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Fulltext Mitochondrial DNA integrity and function are critical for endothelium-dependent vasodilation in rats with metabolic syndrome

Kiyooka T, Ohanyan V, Yin L, Pung YF, Chen YR, Chen CL, et al.

Basic Res Cardiol, 2022 Jan 17;117(1):3.
PMID: 35039940 DOI: 10.1007/s00395-021-00908-1

Endothelial dysfunction in diabetes is generally attributed to oxidative stress, but this view is challenged by observations showing antioxidants do not eliminate diabetic vasculopathy. As an alternative to oxidative stress-induced dysfunction, we interrogated if impaired mitochondrial function in endothelial cells is central to endothelial dysfunction in the metabolic syndrome. We observed reduced coronary arteriolar vasodilation to the endothelium-dependent dilator, acetylcholine (Ach), in Zucker Obese Fatty rats (ZOF, 34 ± 15% [mean ± standard deviation] 10-3 M) compared to Zucker Lean rats (ZLN, 98 ± 11%). This reduction in dilation occurred concomitantly with mitochondrial DNA (mtDNA) strand lesions and reduced mitochondrial complex activities in the endothelium of ZOF versus ZLN. To demonstrate endothelial dysfunction is linked to impaired mitochondrial function, administration of a cell-permeable, mitochondria-directed endonuclease (mt-tat-EndoIII), to repair oxidatively modified DNA in ZOF, restored mitochondrial function and vasodilation to Ach (94 ± 13%). Conversely, administration of a cell-permeable, mitochondria-directed exonuclease (mt-tat-ExoIII) produced mtDNA strand breaks in ZLN, reduced mitochondrial complex activities and vasodilation to Ach in ZLN (42 ± 16%). To demonstrate that mitochondrial function is central to endothelium-dependent vasodilation, we introduced (via electroporation) liver mitochondria (from ZLN) into the endothelium of a mesenteric vessel from ZOF and restored endothelium-dependent dilation to vasoactive intestinal peptide (VIP at 10-5 M, 4 ± 3% vasodilation before mitochondrial transfer and 48 ± 36% after transfer). Finally, to demonstrate mitochondrial function is key to endothelium-dependent dilation, we administered oligomycin (mitochondrial ATP synthase inhibitor) and observed a reduction in endothelium-dependent dilation. We conclude that mitochondrial function is critical for endothelium-dependent vasodilation.

Matched MeSH terms: Acetylcholine/metabolism
Revisiting the role of neurotransmitters in epilepsy: An updated review

Akyuz E, Polat AK, Eroglu E, Kullu I, Angelopoulou E, Paudel YN

Life Sci, 2021 Jan 15;265:118826.
PMID: 33259863 DOI: 10.1016/j.lfs.2020.118826

Epilepsy is a neurologicaldisorder characterized by persistent predisposition to recurrent seizurescaused by abnormal neuronal activity in the brain. Epileptic seizures maydevelop due to a relative imbalance of excitatory and inhibitory neurotransmitters. Expressional alterations of receptors and ion channelsactivated by neurotransmitters can lead to epilepsy pathogenesis.
AIMS: In this updated comprehensive review, we discuss the emerging implication of mutations in neurotransmitter-mediated receptors and ion channels. We aim to provide critical findings of the current literature about the role of neurotransmitters in epilepsy.
MATERIALS AND METHODS: A comprehensive literature review was conducted to identify and critically evaluate studies analyzing the possible relationship between epilepsy and neurotransmitters. The PubMed database was searched for related research articles.
KEY FINDINGS: Glutamate and gamma-aminobutyric acid (GABA) are the main neurotransmitters playing a critical role in the pathophysiology of this balance, and irreversible neuronal damage may occur as a result of abnormal changes in these molecules. Acetylcholine (ACh), the main stimulant of the autonomic nervous system, mediates signal transmission through cholinergic and nicotinic receptors. Accumulating evidence indicates that dysfunction of nicotinic ACh receptors, which are widely expressed in hippocampal and cortical neurons, may be significantly implicated in the pathogenesis of epilepsy. The dopamine-norepinephrine-epinephrine cycle activates hormonal and neuronal pathways; serotonin, norepinephrine, histamine, and melatonin can act as both hormones and neurotransmitters. Recent reports have demonstrated that nitric oxide mediates cognitive and memory-related functions via stimulating neuronal transmission.
SIGNIFICANCE: The elucidation of the role of the main mediators and receptors in epilepsy is crucial for developing new diagnostic and therapeutic approaches.

