Displaying publications 1 - 20 of 58 in total

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  1. An optical biosensor for dichlovos using stacked sol-gel films containing acetylcholinesterase and a lipophilic chromoionophore
    Wong FC, Ahmad M, Heng LY, Peng LB
    Talanta, 2006 Jun 15;69(4):888-93.
    PMID: 18970653 DOI: 10.1016/j.talanta.2005.11.034
    An optical biosensor consisting of a chromoionophore (ETH5294) (CM) doped sol-gel film interfaced with another sol-gel film immobilized with acetylcholinesterase (AChE) was employed to detect the insecticide dichlorvos. The main advantage of this optical biosensor is the use of a sol-gel layer with immobilized CM that possesses lipophilic property. The highly lipophilic nature of the CM and its compatibility with the sol-gel matrix has prevented leaching, which is frequently a problem in optical sensor construction based on pH indicator dyes. The immobilization of the indicator and enzyme was simple and need no chemical modification. The CM layer is pH sensitive and detects the pH changes of the acetylcholine chloride (AChCl) substrate when hydrolyzed by AChE layer deposited above. In the absence of the AChE layer, the pH response of the CM layer is linear from pH 6 to 8 (R(2)=0.98, n=3) and it showed no leaching of the lipophilic chromoionophore. When the AChE layer is deposited on top, the optical biosensor responds to AChCl with a linear dynamic range of 40-90mM AChCl (R(2)=0.984, n=6). The response time of the biosensor is 12min. Based on the optimum incubation time of 15min, a linear calibration curve of dichlorvos against the percentage inhibition of AChE was obtained from 0.5 to 7mg/L of dichlorvos (17-85% inhibition, R(2)=0.991, n=9). The detection limit for dichlorvos was 0.5mg/L. The results of the analysis of 1.7-6.0mg/L of dichlorvos using this optical biosensor agreed well with a gas chromatography-mass spectrometry detection method.
    Matched MeSH terms: Acetylcholine; Acetylcholinesterase
  2. Baicalein impairs vascular tone in normal rat aortas: role of superoxide anions
    Machha A, Achike FI, Mohd MA, Mustafa MR
    Eur J Pharmacol, 2007 Jun 22;565(1-3):144-50.
    PMID: 17442302
    Acute exposure to the flavonoid baicalein inhibited endothelium-dependent relaxation in physiological arteries, although the mechanisms are not fully understood. We investigated the effect of baicalein on vascular tone in Wistar-Kyoto (WKY) rat isolated aortic rings in the presence and absence of oxidative stress to further determine the underlying mechanisms. Exposure to baicalein (10 microM) completely abolished endothelium-dependent relaxation induced by acetylcholine and attenuated significantly the endothelium-independent relaxation induced by sodium nitroprusside. Baicalein, similar to Nomega-nitro-L-arginine methyl ester (L-NAME, 10 microM), potentiated significantly the contractile response of aortic rings to alpha1-adrenoceptor agonist phenylephrine. In the presence of L-NAME the baicalein effect on phenylphrine contraction or acetylcholine relaxation was unaltered, suggesting that these effects of baicalein are (like L-NAME effect) endothelial nitric oxide synthase (eNOS)/endothelium-derived nitric oxide-dependent. Inhibition of cyclooxygenase activity with indomethacin (10 microM) or scavenging of superoxide anions with superoxide dismutase (150 units/ml), but not scavenging of hydrogen peroxide with catalase (800 units/ml), enhanced significantly by an essentially similar extent the relaxation to acetylcholine in baicalein-pretreated aortic rings. Relaxant effect to acetylcholine was significantly attenuated in control aortic rings, but was completely abolished in baicalein-pretreated aortic rings in the presence of reduced form of beta-nicotinamide adenine di-nucleotide (beta-NADH, 300 microM). Baicalein blocked beta-NADH (300 microM)-induced transient contractions, suggesting that baicalein may have inhibited activity of NADH/NADPH-oxidase. Baicalein did not alter the failure of acetylcholine to induce relaxation in the presence of pyrogallol (300 microM). In summary, acute exposure to baicalein impairs eNOS/endothelium-derived nitric oxide-mediated vascular tone in rat aortas through the inhibition of endothelium-derived nitric oxide bioavailability coupled to reduced bioactivity of endothelium-derived nitric oxide and to cyclooxygenase-mediated release of superoxide anions.
    Matched MeSH terms: Acetylcholine/pharmacology
  3. Fulltext Bifurcation/chaos and their practical relevance to chemical and biological systems
    Said S. E. H. Elnashaie
    Pertanika Journal of Science & Technology, 2014;22(2):337-364.
    MyJurnal
    Bifurcation and chaos are important phenomena affecting many physical and chemical systems. They are also related to the stability/instability and multiplicity phenomena associated with these systems. The phenomena are not only of theoretical/mathematical interest but are also important for laboratory, pilot plant and commercial units. This paper concentrates on 3 systems:

