المؤلفون: Chandrakant P Suryawanshi, Dr. R. D. Wagh

مصطلحات موضوعية: Anthracene, Parkinson's Ailment, Oxotremorine, Tremor, Procyclidine

الوصف: Parkinson’s ailment is especially outstanding from other situations based totally on the vital function of tremors. Oxotremorine-triggered oxidative pressure is a commonplace pathway in growing Parkinson’s signs like tremors, salivation, and temperature version. Subsequently, the Oxotremorine-precipitated tremor version changed used to assess Antiparkinsonian tablets. Distinct Anthraquinones derivatives compound 1 to16 have been formulated using appropriate schemes 1to 4 to investigate the Antiparkinsonian impact on Oxotremorine- brought on Parkinson’s symptoms in mice. Procyclidine, an anticholinergic, Antiparkinsonian drug was administered as a generic drug at a dose of 5 mg/kg p. o., 1hr prior to the administration of Oxotremorine (0.5 mg/kg) S.C. Numerous synthetic Anthraquinones compounds administered 200 mg/kg p. o. route of administration to reduce Parkinson’s symptoms. This look at indicates synthetic Anthraquinones compounds 1, 2, 6, eight, 12, and 14 show marked response to Parkinsonism symptoms compared to Procyclidine. From this research it is always worthy to synthesize various novel amino Anthraquinones compounds by considering Carboxamide linkage with various heterocyclic compounds as a neuroprotective agent helpful in PA.

العلاقة: https://zenodo.org/communities/iajprTest; https://zenodo.org/record/7686984Test; https://doi.org/10.5281/zenodo.7686984Test; oai:zenodo.org:7686984

الإتاحة: https://doi.org/10.5281/zenodo.7686984Test
https://doi.org/10.5281/zenodo.7686983Test
https://zenodo.org/record/7686984Test

المؤلفون: Scordino, Miriana, Frinchi, Monica, Urone, Giulia, Nuzzo, Domenico, Mudo, Giuseppa, Di Liberto, Valentina

المساهمون: Scordino, Miriana, Frinchi, Monica, Urone, Giulia, Nuzzo, Domenico, Mudo, Giuseppa, Di Liberto, Valentina

مصطلحات موضوعية: oxotremorine, superoxide dismutase, muscarinic acetylcholine receptor, KNK437, neuroprotection, heat shock protein

الوصف: The differentiation of neural progenitors is a complex process that integrates different signals to drive transcriptional changes, which mediate metabolic, electrophysiological, and morphological cellular specializations. Understanding these adjustments is essential within the framework of stem cell and cancer research and therapy. Human neuroblastoma SH-SY5Y cells, widely used in neurobiology research, can be differentiated into neuronal-like cells through serum deprivation and retinoic acid (RA) supplementation. In our study, we observed that the differentiation process triggers the expression of Heat Shock Protein 70 (HSP70). Notably, inhibition of HSP70 expression by KNK437 causes a dramatic increase in cell death. While undifferentiated SH-SY5Y cells show a dose-dependent decrease in cell survival following exposure to hydrogen peroxide (H2O2), differentiated cells become resistant to H2O2-induced cell death. Interestingly, the differentiation process enhances the expression of SOD1 protein, and inhibition of HSP70 expression counteracts this effect and increases the susceptibility of differentiated cells to H2O2-induced cell death, suggesting that the cascade HSP70-SOD1 is involved in promoting survival against oxidative stress-dependent damage. Treatment of differentiated SH-SY5Y cells with Oxotremorine-M (Oxo), a muscarinic acetylcholine receptor agonist, enhances the expression of HSP70 and SOD1 and counteracts tert-Butyl hydroperoxide-induced cell death and reactive oxygen species (ROS) generation. It is worth noting that co-treatment with KNK437 reduces SOD1 expression and Oxo-induced protection against oxidative stress damage, suggesting the involvement of HSP70/SOD1 signaling in this beneficial effect. In conclusion, our findings demonstrate that manipulation of the HSP70 signal modulates SH-SY5Y differentiation and susceptibility to oxidative stress-dependent cell death and unravels novel mechanisms involved in Oxo neuroprotective functions. Altogether these data provide novel insights into the ...