Matched MeSH terms: Acetylcholine/metabolism
Effects of the total alkaloidal extract of Murraya koenigii leaf on oxidative stress and cholinergic transmission in aged mice

Mani V, Ramasamy K, Ahmad A, Wahab SN, Jaafar SM, Kek TL, et al.

Phytother Res, 2013 Jan;27(1):46-53.
PMID: 22447662 DOI: 10.1002/ptr.4676

Alzheimer's disease (AD) is characterized by signs of major oxidative stress and the loss of cholinergic cells. The present study was designed to investigate the role of the total alkaloidal extract from Murraya koenigii (MKA) leaves on age related oxidative stress and the cholinergic pathway in aged mice. Ascorbic acid (100 mg/kg, p.o.) was used as a standard drug. The MKA improved the level of protective antioxidants such as glutathione peroxidase (GPx), reduced glutathione (GSH), glutathione reductase (GRD), superoxide dismutase (SOD) and catalase (CAT) in brain homogenate at higher doses (20 and 40 mg/kg, p.o.). Moreover, a dose dependent decline was noted in lipid peroxidation (LPO) and the nitric oxide assay (NO) at all doses of MKA (10, 20 and 40 mg/kg, p.o.). Interestingly, significant progress was noted with the supplementation of MKA by an improvement of the acetylcholine (ACh) levels and a reduction in the acetylcholinesterase (AChE) activity in aged mouse brain. In addition, a significant elevation of serum albumin (ALBU), alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST) and total protein as well as a decline in creatinine, total cholesterol, urea nitrogen and glucose levels with MKA also ameliorated the hepatic and renal functions in normal ageing process. The results showed the possible utility of Murraya koenigii leaves in neuroprotection against neurodegenerative disorders such as Alzheimer's disease.

Matched MeSH terms: Acetylcholine/metabolism
Inhibition of gastrointestinal release of acetylcholine by quercetin as a possible mode of action of Psidium guajava leaf extracts in the treatment of acute diarrhoeal disease

Lutterodt GD

J Ethnopharmacol, 1989 May;25(3):235-47.
PMID: 2747259

The electrically stimulated guinea-pig ileum and spontaneously contracting guinea-pig ileum preparations were employed in studies on the effects of an alcoholic extract and two flavonoid compounds, quercetin and quercetin-3-arabinoside, extracted from the leaves of Psidium guajava. The extract showed a morphine-like inhibition of acetylcholine release in the coaxially stimulated ileum, together with an initial increase in muscular tone, followed by a gradual decrease. The morphine-like inhibition was found to be due to quercetin, starting at concentrations of 1.6 micrograms/ml. The glycoside did not show any such action at concentrations of up to 1.28 mg/ml. The extract inhibited spontaneous contractions in the unstimulated ileum with a concentration-response relationship.

Matched MeSH terms: Acetylcholine/metabolism
Total isoflavones from soybean and tempeh reversed scopolamine-induced amnesia, improved cholinergic activities and reduced neuroinflammation in brain

Ahmad A, Ramasamy K, Jaafar SM, Majeed AB, Mani V

Food Chem Toxicol, 2014 Mar;65:120-8.
PMID: 24373829 DOI: 10.1016/j.fct.2013.12.025