    1. The novel auto-thermic Circulating Fluidized Membrane Steam Reformer (CFBMSR) for the efficient production of the clean fuel hydrogen and which shows multiplicity of the steady state (static bifurcation)

    2. A novel fermentor for the efficient production of bio-ethanol that shows static/dynamic bifurcation as well as chaotic behaviour

    3. The neurocycle of the acetylcholine transmitter in the brain using diffusion-reaction models in order to gain insight into their possible connection to Alzheimer and Parkinson Diseases (AD/PD); these are preliminary efforts to investigate the bifurcation and chaotic behaviour of this neurocycle.
    Matched MeSH terms: Acetylcholine
  4. 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; Acetylcholinesterase/genetics; Acetylcholinesterase/metabolism
  5. Fulltext Cholinesterase inhibitors from botanicals
    Ahmed F, Ghalib RM, Sasikala P, Ahmed KK
    Pharmacogn Rev, 2013 Jul;7(14):121-30.
    PMID: 24347920 DOI: 10.4103/0973-7847.120511
    Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed.
    Matched MeSH terms: Acetylcholine; Acetylcholinesterase
  6. Chronic cerebral hypoperfusion-induced memory impairment and hippocampal long-term potentiation deficits are improved by cholinergic stimulation in rats
    Damodaran T, Müller CP, Hassan Z
    Pharmacol Rep, 2019 Jun;71(3):443-448.
    PMID: 31003155 DOI: 10.1016/j.pharep.2019.01.012
    BACKGROUND: Chronic cerebral hypoperfusion (CCH) can induce the accumulation of reactive oxygen species, which leads to oxidative damage, neuronal injury, and central cholinergic dysfunction in vulnerable regions of the brain, such as the hippocampus and cerebral cortex. These effects can lead to significant cognitive impairments in clinical populations of vascular dementia (VaD). The present studies aimed to investigate the role of the cholinergic system in memory functions and hippocampal long-term potentiation (LTP) impairments induced by CCH in rats.

    METHODS: Male Sprague Dawley rats were subjected to permanent bilateral occlusion of common carotid arteries (PBOCCA) or sham surgery. Then, PBOCCA rats received ip injections with, either vehicle (control group), the muscarinic receptor agonist oxotremorine (0.1 mg/kg), or the acetylcholinesterase inhibitor physostigmine (0.1 mg/kg). Cognitive functions were evaluated using a passive avoidance task and the Morris water maze test. In addition, hippocampal LTP was recorded in vivo under anaesthesia.

    RESULTS: The PBOCCA rats exhibited significant deficits in passive avoidance retention and spatial learning and memory tests. They also showed a suppression of LTP formation in the hippocampus. Oxotremorine and physostigmine significantly improved the learning and memory deficits as well as the suppression of LTP in PBOCCA rats.

    CONCLUSIONS: The present data suggest that the cholinergic system plays an important role in CCH-induced cognitive deficits and could be an effective therapeutic target for the treatment of VaD.