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/36978935; info:eu-repo/semantics/altIdentifier/wos/WOS:000952904100001; volume:12; issue:3; firstpage:1; lastpage:17; numberofpages:17; journal:ANTIOXIDANTS; https://hdl.handle.net/10447/590711Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85151371751; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10045076Test/

الإتاحة: https://doi.org/10.3390/antiox12030687Test
https://hdl.handle.net/10447/590711Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10045076Test/

المؤلفون: Miriana Scordino, Monica Frinchi, Giulia Urone, Domenico Nuzzo, Giuseppa Mudò, Valentina Di Liberto

المصدر: Antioxidants; Volume 12; Issue 3; Pages: 687

مصطلحات موضوعية: oxotremorine, muscarinic acetylcholine receptor, KNK437, neuroprotection, heat shock proteins, superoxide dismutase

جغرافية الموضوع: agris

الوصف: The differentiation of neural progenitors is a complex process that integrates different signals to drive transcriptional changes, which mediate metabolic, electrophysiological, and morphological cellular specializations. Understanding these adjustments is essential within the framework of stem cell and cancer research and therapy. Human neuroblastoma SH-SY5Y cells, widely used in neurobiology research, can be differentiated into neuronal-like cells through serum deprivation and retinoic acid (RA) supplementation. In our study, we observed that the differentiation process triggers the expression of Heat Shock Protein 70 (HSP70). Notably, inhibition of HSP70 expression by KNK437 causes a dramatic increase in cell death. While undifferentiated SH-SY5Y cells show a dose-dependent decrease in cell survival following exposure to hydrogen peroxide (H2O2), differentiated cells become resistant to H2O2-induced cell death. Interestingly, the differentiation process enhances the expression of SOD1 protein, and inhibition of HSP70 expression counteracts this effect and increases the susceptibility of differentiated cells to H2O2-induced cell death, suggesting that the cascade HSP70-SOD1 is involved in promoting survival against oxidative stress-dependent damage. Treatment of differentiated SH-SY5Y cells with Oxotremorine-M (Oxo), a muscarinic acetylcholine receptor agonist, enhances the expression of HSP70 and SOD1 and counteracts tert–Butyl hydroperoxide-induced cell death and reactive oxygen species (ROS) generation. It is worth noting that co-treatment with KNK437 reduces SOD1 expression and Oxo-induced protection against oxidative stress damage, suggesting the involvement of HSP70/SOD1 signaling in this beneficial effect. In conclusion, our findings demonstrate that manipulation of the HSP70 signal modulates SH-SY5Y differentiation and susceptibility to oxidative stress-dependent cell death and unravels novel mechanisms involved in Oxo neuroprotective functions. Altogether these data provide novel insights into the ...

وصف الملف: application/pdf

العلاقة: https://dx.doi.org/10.3390/antiox12030687Test

الإتاحة: https://doi.org/10.3390/antiox12030687Test

المؤلفون: Zwart, Ruud¹ zwart_ruud@lilly.com, Reed, Hannah¹, Sher, Emanuele¹

المصدر: Biochemical & Biophysical Research Communications. Jan2018, Vol. 495 Issue 1, p481-486. 6p.

مصطلحات موضوعية: *METHYL aspartate receptors, *OXOTREMORINE, *MUSCARINIC acetylcholine receptors, *NEUROPLASTICITY, *HIPPOCAMPUS (Brain)

مستخلص: Muscarinic acetylcholine M1 receptors play an important role in synaptic plasticity in the hippocampus and cortex. Potentiation of NMDA receptors as a consequence of muscarinic acetylcholine M1 receptor activation is a crucial event mediating the cholinergic modulation of synaptic plasticity, which is a cellular mechanism for learning and memory. In Alzheimer's disease, the cholinergic input to the hippocampus and cortex is severely degenerated, and agonists or positive allosteric modulators of M1 receptors are therefore thought to be of potential use to treat the deficits in cognitive functions in Alzheimer's disease. In this study we developed a simple system in which muscarinic modulation of NMDA receptors can be studied in vitro . Human M1 receptors and NR1/2B NMDA receptors were co-expressed in Xenopus oocytes and various muscarinic agonists were assessed for their modulatory effects on NMDA receptor-mediated responses. As expected, NMDA receptor-mediated responses were potentiated by oxotremorine-M, oxotremorine or xanomeline when the drugs were applied between subsequent NMDA responses, an effect which was fully blocked by the muscarinic receptor antagonist atropine. However, in oocytes expressing NR1/2B NMDA receptors but not muscarinic M1 receptors, oxotremorine-M co-applied with NMDA also resulted in a potentiation of NMDA currents and this effect was not blocked by atropine, demonstrating that oxotremorine-M is able to directly potentiate NMDA receptors. Oxotremorine, which is a close analogue of oxotremorine-M, and xanomeline, a chemically distinct muscarinic agonist, did not potentiate NMDA receptors by this direct mechanism. Comparing the chemical structures of the three different muscarinic agonists used in this study suggests that the tri-methyl ammonium moiety present in oxotremorine-M is important for the compound's interaction with NMDA receptors. [ABSTRACT FROM AUTHOR]