The present study was undertaken to compare the neuroprotective effects between total isoflavones from soybean and tempeh against scopolamine-induced cognitive dysfunction. Total isoflavones (10, 20 and 40mg/kg) from soybean (SI) and tempeh (TI) were administered orally to different groups of rats (n=6) for 15days. Piracetam (400mg/kg, p.o.) was used as a standard drug while scopolamine (1mg/kg, i.p.) was used to induce amnesia in the animals. Radial arm and elevated plus mazes served as exteroceptive behavioural models to measure memory. Brain cholinergic activities (acetylcholine and acetylcholinesterase) and neuroinflammatory activities (COX-1, COX-2, IL-1β and IL10) were also assessed. Treatment with SI and TI significantly reversed the scopolamine effect and improved memory with TI group at 40mg/kg, p.o. exhibiting the best improvement (p<0.001) in rats. The TI (10, 20 and 40mg/kg, p.o.) significantly increased (p<0.001) acetylcholine and reduced acetylcholinesterase levels. Meanwhile, only a high dose (40mg/kg, p.o.) of SI showed significant improvement (p<0.05) in the cholinergic activities. Neuroinflammation study also showed that TI (40mg/kg, p.o.) was able to reduce inflammation better than SI. The TI ameliorates scopolamine-induced memory in rats through the cholinergic neuronal pathway and by prevention of neuroinflammation.

Matched MeSH terms: Acetylcholine/metabolism
In vitro anticholinergic and antihistaminic activities of Acorus calamus Linn. leaves extracts

Vijayapandi P, Annabathina V, SivaNagaSrikanth B, Manjunath V, Boggavarapu P, Mohammed P AK, et al.

Afr J Tradit Complement Altern Med, 2012;10(1):95-101.
PMID: 24082330

The present investigation was aimed at determining the effects of hexane, acetone, methanol and aqueous extracts of Acorus calamus leaves (ACHE, ACAE, ACME and ACAQE) on cholinergic and histaminic system using isolated frog rectus abdominis muscle and guinea pig ileum. A dose dependent potentiation of Ach response (anticholinesterase like effect) was found with ACAE and ACME at 0.25, 0.5, 0.75 and 1 mg/ml, but at higher dose of ACAE, ACME, ACAQE and ACHE (5, 20 mg/ml) inhibit the Ach response (antinicotinic effect). These results revealed biphasic effect of Acorus calamus leaves extracts on acetylcholine induced contractile response in isolated frog rectus abdominis muscle preparation (i.e. potentiation effect at lower dose and inhibitory effect at higher dose). Studies on isolated guinea pig ileum demonstrated antihistaminic effect in a dose dependent manner (100-1000 µg/ml) with ACAE, ACME and ACAQE. In addition, the dose dependent inhibition of Ach response (antimuscarinic effect) was observed with ACAE and ACME. In conclusion, Acorus calamus leaves extracts exerts antinicotinic, anticholinesterase like activities in isolated frog rectus abdominis muscle and antihistaminic, antimuscarinic effect in guinea pig ileum. It has been suggested that these observed activities can be further studied for therapeutic potential of Acorus calamus leaves in the treatment of cognitive disorders and asthma.

Matched MeSH terms: Acetylcholine/metabolism
Sesame indicum, a nutritional supplement, elicits antiamnesic effect via cholinergic pathway in scopolamine intoxicated mice

Chidambaram SB, Pandian A, Sekar S, Haridass S, Vijayan R, Thiyagarajan LK, et al.

Environ Toxicol, 2016 Dec;31(12):1955-1963.
PMID: 26434561 DOI: 10.1002/tox.22196

PURPOSE: Present study was undertaken to evaluate the antiamnesic effect of Sesamum indicum (S. indicum) seeds (standardized for sesamin, a lignan, content) in scopolamine, a muscarinic antagonist intoxicated mice.
METHODS: Male Swiss albino mice (18-22 g bw) were pretreated with methanolic extract of sesame seeds (MSSE) (100 and 200 mg/kg/day, p.o) for a period of 14 days. Scopolamine (0.3 mg/kg, i.p.) was injected on day 14, 45 ± 10 min after MSSE administration. Antiamnesic effect of MSSE was evaluated using step-down latency (SDL) on passive avoidance apparatus and transfer latency (TL) on an elevated plus maze. To unravel the mechanism of action, we examined the effects of MSSE on the genes such as acetyl cholinesterase (AChE), muscarinic receptor M1 subtype (mAChRM1 ), and brain derived neurotrophic factor (BDNF) expression within hippocampus of experimental mice. Further, its effects on bax and bcl-2 were also evaluated. Histopathological examination of hippocampal CA1 region was performed using cresyl violet staining.
RESULTS: MSSE treatment produced a significant and dose dependent increase in step down latency in passive avoidance test and decrease in transfer latency in elevated plus maze in scopolamine intoxicated injected mice. MSSE down-regulated AChE and mAChRM1 and up-regulated BDNF mRNA expression. Further, it significantly down-regulated the bax and caspase 3 and up-regulated bcl-2 expression in scopolamine intoxicated mice brains. Mice treated with MSSE showed increased neuronal counts in hippocampal CA1 region when compared with scopolamine-vehicle treated mice.
CONCLUSION: Sesame seeds have the ability to interact with cholinergic components involved in memory function/restoration and also an interesting candidate to be considered for future cognitive research. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1955-1963, 2016.