    Matched MeSH terms: Acetylcholine/pharmacology
  7. Chronic treatment with flavonoids prevents endothelial dysfunction in spontaneously hypertensive rat aorta
    Machha A, Mustafa MR
    J Cardiovasc Pharmacol, 2005 Jul;46(1):36-40.
    PMID: 15965352
    Flavonoids are known to possess cardioprotective properties. Vascular endothelial function is a surrogate marker for cardiovascular diseases, including hypertension. We have studied the effects of chronic flavonoid treatment on vascular endothelial functions in spontaneously hypertensive rats (SHR). Starting from 6-7 weeks old, SHR were given flavonoids (baicalein, flavone, or quercetin) orally (10 mg/kg, once daily) to the SHRs for 4 weeks. Aortas from all the flavonoid-treated animals showed remarkably higher endothelium-dependent relaxations to acetylcholine, to a similar extent as those pretreated with the angiotensin-converting enzyme inhibitor, captopril. However, in contrast to other experimental groups, flavone pretreatment also enhanced the endothelium-independent relaxations to sodium nitroprusside. In addition, treatment with either flavone or quercetin induced a significant attenuation in systolic blood pressure of the hypertensive animals. The present results suggest that chronic treatment with the flavonoids (baicalein, flavone, and quercetin) preserves vascular endothelial functions in hypertensive animals through several possible actions, including increasing endothelial nitric oxide production and bioavailability and reduction in blood pressure.
    Matched MeSH terms: Acetylcholine/pharmacology
  8. Ciproxifan improves cholinergic transmission, attenuates neuroinflammation and oxidative stress but does not reduce amyloid level in transgenic mice
    Mani V, Jaafar SM, Azahan NSM, Ramasamy K, Lim SM, Ming LC, et al.
    Life Sci, 2017 Jul 01;180:23-35.
    PMID: 28501482 DOI: 10.1016/j.lfs.2017.05.013
    AIM: The present study is aimed to investigate the ability of ciproxifan, a histamine H3 receptor antagonist to inhibit β-amyloid (Aβ)-induced neurotoxicity in SK-N-SH cells and APP transgenic mouse model.

    MATERIALS AND METHODS: In vitro studies was designed to evaluate the neuroprotective effects of ciproxifan in Aβ25-35 - induced SK-N-SH cells. For the in vivo study, ciproxifan (1 and 3mg/kg, i.p.) was administrated to transgenic mice for 15days and behaviour was assessed using the radial arm maze (RAM). Brain tissues were collected to measure Aβ levels (Aβ1-40 and Aβ1-42), acetylcholine (ACh), acetylcholinesterase (AChE), nitric oxide (NO), lipid peroxidation (LPO), antioxidant activities, cyclooxygenases (COX) and cytokines (IL-1α, IL-1β and IL-6), while plasma was collected to measure TGF-1β.

    RESULTS: The in vitro studies demonstrated neuroprotective effect of ciproxifan by increasing cell viability and inhibiting reactive oxygen species (ROS) in Aβ25-35-induced SK-N-SH cells. Ciproxifan significantly improved the behavioural parameters in RAM. Ciproxifan however, did not alter the Aβ levels in APP transgenic mice. Ciproxifan increased ACh and showed anti-oxidant properties by reducing NO and LPO levels as well as enhancing antioxidant levels. The neuroinflammatory analysis showed that ciproxifan reduced both COX-1 and COX-2 activities, decreased the level of pro-inflammatory cytokines IL-1α, IL-1β and IL-6 and increased the level of anti-inflammatory cytokine TGF-1β.

    CONCLUSION: This present study provides scientific evidence of the use of ciproxifan via antioxidant and cholinergic pathways in the management of AD.