المؤلفون: Zwart, Ruud¹ zwart_ruud@lilly.com, Reed, Hannah¹, Clarke, Sophie¹, Sher, Emanuele¹

المصدر: European Journal of Pharmacology. Nov2016, Vol. 791, p221-228. 8p.

مصطلحات موضوعية: *MUSCARINIC acetylcholine receptors, *OXOTREMORINE, *POTASSIUM antagonists, *RESPONSE inhibition, *THIADIAZOLES, *PHARMACOLOGY

مستخلص: Inhibition of KCNQ (Kv7) potassium channels by activation of muscarinic acetylcholine receptors has been well established, and the ion currents through these channels have been long known as M-currents. We found that this cross-talk can be reconstituted in Xenopus oocytes by co-transfection of human recombinant muscarinic M1 receptors and KCNQ2/3 potassium channels. Application of the muscarinic acetylcholine receptor agonist Oxotremorine-methiodide (Oxo-M) between voltage pulses to activate KCNQ2/3 channels caused inhibition of the subsequent KCNQ2/3 responses. This effect of Oxo-M was blocked by the muscarinic acetylcholine receptor antagonist atropine. We also found that KCNQ2/3 currents were inhibited when Oxo-M was applied during an ongoing KCNQ2/3 response, an effect that was not blocked by atropine, suggesting that Oxo-M inhibits KCNQ2/3 channels directly. Indeed, also in oocytes that were transfected with only KCNQ2/3 channels, but not with muscarinic M1 receptors, Oxo-M inhibited the KCNQ2/3 response. These results show that besides the usual muscarinic acetylcholine receptor-mediated inhibition, Oxo-M also inhibits KCNQ2/3 channels by a direct mechanism. We subsequently tested xanomeline, which is a chemically distinct muscarinic acetylcholine receptor agonist, and oxotremorine, which is a close analogue of Oxo-M. Both compounds inhibited KCNQ2/3 currents via activation of M1 muscarinic acetylcholine receptors but, in contrast to Oxo-M, they did not directly inhibit KCNQ2/3 channels. Xanomeline and oxotremorine do not contain a positively charged trimethylammonium moiety that is present in Oxo-M, suggesting that such a charged moiety could be a crucial component mediating this newly described direct inhibition of KCNQ2/3 channels. [ABSTRACT FROM AUTHOR]

المؤلفون: Tian, Lin¹, Qin, Xingna¹, Sun, Jinling¹, Li, Xinwang¹ lixw701@sina.cn, Wei, Li² 18930173636@189.cn

المصدر: Pharmacology, Biochemistry & Behavior. Mar2016, Vol. 142, p56-63. 8p.

مصطلحات موضوعية: *OXOTREMORINE, *DRUG administration, *IMPULSIVE personality, *LABORATORY rats, *ACETYLCHOLINE, *DOPAMINERGIC mechanisms

مستخلص: The effect of acetylcholine on impulsive choice is thought to be due to interactions between cholinergic and dopaminergic systems, but this hypothesis has not been proven. This study investigated whether D 1 -like receptors were involved in the effects of the muscarinic cholinergic agonist oxotremorine on impulsive choice in high-impulsive rats (HI rats, n = 8) and low-impulsive rats (LI rats, n = 8) characterized by basal levels of impulsive choice in a delay-discounting task. The results revealed that oxotremorine (0.05 mg/kg) significantly increased the choice of the large reinforcer in HI rats, whereas decreased the choice of the large reinforcer in LI rats. The D 1 -like antagonist SCH 23390 produced significant reductions in the large-reinforcer choice in HI rats (0.01 mg/kg) and LI rats (0.005, 0.0075, and 0.01 mg/kg). SCH 23390 significantly inhibited the increase in the choice of the large reinforcer induced by oxotremorine (0.05 mg/kg) in HI rats at doses of 0.005 and 0.0075 mg/kg, but enhanced the effect of oxotremorine in LI rats only at the dose of 0.0075 mg/kg. These findings suggested that D 1 -like receptors might be involved in the differential effects of oxotremorine on impulsive choice between HI rats and LI rats. [ABSTRACT FROM AUTHOR]

