural products in the treatment and prevention of AD has attracted great attention. Kaempferol (KMP), one of the prominent members of flavonols, exerts its ameliorative actions via attenuating oxidative stress and inflammation, reducing Aß-induced neurotoxicity, and regulating the cholinergic system. Therefore, in this review article, we outlined the possible effects of KMP in the prevention and treatment of AD. PRACTICAL APPLICATIONS: Kaempferol (KMP) exerts its ameliorative actions against AD via attenuating oxidative stress and inflammation, reducing Aß-induced neurotoxicity, and regulating the cholinergic system. The beneficial effects of KMP were addressed in both in vitro and in vivo studies; however, conducting further research can warrant its long-term effects as a safe agent. Therefore, after confirming its favorable functions in the prevention and treatment of AD, it could be used as a safe and effective agent.

Acetylcholine in Carcinogenesis and Targeting Cholinergic Receptors in Oncology.

Tumor cells modulate and are modulated by their microenvironments, which include the nervous system. Accumulating evidence links the overexpression and activity of nicotinic and muscarinic cholinergic receptor subtypes to tumorigenesis in breast, ovarian, prostate, gastric, pancreatic, and head and neck cancers. Nicotinic and muscarinic receptors have downstream factors are associated with angiogenesis, cell proliferation and migration, antiapoptotic signaling, and survival. Clinical trials analyzing the efficacy of various therapies targeting cholinergic signaling or downstream pathways of acetylcholine have shed promising light on novel cancer therapeutics. Although the evidence for cholinergic signaling involvement in tumor development is substantial, a more detailed understanding of the acetylcholine-induced mechanisms of tumorigenesis remains to be unlocked. Such an understanding would enable the development of clinical applications ranging from the identification of novel biomarkers to the utilization of existing drugs to modulate cholinergic signaling to the development of novel cancer therapies, as discussed in this review.

Resveratrol attenuates behavioural impairment associated with learning and memory in rats with diabetes induced by a high-fat diet and streptozotocin.

BACKGROUND AND PURPOSE: A high-fat diet (HFD) is a common risk factor for Type 2 diabetes mellitus (T2DM) and its associated cognitive impairments. In models of diabetes, resveratrol, a modulator of SIRT1, regulates the fasting glucose and antioxidant levels, as well as the lipid profile. Resveratrol may also alleviate the cognitive dysfunctions associated with diabetes. EXPERIMENTAL APPROACH: Albino rats were fed a HFD, (60% kcal fat) after treatment with streptozotocin (45 mg·kg-1 ,i.p., single dose) to induce an experimental model of T2DM. After 14 weeks of the animals in confirmed diabetic condition, they were treated with metformin (200 mg·kg-1 ,i.p.) or resveratrol (50 or 100 mg·kg-1 ,i.p.) for 4 weeks. Levels of oxidative-nitroso-stress, SIRT1, TGF-ß1, inflammation and cholinergic activity were determined in plasma, hippocampus and cerebral cortex. A battery of behavioural studies associated with learning memory were performed during and after the experimental protocol. KEY RESULTS: Treatment with resveratrol attenuated the increased glucose levels (pre- and post-prandial), impaired glucose tolerance, HbA1c, and decreased the body weights of the T2DM rats. Moreover, resveratrol ameliorated the impaired learning and memory associated with increased SIRT1 and decreased TGF-ß1, TNF-α, oxidative-nitroso-stress, and cholinergic activities in the plasma and the brains of the T2DM animals. CONCLUSION AND IMPLICATION: Our results demonstrated that SIRT1 modulation interacted with TGF-ß1 signalling, and mitigated hyperglycaemia and subsequent learning-memory impairments in the T2DM animals. Our study also suggested novel therapeutic targets, including TGF-ß1, which may add to our knowledge of resveratrol, when used to treat impaired memory associated with diabetes.