    Matched MeSH terms: Acetylcholine; Acetylcholinesterase
  9. Fulltext Clinacanthus nutans Leaves Extract Reverts Endothelial Dysfunction in Type 2 Diabetes Rats by Improving Protein Expression of eNOS
    Azemi AK, Mokhtar SS, Rasool AHG
    Oxid Med Cell Longev, 2020;2020:7572892.
    PMID: 32879653 DOI: 10.1155/2020/7572892
    Diabetes mellitus is associated with endothelial dysfunction; it causes progressive vascular damage resulting from an impaired endothelium-dependent vasorelaxation. In the diabetes state, presence of hyperglycemia and insulin resistance predisposes to endothelial dysfunction. Clinacanthus nutans, widely used as a traditional medicine for diabetes is reported to have hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory properties. However, the possibility of C. nutans affecting the vascular endothelial function in diabetes remains unclear. This study was aimed at evaluating the effects of C. nutans methanolic leaves extract (CNME) on endothelial function in a type 2 diabetes (T2DM) rat model. Sixty male Sprague-Dawley rats were divided into five groups (n = 12 per group): nondiabetic control, nondiabetic treated with four weeks of CNME (500 mg/kg/daily), untreated diabetic rats, diabetic treated with metformin (300 mg/kg/daily), and diabetic treated with CNME (500 mg/kg/daily). T2DM was induced by a single intraperitoneal injection of low-dose streptozotocin (STZ) to rats fed with high-fat diet (HFD). Endothelial-dependent and endothelial-independent relaxations and contractions of the thoracic aorta were determined using the organ bath. Aortic endothelial nitric oxide synthase (eNOS) expression was determined using Western blotting. Endothelial-dependent relaxation was reduced in diabetic rats. Both diabetic groups treated with CNME or metformin significantly improved the impairment in endothelium-dependent vasorelaxation; this was associated with increased expression of aortic eNOS protein. CNME- and metformin-treated groups also reduced aortic endothelium-dependent and aortic endothelium-independent contractions in diabetics. Both of these diabetic-treated groups also reduced blood glucose levels and increased body weight compared to the untreated diabetic group. In conclusion, C. nutans improves endothelial-dependent vasodilatation and reduces endothelial-dependent contraction, thus ameliorating endothelial dysfunction in diabetic rats. This may occur due to its effect on increasing eNOS protein expression.
    Matched MeSH terms: Acetylcholine/pharmacology
  10. Delay and misdiagnosis in adult myasthenia gravis: A case report
    Kwa, Siew Kim, Zainab Abdul Majeed, Tan, Kah Nian
    International e-Journal of Science, Medicine & Education, 2016;10(3):37-39.
    MyJurnal
    Myasthenia gravis (MG) is a rare autoimmune disorder
    characterised by fluctuating and variable combination
    of muscle weakness and fatigue. Most cases are due to
    T-cell mediated autoantibodies against post-synaptic
    acetylcholine receptors (AChR-Ab), thus preventing
    acetylcholine from binding and signalling skeletal
    muscle to contract.1
    The annual incidence is 7-23 new cases per million.1
    It can occur at any age but with two peaks; an earlyonset
    (20-40 years) female-predominant and a late-onset
    (60-80 years) male-predominant peak. MG is classified
    into ocular and generalised (80%). More than half the
    patients initially present with ptosis and diplopia but half
    will progress to generalised disease with involvement of
    bulbar, limb and respiratory weakness. Those presenting
    as generalised MG can also develop eye signs later.1
    It is important to recognise MG early because it is
    highly treatable. Untreated disease leads to permanent
    weakness.2 Treatment reduces mortality from lifethreatening
    myasthenic crisis.1,3 Misdiagnosis leads to
    potentially harmful interventions and inappropriate
    management.4,5 Diagnosis in late-onset MG is easily
    missed2,3,4,5 because of overlapping symptoms with
    other diseases common in the elderly. We report a case
    of delay and misdiagnosis in an elderly patient with