Matched MeSH terms: Acetylcholine/metabolism
Effect of newer anti-epileptic drugs (AEDs) on the cognitive status in pentylenetetrazol induced seizures in a zebrafish model

Choo BKM, Kundap UP, Johan Arief MFB, Kumari Y, Yap JL, Wong CP, et al.

Prog Neuropsychopharmacol Biol Psychiatry, 2019 06 08;92:483-493.
PMID: 30844417 DOI: 10.1016/j.pnpbp.2019.02.014

Epilepsy is marked by seizures that are a manifestation of excessive brain activity and is symptomatically treatable by anti-epileptic drugs (AEDs). Unfortunately, the older AEDs have many side effects, with cognitive impairment being a major side effect that affects the daily lives of people with epilepsy. Thus, this study aimed to determine if newer AEDs (Zonisamide, Levetiracetam, Perampanel, Lamotrigine and Valproic Acid) also cause cognitive impairment, using a zebrafish model. Acute seizures were induced in zebrafish using pentylenetetrazol (PTZ) and cognitive function was assessed using the T-maze test of learning and memory. Neurotransmitter and gene expression levels related to epilepsy as well as learning and memory were also studied to provide a better understanding of the underlying processes. Ultimately, impaired cognitive function was seen in AED treated zebrafish, regardless of whether seizures were induced. A highly significant decrease in γ-Aminobutyric Acid (GABA) and glutamate levels was also discovered, although acetylcholine levels were more variable. The gene expression levels of Brain-Derived Neurotrophic Factor (BDNF), Neuropeptide Y (NPY) and Cyclic Adenosine Monophosphate (CAMP) Responsive Element Binding Protein 1 (CREB-1) were not found to be significantly different in AED treated zebrafish. Based on the experimental results, a decrease in brain glutamate levels due to AED treatment appears to be at least one of the major factors behind the observed cognitive impairment in the treated zebrafish.

Matched MeSH terms: Acetylcholine/metabolism
Butyrylcholinesterase: A Multifaceted Pharmacological Target and Tool

Ha ZY, Mathew S, Yeong KY

Curr Protein Pept Sci, 2020;21(1):99-109.
PMID: 31702488 DOI: 10.2174/1389203720666191107094949

Butyrylcholinesterase is a serine hydrolase that catalyzes the hydrolysis of esters in the body. Unlike its sister enzyme acetylcholinesterase, butyrylcholinesterase has a broad substrate scope and lower acetylcholine catalytic efficiency. The difference in tissue distribution and inhibitor sensitivity also points to its involvement external to cholinergic neurotransmission. Initial studies on butyrylcholinesterase showed that the inhibition of the enzyme led to the increment of brain acetylcholine levels. Further gene knockout studies suggested its involvement in the regulation of amyloid-beta, a brain pathogenic protein. Thus, it is an interesting target for neurological disorders such as Alzheimer's disease. The substrate scope of butyrylcholinesterase was recently found to include cocaine, as well as ghrelin, the "hunger hormone". These findings led to the development of recombinant butyrylcholinesterase mutants and viral gene therapy to combat cocaine addiction, along with in-depth studies on the significance of butyrylcholinesterase in obesity. It is observed that the pharmacological impact of butyrylcholinesterase increased in tandem with each reported finding. Not only is the enzyme now considered an important pharmacological target, it is also becoming an important tool to study the biological pathways in various diseases. Here, we review and summarize the biochemical properties of butyrylcholinesterase and its roles, as a cholinergic neurotransmitter, in various diseases, particularly neurodegenerative disorders.

Matched MeSH terms: Acetylcholine/metabolism