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Neuromuscular Physiology
Published in Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan, Strength and Conditioning in Sports, 2023
Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan
To stop the depolarization and muscle fiber contraction, a first step is the degradation of ACh. The enzyme AChE is located in the basement membrane near the sarcolemma and is positioned between the site of ACh release and the AChRs (109, 125, 127). Although AChE is continuously activated, ACh cannot alter the ACh–AChR interface because during depolarization there are more molecules of transmitter released than there are molecules of enzyme present in the basement membrane. After the opening of AChR channels, ACh molecules detach and diffuse toward the basement membrane. The transmitter is then deactivated by hydrolysis and transmission is eventually finished within a few milliseconds. ACh hydrolysis products, choline and acetic acid, are taken up by the axon terminals, converted into ACh, and repackaged into vesicles. Acetylcholine is re-synthesized from choline and acetyl coenzyme A catalyzed by choline acetyltransferase. The rate-limiting step in the synthesis of ACh is transport of choline into the nerve terminal via a high-affinity choline transporter (30).
Pre-Clinical In-Vivo and In-Vitro Methods For Evaluation of Anti-Alzheimer’s Drugs
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
Shilpa A. Deshpande, Niraj S. Vyawahare
Specific degeneration of cholinergic neurons, downregulation of choline acetyltransferase, the enzyme responsible for the synthesis of acetylcholine (ACh), and elevation of acetylcholineserase (AChE) enzyme, as well as reduced choline uptake and ACh release, result in severe deficits of cholinergic function observed in AD. The concentrations of the monoamine metabolites homovanilic acid (HVA), di- hydroxyphenylacetic acid (DOPAC), and 5-hydroxyindolacetic acid (5-HIAA), as well as the monoamine synthesis cofactor biopterin, are found to be significantly decreased in AD. Glutamate plays an especially important role in neuronal plasticity underlying learning and memory, and is found to be significantly elevated in the CSF of AD subjects. Reduced levels of the major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in CSF were also observed in patients with AD.
Diseases of the Nervous System
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Recent publications suggest that various etiological factors are responsible for senile dementia. The neuritic or senile plaques in Alzheimer’s disease consist of a dense core of extracellular amyloid surrounded by enlarged neurites containing degenerating mitochondria and lamellar lysosomes with increased hydrolase activity.554 Neurotransmitter substances,476,501 such as dopamine and norepinephrine, and the gabanergic system show significant losses with age, but there are no specific changes in Alzheimer dementia. Monoamine oxidase activity is increased in the brain in Alzheimer’s disease, and the levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid are decreased. Changes in the cholinergic system seem to be related, and choline acetyltransferase activity is reduced and acetylcholine increased in certain cortical areas in Alzheimer’s disease and related disorders.151,218,456,461,469,478,502
Pharmacotherapeutic combinations for the treatment of Alzheimer’s disease
Published in Expert Opinion on Pharmacotherapy, 2022
Tomoyuki Nagata, Shunichiro Shinagawa, Shinichiro Nakajima, Yoshihiro Noda, Masaru Mimura
Since the 1970s, several novel hypotheses explaining the pathophysiology of AD have emerged, and therapeutic agents have been developed [3]. One of the leading hypotheses, the ‘cholinergic hypothesis,’ originated from the finding that choline acetyltransferase levels are reduced in postmortem brain tissue in AD patients, suggesting a cholinergic deficiency that has been linked to clinical cognitive dysfunction [4]. Moreover, the link between glutamatergic neuron dysfunction and memory impairment has been discussed since the 1980s, suggesting that an amantadine derivative could be used as a modulator to block glutamatergic hyperactivity in neurodegeneration [5]. Such evidence of alterations in the cholinergic system and glutamatergic neurons accelerated the development of three cholinesterase inhibitors (ChEI: donepezil, galantamine, and rivastigmine) and the clinical application of one N-methyl-D-aspartate (NMDA) receptor antagonist (memantine), resulting in the approval of anti-dementia drugs as symptomatic therapies for patients with AD [6]. Furthermore, memantine attenuates the ‘synaptic noise’ of the glutamate background, leading to an improved reduction of long-term potentiation relevant to learning disruption in AD. In addition, ChEI enhances the physiological signal level at the post-synapses of cholinergic neurons [7]. Therefore, based on the theory that glutamatergic-cholinergic interactions promote synaptic activation in vivo, a combination therapy comprised of ChEI and memantine has been considered, and clinical trials have shown promising results [7].
Anticholinergics and falls in older adults
Published in Expert Review of Clinical Pharmacology, 2022
Acetylcholine is a neurotransmitter synthesized from choline and acetyl-CoA during catalysis of choline acetyltransferase [36], and produces nerve signaling by binding to nicotinic and muscarinic receptors on the postsynaptic membrane of neurons. Muscarinic receptors are abundant in the effector cells innervated by the post-ganglionic fibers of parasympathetic nerves [37]. Receptor binding leads to excitation of parasympathetic nerve endings [38], leading to the inhibition of heart activity and bronchial smooth muscles, smooth muscles of the gastrointestinal tract, contraction of the bladder and pupillary sphincters, and increased secretion of digestive glands [39]. Nicotinic receptors are found in the postsynaptic membranes of sympathetic and parasympathetic neurons and the terminal membranes of neuromuscular junctions [40,41]. Excitation of post-ganglionic neurons through nicotinic acetylcholine receptor binding then leads to activation of skeletal muscles.
Novel biomarkers in Alzheimer’s disease using high resolution proteomics and metabolomics: miRNAS, proteins and metabolites
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
Diana Navas-Carrillo, José Miguel Rivera-Caravaca, Arturo Sampedro-Andrada, Esteban Orenes-Piñero
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting almost 50 million people around the world. It is the most common cause of dementia worldwide [1]. AD is characterized by two landmark pathologies, extracellular senile plaques consisting of amyloid-beta (Aβ) peptides and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau proteins [2]. As the disease progresses, amyloid and neurofibrillary proteins accumulate in localized areas of the brain, forming plaques and tangles that disrupt neuronal signaling and ultimately lead to the loss of neurons and brain tissue [3]. These features result in loss of neurogenesis and synaptic plasticity in the hippocampus, the main region of the brain involved in regulation of cognition and memory [4]. The pathogenesis is also associated with a deficit in multiple neurotransmitters, including cholinergic markers, choline acetyltransferase and acetylcholinesterase, as well as deficiencies of serotonin, noradrenalin, somatostatin and corticotrophin-releasing factors [5]. Apolipoprotein E4 alleles are involved in the predisposition to develop the disease [6]. Therefore, it can be said that whilst the etiology of AD is still somewhat dubious, it is recognized as an interaction between genetic and environmental factors.