Consequences of Acetylcholine imbalance

Currently, it is possible to study the pathogenesis of Tourette's syndrome (TS) in more detail, due to more advanced methods of neuroimaging. However, medical and surgical treatment options are limited by a lack of understanding of the nature of the disorder and its relationship to some psychiatric disorders, the most common of which is obsessive-compulsive disorder (OCD). It is believed that the origin of chronic tic disorders is based on an imbalance of excitatory and inhibitory influences in the Cortico-Striato-Thalamo-Cortical circuits (CSTC)...

In recent years, gut microbiome alterations have been linked with complex underlying mechanisms of neurodegenerative disorders including Alzheimer's disease (AD). The gut microbiota modulates gut brain axis by facilitating development of hypothalamic-pituitary-adrenal axis and synthesis of neuromodulators. The study was designed to unravel the effect of combined consumption of probiotics; Lactobacillus rhamnosus GG (LGG®) and Bifidobacterium BB-12 (BB-12®) (1 × 109  CFU) on AlCl3 -induced AD mouse model in comparison with potent acetylcholine esterase inhibitor drug for AD, donepezil...

Autonomic imbalance and metabolic inflammation are important pathological processes in diabetic cardiomyopathy. Gut microbiota dysbiosis and increased levels of bacterial component lipopolysaccharide (LPS) are associated with diabetic myocardial injury, but the mechanism by which gut microbes affect metabolic inflammation and cardiac injury remains unclear. We determined whether pyridostigmine (PYR), which inhibits cholinesterase to improve vagal activity, could regulate the disordered gut microbiota and attenuate gut barrier dysfunction, metabolic endotoxemia, and inflammation in diabetes...

Nicotinic acetylcholine receptors (nAChRs) are master regulators of immune functions via the cholinergic anti-inflammatory pathway and are expressed in microglia, the brain's resident immune cells. There is an extensive dialogue between the neurons and the glial cells around them from which microglia are tasked with monitoring, nurturing, and defending their microenvironment. Dysregulation of any of these processes can have devastating and long-lasting consequences involving microglia-mediated neuroinflammation associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, amongst others...

Fatal familial insomnia (FFI) is a rare neurodegenerative disease caused by a dominantly inherited single amino acid substitution (D178N) within the prion protein (PrP). No in vitro human brain tissue model for this disease has previously been available. Consequently, how this mutation exerts its damaging effect on brain cells is still unknown. Using CRISPR-Cas9 engineered induced pluripotent stem cells, we made D178N cerebral organoids and compared these with isotype control organoids. We found that, in the absence of other hallmarks of FFI, the D178N organoids exhibited astrogliosis with cellular oxidative stress...

The autonomic nervous system can control immune cell activation via both sympathetic adrenergic and parasympathetic cholinergic nerve release of norepinephrine and acetylcholine. The hypothesis put forward in this paper suggests that autonomic nervous system dysfunction leads to dysregulation of immune tolerance mechanisms in brain-resident and peripheral immune cells leading to excessive production of pro-inflammatory cytokines such as Tumor Necrosis Factor alpha (TNF-α). Inactivation of Glycogen Synthase Kinase-3β (GSK3β) is a process that takes place in macrophages and microglia when a toll-like receptor 4 (TLR4) ligand binds to the TLR4 receptor...

Aging of the cardiovascular regulatory function manifests as an imbalance between the sympathetic and parasympathetic (vagal) components of the autonomic nervous system (ANS). The most characteristic change is sympathetic overdrive, which is manifested by an increase in the muscle sympathetic nerve activity (MSNA) burst frequency with age. Age-related changes that occur in vagal nerve activity is less clear. The resting tonic parasympathetic activity can be estimated noninvasively by measuring the increase in heart rate occurring in response to muscarinic cholinergic receptor blockade; animal study models have shown this to diminish with age...

Alcohol use disorder (AUD) encompasses the dysregulation of multiple brain circuits involved in executive function leading to excessive consumption of alcohol, despite negative health and social consequences and feelings of withdrawal when access to alcohol is prevented. Ethanol exerts its toxicity through changes to multiple neurotransmitter systems, including serotonin, dopamine, gamma-aminobutyric acid, glutamate, acetylcholine, and opioid systems. These neurotransmitter imbalances result in dysregulation of brain circuits responsible for reward, motivation, decision making, affect, and the stress response...

PURPOSE: In the present study, the therapeutic efficacy of a selective BKCa channel opener (compound X) in the treatment of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) was investigated. METHODS: PAH was induced in male Wistar rats by a single injection of MCT. After two weeks, the MCT-treated group was divided into two groups that were either treated with compound X or vehicle. Compound X was administered daily at 28 mg/kg. Electrocardiographic, echocardiographic, and haemodynamic analyses were performed; ex vivo evaluations of pulmonary artery reactivity, right ventricle (RV) and lung histology as well as expression levels of α and β myosin heavy chain, brain natriuretic peptide, and cytokines (TNFα and IL10) in heart tissue were performed...