    co-morbidities. (Copied from article).
    Matched MeSH terms: Acetylcholine
  11. Direct effects of quercetin on impaired reactivity of spontaneously hypertensive rat aortae: comparative study with ascorbic acid
    Ajay M, Achike FI, Mustafa AM, Mustafa MR
    Clin Exp Pharmacol Physiol, 2006 Apr;33(4):345-50.
    PMID: 16620299
    1. There is a growing interest in the anti-oxidant characteristics and use of flavonoids in the management of cardiovascular diseases. The cardiovascular mechanism of action of these plant derivatives remains controversial. This study compared the effects of the flavonoid quercetin with those of the anti-oxidant vitamin ascorbic acid (vitamin C) on the reactivity of aortic rings from spontaneously hypertensive rats (SHR). 2. The phenylephrine (PE)-induced contractile and the endothelium-dependent and independent relaxant responses of aortic rings from 21 to 22 week old SHR and age-matched normotensive Wistar (WKY) rats were observed in the presence of quercetin or ascorbic acid. All the experiments were performed in the presence of the cyclooxygenase inhibitor, indomethacin (10 micromol/L). 3. The endothelium-dependent and independent relaxations to acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were significantly lesser in the SHR compared to the WKY tissues whereas the contractile responses to PE were similar in both tissues. Pretreatment of WKY rings with quercetin or ascorbic acid had no effect on the responses to ACh or PE. In the SHR tissues, however, quercetin or ascorbic acid significantly improved the relaxation responses to ACh and reduced the contractions to PE with greater potency for quercetin. Both compounds lacked any effects on the responses to SNP in either aortic ring types. N(omega)-nitro-L-arginine methyl ester (l-NAME, 10 micromol/L) significantly attenuated the vasodepressor effects of quercetin and ascorbic acid, raising the responses to PE to a level similar to that observed in the control SHR tissues. In l-NAME pretreated aortic rings, quercetin and ascorbic acid inhibited the contractile responses to PE with the same magnitude in WKY and SHR tissues. 4. The present results suggest that acute exposure to quercetin improves endothelium-dependent relaxation and reduces the contractile responses of hypertensive aortae with a greater potency than ascorbic acid. This suggests a better vascular protection with this flavonoid than ascorbic acid in the SHR model of hypertension and possibly in human cardiovascular diseases.
    Matched MeSH terms: Acetylcholine/pharmacology
  12. Effect of acetylcholine and morphine on bronchial smooth muscle contraction and its modulation by steroid hormones
    Nabishah BM, Morat PB, Khalid BA, Kadir BA
    Clin Exp Pharmacol Physiol, 1990 Dec;17(12):841-7.
    PMID: 2092952
    1. The effects of corticosteroid pretreatment on acetylcholine (ACH)-induced contraction of bronchial smooth muscle (BSM) were studied. 2. ACH dose-response curves for dexamethasone (DM)- and corticosterone (B)-treated but not deoxycorticosterone (DOC)-treated BSM were significantly shifted to the right; this provides evidence that glucocorticoid treatment reduced the sensitivity of BSM to ACH. 3. Morphine enhanced BSM contraction in response to ACH by 20%. DM suppressed this enhancement. 4. These findings correlated well with the reduction of muscarinic receptor numbers in BSM by glucocorticoids in our previous study. In addition, glucocorticoids reduced the sensitivity of BSM to opioids.
    Matched MeSH terms: Acetylcholine/pharmacology*
  13. 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
  14. Effect of quercetin on altered vascular reactivity in aortas isolated from streptozotocin-induced diabetic rats
    Ajay M, Achike FI, Mustafa AM, Mustafa MR
    Diabetes Res Clin Pract, 2006 Jul;73(1):1-7.
    PMID: 16378655 DOI: 10.1016/j.diabres.2005.11.004