المؤلفون: Hu, Li, He, Fengli, Huang, Meifeng, Zhao, Qian, Cheng, Lamei, Said, Neveen, Zhou, Zhiguang, Liu, Feng, Dai, Yan-Shan

المصدر: Scientific Reports; 10/16/2020, Vol. 10 Issue 1, p1-10, 10p

مصطلحات موضوعية: INSULIN, GLUCOSE, OXOTREMORINE, MUSCARINIC receptors, PHOSPHATIDYLINOSITOL 3-kinases

مستخلص: SPARC-deficient mice have been shown to exhibit impaired glucose tolerance and insulin secretion, but the underlying mechanism remains unknown. Here, we showed that SPARC enhanced the promoting effect of Muscarinic receptor agonist oxotremorine-M on insulin secretion in cultured mouse islets. Overexpression of SPARC down-regulated RGS4, a negative regulator of β-cell M3 muscarinic receptors. Conversely, knockdown of SPARC up-regulated RGS4 in Min6 cells. RGS4 was up-regulated in islets from sparc −/− mice, which correlated with decreased glucose-stimulated insulin secretion (GSIS). Furthermore, inhibition of RGS4 restored GSIS in the islets from sparc −/− mice, and knockdown of RGS4 partially decreased the promoting effect of SPARC on oxotremorine-M-stimulated insulin secretion. Phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 abolished SPARC-induced down-regulation of RGS4. Taken together, our data revealed that SPARC promoted GSIS by inhibiting RGS4 in pancreatic β cells. [ABSTRACT FROM AUTHOR]

: Copyright of Scientific Reports is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Volpato, Daniela, Kauk, Michael, Messerer, Regina, Bermudez, Marcel, Wolber, Gerhard, Bock, Andreas, Hoffmann, Carsten, Holzgrabe, Ulrike

مصطلحات موضوعية: allosteric modulators, acetylcholine-receptors, molecular-mechanisms, alzheimers-disease, agonist, binding, site, oxotremorine, ddc:570

الوصف: The muscarinic M-1 acetylcholine receptor is an important drug target for the treatment of various neurological disorders. Designing M-1 receptor-selective drugs has proven challenging, mainly due to the high conservation of the acetylcholine binding site among muscarinic receptor subtypes. Therefore, less conserved and topographically distinct allosteric binding sites have been explored to increase M-1 receptor selectivity. In this line, bitopic ligands, which target orthosteric and allosteric binding sites simultaneously, may provide a promising strategy. Here, we explore the allosteric, M-1-selective BQCAd scaffold derived from BQCA as a starting point for the design, synthesis, and pharmacological evaluation of a series of novel bitopic ligands in which the orthosteric moieties and linker lengths are systematically varied. Since beta-arrestin recruitment seems to be favorable to therapeutic implication, all the compounds were investigated by G protein and beta-arrestin assays. Some bitopic ligands are partial to full agonists for G protein activation, some activate beta-arrestin recruitment, and the degree of beta-arrestin recruitment varies according to the respective modification. The allosteric BQCAd scaffold controls the positioning of the orthosteric ammonium group of all ligands, suggesting that this interaction is essential for stimulating G protein activation. However, beta-arrestin recruitment is not affected. The novel set of bitopic ligands may constitute a toolbox to study the requirements of beta-arrestin recruitment during ligand design for therapeutic usage.

وصف الملف: 10 Seiten; application/pdf

العلاقة: https://refubium.fu-berlin.de/handle/fub188/29529Test; http://dx.doi.org/10.17169/refubium-29273Test

الإتاحة: https://doi.org/10.17169/refubium-29273Test
https://doi.org/10.1021/acsomega.0c04220Test
https://refubium.fu-berlin.de/handle/fub188/29529Test

المؤلفون: Floody, Owen R.¹ ofloody@bucknell.edu

المصدر: Pharmacology, Biochemistry & Behavior. Sep2013, Vol. 110, p75-88. 14p.