Cholinergic signaling plays a key role in regulating striatal function. The principal source of acetylcholine in the striatum is the cholinergic interneurons which, although low in number, densely arborize to modulate striatal neurotransmission. This modulation occurs via strategically positioned nicotinic and muscarinic acetylcholine receptors that influence striatal dopamine, GABA and other neurotransmitter release. Cholinergic interneurons integrate multiple striatal synaptic inputs and outputs to regulate motor activity under normal physiological conditions...

The mitochondrial unfolded protein response (UPR(mt)) is involved in numerous diseases that have the common feature of mitochondrial dysfunction. However, its pathophysiological relevance in the context of hypoxia/reoxygenation (H/R) in endothelial cells remains elusive. Previous studies have demonstrated that acetylcholine (ACh) protects against cardiomyocyte injury by suppressing generation of mitochondrial reactive oxygen species (mtROS). This study aimed to explore the role of UPR(mt) in endothelial cells during H/R and to clarify the beneficial effects of ACh...

Obesity is involved in several cardiovascular diseases including coronary artery disease and endothelial dysfunction. Endothelial Endothelium vasodilator and vasoconstrictor agonists play a key role in regulation of vascular tone. In this study, we evaluated coronary vascular response in an 8 weeks diet-induced obese C57BL/6 mice model. Coronary perfusion pressure in response to acetylcholine in isolated hearts from obese mice showed increased vasoconstriction and reduced vasodilation responses compared with control mice...

Basal ganglia disorders such as Parkinson's disease, dystonia, and Huntington's disease are characterized by a dysregulation of the basal ganglia neuromodulators (dopamine, acetylcholine, and others), which impacts cortico-striatal transmission. Basal ganglia disorders are often associated with an imbalance between the midbrain dopaminergic and striatal cholinergic systems. In contrast to the extensive research and literature on the consequences of a malfunction of midbrain dopaminergic signaling on the plasticity of the cortico-striatal synapse, very little is known about the role of striatal cholinergic interneurons in normal and pathological control of cortico-striatal transmission...

CHRNA1 encodes the α subunit of nicotinic acetylcholine receptors (nAChRs) and is expressed at the neuromuscular junction. Moreover, it is one of the causative genes of Congenital Myasthenic Syndromes (CMS). CHRNA1 undergoes alternative splicing to produce two splice variants: P3A(-), without exon P3A, and P3A(+), with the exon P3A. Only P3A(-) forms functional nAChR. Aberrant alternative splicing caused by intronic or exonic point mutations in patients leads to an extraordinary increase in P3A(+) and a concomitant decrease in P3A(-)...

In drug users, drug-related cues alone can induce dopamine release in the dorsal striatum. Instructive cues activate inputs to the striatum from both dopaminergic and cholinergic neurons, which are thought to work together to support motor learning and motivated behaviors. Imbalances in these neuromodulatory influences can impair normal action selection and might thus contribute to pathologically repetitive and compulsive behaviors such as drug addiction. Dopamine and acetylcholine can have either antagonistic or synergistic effects on behavior, depending on the state of the animal and the receptor signaling systems at play...

The basal forebrain cholinergic complex comprising medial septum, horizontal and vertical diagonal band of Broca, and nucleus basalis of Meynert provides the mayor cholinergic projections to the cerebral cortex and hippocampus. The cholinergic neurons of this complex have been assumed to undergo moderate degenerative changes during aging, resulting in cholinergic hypofunction that has been related to the progressing memory deficits with aging. However, the previous view of significant cholinergic cell loss during aging has been challenged...

Reactive oxygen species (ROS) are produced within the body during oxygen metabolism and living organisms have developed several defense mechanisms to protect themselves from oxidative stress. Under normal conditions, ROS and antioxidant systems are in balance. Oxidative stress is caused by the imbalance between production of pro-oxidants and the antioxidant defenses. The defense mechanisms include antioxidant enzymes like superoxide dismutase (SOD) or glutathione peroxidase (GPX) and several no enzymatic free radical scavengers...

Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling...

Vascular system is a large complex of tubes with different diameters which are able to perceive changes of endogenous milieu, to integrate and modulate signals of intercellular communication and to respond and adapt by a local production of different kinds of mediators affecting vascular structure and function. For a long time, it has been assumed that the main determinant of vasomotor function was the nervous system and the monolayer of endothelial cells was only a physical barrier between the vessel wall and blood...

Traumatic, infectious, metabolic, and chemical noxa to the nervous system are the etiology of a crippling disease generally termed neuropathy. Motor disorders, altered sensibility, and pain are the pathognomonic traits. Cellular alterations induced by this chronic pathology include mitochondrial dysfunctions that lead to the activation of the apoptotic cascade. Energy imbalance can compromise the maintenance of mitochondrial membrane potential, furthering the release of cytochrome C and the subsequent cleavage and activation of caspases...