    The present work examined ex vivo the acute effect of quercetin on diabetic rat aortic ring reactivity in response to endothelium-dependent (acetylcholine, ACh) and endothelium-independent (sodium nitroprusside, SNP) relaxants, and to the alpha(1)-adrenergic agonist phenylephrine (PE). Responses were compared to those of aortic rings from age- and sex-matched euglycemic rats. Compared to euglycemic rat aortic rings, diabetic rings showed less relaxation in response to ACh and SNP, and greater contraction in response to PE. Pretreatment with quercetin (10microM, 20min) increased ACh-induced relaxation and decreased PE-induced contraction in diabetic, but did not affect euglycemic rat aortic ring responses. Following pretreatment with the nitric oxide synthase inhibitor Nomega-nitro-l-arginine methyl ester (l-NAME, 10microM), quercetin reduced PE-induced contractions in both aortic ring types, although l-NAME attenuated the reduction in the diabetic rings. Quercetin did not alter SNP vasodilatory effects in either ring type compared to their respective controls. These findings indicate that quercetin acutely improved vascular responsiveness in blood vessels from diabetic rats, and that these effects were mediated, at least in part, by enhanced endothelial nitric oxide bioavailability. These effects of quercetin suggest the possible beneficial effects of quercetin in vivo in experimental diabetes and possibly in other cardiovascular diseases.
    Matched MeSH terms: Acetylcholine/pharmacology
  15. Effects of ascorbic acid on impaired vascular reactivity in aortas isolated from age-matched hypertensive and diabetic rats
    Ajay M, Mustafa MR
    Vascul. Pharmacol., 2006 Aug;45(2):127-33.
    PMID: 16807125 DOI: 10.1016/j.vph.2006.05.001
    Impaired vascular reactivity is a hallmark of several cardiovascular diseases that include hypertension and diabetes. This study compared the changes in vascular reactivity in age-matched experimental hypertension and diabetes, and, subsequently, tested whether these changes could be affected directly by ascorbic acid (10 microM). Endothelium-derived nitric oxide (NO) modulation of ascorbic acid effects was also investigated. All the experiments were performed in the presence of a cyclooxygenase inhibitor, indomethacin (10 microM). Results showed that the endothelium-dependent and -independent relaxations induced by acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were blunted to a similar extent in isolated aortic rings from age-matched spontaneously hypertensive (SHR) (R(max): ACh = 72.83+/-1.86%, SNP = 96.6+/-1.90%) and diabetic (Rmax: ACh = 64.09+/-5.14%, SNP = 95.84+/-1.41%) rats compared with aortic rings of normal rats (Rmax: ACh = 89%, SNP = 104.0+/-1.0%). The alpha1-receptor-mediated contractions induced by phenylephrine (PE) were augmented in diabetic (Cmax = 148.8+/-9.0%) rat aortic rings compared to both normal (Cmax = 127+/-6.9%) and SHR (Cmax = 118+/-4.5%) aortic rings. Ascorbic acid pretreatment was without any significant effects on the vascular responses to ACh, SNP and PE in aortic rings from normal rats. Ascorbic acid significantly improved ACh-induced relaxations in SHR (Rmax = 89.09+/-2.82%) aortic rings to a level similar to that observed in normal aortic rings, but this enhancement in ACh-induced relaxations was only partial in diabetic aortic rings. Ascorbic acid lacked any effects on SNP-induced relaxations in both SHR and diabetic aortic rings. Ascorbic acid markedly attenuated contractions induced by PE in aortic rings from both SHR (Cmax = 92.9+/-6.68%) and diabetic (Cmax = 116.9+/-9.4%) rats. Additionally, following inhibition of nitric oxide synthesis with l-NAME, ascorbic acid attenuated PE-induced contractions in all aortic ring types studied. These results suggest that (1) vascular hyper-responsiveness to alpha(1)-receptor agonists in diabetic arteries is independent of endothelial nitric oxide dysfunction; (2) ascorbic acid directly modulates contractile responses of hypertensive and diabetic rat aortas, likely through mechanisms in part independent of preservation of endothelium-derived nitric oxide.
    Matched MeSH terms: Acetylcholine/pharmacology
  16. 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; Acetylcholinesterase/metabolism
  17. Fulltext Embelin Prevents Seizure and Associated Cognitive Impairments in a Pentylenetetrazole-Induced Kindling Zebrafish Model
    Kundap UP, Paudel YN, Kumari Y, Othman I, Shaikh MF