مصطلحات موضوعية: *OXOTREMORINE, *SCOPOLAMINE, *HAMSTERS as laboratory animals, *ACETYLCHOLINE, *MUSCARINIC agents, *PLACEBOS, *THERAPEUTICS

مستخلص: Abstract: Acetylcholine (ACh) has not been tested for a role in the development of sexual exhaustion in males. However, male hamsters receiving infusions into the medial preoptic area (MPOA) of the muscarinic agonist oxotremorine (OXO) or antagonist scopolamine (SCO) show changes in the postejaculatory interval, one of the measures that changes most consistently as exhaustion approaches. In addition, central SCO treatments cause changes in the patterning of intromissions that resemble those signaling exhaustion. To extend these observations and more thoroughly test the dependence of sexual exhaustion on ACh, male hamsters received MPOA treatments of OXO, SCO or the combination of the two before mating to exhaustion. Relative to placebo, OXO infusions caused small but consistent increases in ejaculation frequency and long intromission latency, delaying the appearance of exhaustion. Scopolamine treatments did the reverse, dramatically accelerating the development of exhaustion. Consistent with and possibly responsible for these changes were effects on the quality of performance prior to exhaustion. These included differences in overall copulatory efficiency (e.g., ejaculations/intromission), which was increased by OXO and decreased by SCO. They also extended to several standard measures of copulatory behavior, including intromission frequency, ejaculation latency and the postejaculatory interval: Most of these were increased by SCO and decreased by OXO. Finally, whereas most or all effects of OXO were counteracted by SCO, most or all of the responses to SCO resisted change by added OXO. This asymmetry in the responses to combined treatment raises the possibility that the effects of these drugs on sexual exhaustion and other elements of male behavior are mediated by distinct muscarinic receptors. [Copyright &y& Elsevier]

المؤلفون: Paulina Valuskova, Vladimir Riljak, Sandor T. Forczek, Vladimir Farar, Jaromir Myslivecek

المصدر: Frontiers in Pharmacology, Vol 10 (2019)

مصطلحات موضوعية: M4 muscarinic receptor, biorhythm, motor activity, temperature, scopolamine, oxotremorine, Therapeutics. Pharmacology, RM1-950

الوصف: Mice are nocturnal animals. Surprisingly, the majority of physiological/pharmacological studies are performed in the morning, i.e., in the non-active phase of their diurnal cycle. We have shown recently that female (not male) mice lacking the M4 muscarinic receptors (MR, M4KO) did not differ substantially in locomotor activity from their wild-type counterparts (C57Bl/6Tac) during the inactive period. Increased locomotion has been shown in the active phase of their diurnal cycle. We compared the effects of scopolamine, oxotremorine, and cocaine on locomotor response, hypothermia and spontaneous behavior in the open field arena in the morning (9:00 AM) and in the evening (9:00 PM) in WT and in C57Bl/6NTac mice lacking the M4 MR. Furthermore, we also studied morning vs. evening densities of muscarinic, GABAA, D1-like, D2-like, NMDA and kainate receptors using autoradiography in the motor, somatosensory and visual cortex and in the striatum, thalamus, hippocampus, pons, and medulla oblongata. At 9:00 AM, scopolamine induced an increase in motor activity in WT and in M4KO, yet no significant increase was observed at 9:00 PM. Oxotremorine induced hypothermic effects in both WT and M4KO. Hypothermic effects were more evident in WT than in M4KO. Hypothermia in both cases was more pronounced at 9:00 AM than at 9:00 PM. Cocaine increased motor activity when compared to saline. There was no difference in behavior in the open field between WT and M4KO when tested at 9:00 AM; however, at 9:00 PM, activity of M4KO was doubled in comparison to that of WT. Both WT and KO animals spent less time climbing in their active phase. Autoradiography revealed no significant morning vs. evening difference. Altogether, our results indicate the necessity of comparing morning vs. evening drug effects

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/article/10.3389/fphar.2019.00237/fullTest; https://doaj.org/toc/1663-9812Test

الوصول الحر: https://doaj.org/article/c14be0b6d896421c97864d1fc954c36eTest