    Front Pharmacol, 2019;10:315.
    PMID: 31057394 DOI: 10.3389/fphar.2019.00315
    Epilepsy is a neuronal disorder associated with several neurological and behavioral alterations characterized by recurrent spontaneous epileptic seizures. Despite having more than 20 anti-epileptic drugs (AEDs), they only provide a symptomatic treatment. As well as, currently available AEDs also displayed cognitive alterations in addition to retarding seizure. This leads to the need for exploring new molecules that not only retard seizure but also improve cognitive impairment. Embelin (EMB) is a benzoquinone derivative which has already demonstrated its pharmacological potentials against arrays of neurological conditions. The current study developed a chronic kindling model in adult zebrafish by using repeated administration of small doses of pentylenetetrazole (PTZ) and a single dose of Kainic acid (KA) to investigate the associated memory impairment. This has been done by using the three-axis maze which is a conventional method to test the learning ability and egocentric memory in zebrafish. As well as, the ameliorative potential of EMB has been evaluated against chronic epilepsy-related memory alterations. Moreover the expression level of pro-inflammatory genes such as C-C motif ligand 2 (CCL2), toll-like receptor-4 (TLR4), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interferon-γ (IFN-γ) were evaluated. The level of several neurotransmitters such as γ-aminobutyric acid (GABA), acetylcholine (Ach) and glutamate (Glu) was evaluated by liquid chromatography-mass spectrometry (LC-MS). The results showed that daily dose of PTZ 80 mg/kg for 10 days successfully induces a kindling effect in zebrafish, whereas the single dose of KA did not. As compared to control, the PTZ and KA group demonstrates impairment in memory as demonstrated by the three-axis maze. The PTZ group treated with a series of EMB doses (ranging from 0.156 to 0.625 mg/kg) was found to have retarded seizure as well as significantly reduces epilepsy-induced memory alteration. In addition, EMB treatment reduces the expression of inflammatory markers implicating its anti-inflammatory potential. Moreover, levels of GABA, Ach, and glutamate are increased in EMB administered group as compared to the PTZ administered group. Overall, findings demonstrate that EMB might be a potential candidate against chronic epilepsy-related cognitive dysfunction as EMB prevents the seizures, so we expect it to prevent the associated neuroinflammation and learning deficit.
    Matched MeSH terms: Acetylcholine
  18. Endothelium-dependent vascular relaxation is abnormal in the coronary microcirculation of atherosclerotic primates
    Sellke FW, Armstrong ML, Harrison DG
    Circulation, 1990 May;81(5):1586-93.
    PMID: 2110036
    Atherosclerosis impairs endothelium-dependent relaxation of large conduit arteries. Because coronary resistance vessels are spared from the development of overt atherosclerosis, endothelium-dependent responses were examined in these vascular segments. Malaysian cynomolgus monkeys (n = 6) were made atherosclerotic by being fed a 0.7% cholesterol diet for 18 months. Control monkeys (n = 6) were fed a standard diet. Coronary microvessels (122-220 microns) were studied in a pressurized (20 mm Hg), no-flow state using a video-imaging apparatus. Relaxations of microvessels, preconstricted with the thromboxane analogue U46619, were determined in response to acetylcholine, bradykinin, the calcium ionophore A23187, adenosine, and sodium nitroprusside. Microvascular relaxations to bradykinin and A23187 were reduced in atherosclerotic monkeys compared with controls, whereas acetylcholine produced additional contraction in atherosclerotic monkeys. Responses of preconstricted microvessels to adenosine and sodium nitroprusside were identical in atherosclerotic and control animals. Indomethacin did not alter responses in control or atherosclerotic animals. Histologic examination revealed neither intimal thickening nor plaque formation in microvessels of this size class despite marked changes in conduit arteries. Electron microscopy showed minor alterations of endothelial cell morphology in microvessels of atherosclerotic animals. In conclusion, long-term hypercholesterolemia markedly impairs endothelium-dependent vascular relaxation in the coronary microcirculation where overt atherosclerosis does not develop. These changes in endothelial cell function may significantly alter regulation of myocardial perfusion by neurohumoral stimuli.
    Matched MeSH terms: Acetylcholine/pharmacology
  19. Fulltext Enhanced Contextual Fear Memory and Elevated Astroglial Glutamate Synthase Activity in Hippocampal CA1 BChE shRNA Knockdown Mice
    Chen S, Lin Z, Tan KL, Chen R, Su W, Zhao H, et al.
    Front Psychiatry, 2020;11:564843.
    PMID: 33061920 DOI: 10.3389/fpsyt.2020.564843
    Butyrylcholinesterase (BChE) efficiently hydrolyzes acetylcholine (ACh) at high concentrations when acetylcholinesterase (AChE) is substrate-inhibited. Recent studies have shown that BChE also has a function that is independent of ACh, but it has not been fully explored. Low BChE expression is accompanied with higher stress-induced aggression and ghrelin levels in stress models, and BChE knockout mice exhibit cognitive and memory impairments. However, the role of BChE in posttraumatic stress disorder (PTSD) remains unclear. In the present study, we investigated the role of BChE in contextual fear memory and its regulatory effect on the expression of factors related to the glutamate (Glu)-glutamine (Gln) cycle via knockdown studies. We used AAVs and lentiviruses to knockdown BChE expression in the mouse hippocampal CA1 region and C8D1A astrocytes. Our behavioral data from those mice injected with AAV-shBChE in the hippocampal CA1 region showed strengthened fear memory and increased dendritic spine density. Elevated Glu levels and glutamine synthetase (GS) enzyme activity were detected in contextual fear conditioned-BChE knockdown animals and astrocytes. We observed that an AAV-shBChE induced lowering of BChE expression in the hippocampus CA1 region enhanced contextual fear memory expression and promoted the astrocytic Glu-Gln cycle but did not elevate ACh-hydrolyzing activity. This study provides new insight into the regulatory role of BChE in cognition and suggests potential target for stress-related psychiatric disorder such as PTSD where patients experience fear after exposure to severe life-threatening traumatic events.
    Matched MeSH terms: Acetylcholine; Acetylcholinesterase
  20. Fulltext Enhanced memory in Wistar rats by virgin coconut oil is associated with increased antioxidative, cholinergic activities and reduced oxidative stress
    Rahim NS, Lim SM, Mani V, Abdul Majeed AB, Ramasamy K
    Pharm Biol, 2017 Dec;55(1):825-832.
    PMID: 28118770 DOI: 10.1080/13880209.2017.1280688
    CONTEXT: Virgin coconut oil (VCO) has been reported to possess antioxidative, anti-inflammatory and anti-stress properties.

    OBJECTIVE: Capitalizing on these therapeutic effects, this study investigated for the first time the potential of VCO on memory improvement in vivo.

    MATERIALS AND METHODS: Thirty male Wistar rats (7-8 weeks old) were randomly assigned to five groups (n = six per group). Treatment groups were administered with 1, 5 and 10 g/kg VCO for 31 days by oral gavages. The cognitive function of treated-rats were assessed using the Morris Water Maze Test. Brains were removed, homogenized and subjected to biochemical analyses of acetylcholine (ACh) and acetylcholinesterase (AChE), antioxidants [superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx) and glutathione reductase (GRx)], lipid peroxidase [malondialdehyde (MDA)] as well as nitric oxide (NO). α-Tocopherol (αT; 150 mg/kg) was also included for comparison purposes.

    RESULTS: VCO-fed Wistar rats exhibited significant (p  33%) and NO (≥ 34%). Overall, memory improvement by VCO was comparable to αT.

    DISCUSSION AND CONCLUSION: VCO has the potential to be used as a memory enhancer, the effect of which was mediated, at least in part, through enhanced cholinergic activity, increased antioxidants level and reduced oxidative stress.

    Matched MeSH terms: Acetylcholine/analysis
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