Centhaquin antinociception in mice is mediated by α2A- and α2B- but not α2C-adrenoceptors

Bhalla, Shaifali; Ali, Izna; Andurkar, Shridhar V.; Gulati, Anil

doi:10.1016/j.ejphar.2013.05.004

Cited by 13 publications

(5 citation statements)

References 57 publications

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“…It leads to a significant improvement in CO and MAP after resuscitation ( Figure 1 ). It also acts on the α2A ARs in the brain to produce sympathetic actions, causes dilation of arteries, and reduces the SVR ( Bhalla et al, 2013 ) along with increasing tissue perfusion. Moreover, CQ has shown no significant binding to β-adrenergic receptors, and thus chances of producing arrhythmia are meager.…”

Section: Development Of Centhaquine An α-2 Agonist As a Resuscitative...mentioning

confidence: 99%

Role of adrenergic receptors in shock

Geevarghese¹,

Patel

Gulati

et al. 2023

Front. Physiol.

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Shock is a severe, life-threatening medical condition with a high mortality rate worldwide. All four major categories of shock (along with their various subtypes)—hypovolemic, distributive, cardiogenic, and obstructive, involve a dramatic mismatch between oxygen supply and demand, and share standard features of decreased cardiac output, reduced blood pressure, and overall hypoperfusion. Immediate and appropriate intervention is required regardless of shock type, as a delay can result in cellular dysfunction, irreversible multiple organ failure, and death. Studies have shown that dysfunction and downregulation of adrenergic receptors (ARs) are often implicated in these shock conditions; for example, their density is shown to be decreased in hypovolemic and cardiogenic shock, while their reduced signaling in the brain and vasculature decrease blood perfusion and oxygen supply. There are two main categories of ARs, α, and β, each with its subtypes and distributions. Our group has demonstrated that a dose of .02 mg/kg body wt of centhaquine (CQ) specifically activates α2B ARs on venous circulation along with the central α2A ARs after hypovolemic/hemorrhagic shock. Activating these receptors by CQ increases cardiac output (CO) and reduces systemic vascular resistance (SVR), with a net increase in blood pressure and tissue perfusion. The clinical trials of CQ conducted by Pharmazz Inc. in India have demonstrated significantly improved survival in shock patients. CQ improved blood pressure and shock index, indicating better blood circulation, and reduced lactate levels in the blood compared to in-use standard resuscitative agents. After successful clinical trials, CQ is being marketed as a drug (Lyfaquin®) for hypovolemic/hemorrhagic shock in India, and United States FDA has approved the phase III IND application. It is anticipated that the phase III trial in the United States will begin in 2023. Thus, we have demonstrated that α2 ARs could be suitable targets for treating or managing hypovolemic/hemorrhagic shock. Further understanding of ARs in shock would help find new potential pharmacological targets.

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Section: Development Of Centhaquine An α-2 Agonist As a Resuscitative...mentioning

confidence: 99%

Role of adrenergic receptors in shock

Geevarghese¹,

Patel

Gulati

et al. 2023

Front. Physiol.

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“…(DSS 1 BRL 3 1 CLO 3). The dose of BRL 44408 was selected based on literature data (Bhalla et al, 2013).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of 2A-Adrenoceptors Ameliorates Dextran Sulfate Sodium-Induced Acute Intestinal Inflammation in Mice

Zádori

Tóth

Fehér

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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It has been hypothesized that a 2 -adrenoceptors (a 2 -ARs) may be involved in the pathomechanism of colitis; however, the results are conflicting because both aggravation and amelioration of colonic inflammation have been described in response to a 2 -AR agonists.Therefore, we aimed to analyze the role of a 2 -ARs in acute murine colitis. The experiments were carried out in wild-type, a 2A -, a 2B -, and a 2C -AR knockout (KO) C57BL/6 mice. Colitis was induced by dextran sulfate sodium (DSS, 2%); alpha 2 -AR ligands were injected i.p. The severity of colitis was determined both macroscopically and histologically. Colonic myeloperoxidase (MPO) and cytokine levels were measured by enzyme-linked immunosorbent assay and proteome profiler array, respectively. The nonselective a 2 -AR agonist clonidine induced a modest aggravation of DSSinduced colitis. It accelerated the disease development and markedly enhanced the weight loss of animals, but did not influence the colon shortening, tissue MPO levels, or histologic score. Clonidine induced similar changes in a 2B -and a 2C -AR KO mice, whereas it failed to affect the disease activity index scores and caused only minor weight loss in a 2A -AR KO animals. In contrast, selective inhibition of a 2A -ARs by BRL 44408 significantly delayed the development of colitis; reduced the colonic levels of MPO and chemokine (C-C motif) ligand 3, chemokine (C-X-C motif) ligand 2 (CXCL2), CXCL13, and granulocytecolony stimulating factor; and elevated that of tissue inhibitor of metalloproteinases-1. In this work, we report that activation of a 2 -ARs aggravates murine colitis, an effect mediated by the a 2A -AR subtype, and selective inhibition of these receptors reduces the severity of gut inflammation.

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“…vascular tissues) and centrally only in the spinal cord and thalamus. Consistent with this expression pattern, the phenotypes of α2B-adrenoceptor knockout mouse were described with respect to physiological parameters such as blood pressure (Bhalla et al 2013). Only recently, it was shown that the α2Badrenoceptor is more widely expressed in the brain and a role in gating and filtering of incoming sensory information has been suggested based on the behavioral phenotype of the knockout mice (Luhrs et al 2016).…”

Section: Discussionmentioning

confidence: 72%

Dissociable contributions of the amygdala to the immediate and delayed effects of emotional arousal on memory

Schuemann

Sommer

2018

Preprint

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Emotionally arousal enhances memory encoding and consolidation leading to better immediate and delayed memory. Although the central noradrenergic system and the amygdala play critical roles in both effects of emotional arousal, we have recently shown that these effects are at least partly independent of each other, suggesting distinct underlying neural mechanisms.Here we aim to dissociate the neural substrates of both effects in 70 female participants using an emotional memory paradigm to investigate how neural activity, as measured by fMRI, and a polymorphism in the α2B-noradrenoceptor vary for these effects. To also test whether the immediate and delayed effects of emotional arousal on memory are stable traits, we invited back participants who were a part of a large-scale behavioral memory study about 3.5 years ago. We replicated the low correlation of the immediate and delayed emotional enhancement of memory across participants (r = 0.16) and observed, moreover, that only the delayed effect was, to some degree, stable over time (r = 0.23). Bilateral amygdala activity, as well as its coupling with the visual cortex and the fusiform gyrus, was related to the preferential encoding of emotional stimuli, which is consistent with affect-biased attention. Moreover, the adrenoceptor genotype modulated the bilateral amygdala activity associated with this effect. The left amygdala and its coupling with the hippocampus was specifically associated with the more efficient consolidation of emotional stimuli, which is consistent with amygdalar modulation of hippocampal consolidation.

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Centhaquin antinociception in mice is mediated by α2A- and α2B- but not α2C-adrenoceptors

Cited by 13 publications

References 57 publications

Role of adrenergic receptors in shock

Role of adrenergic receptors in shock

Inhibition of 2A-Adrenoceptors Ameliorates Dextran Sulfate Sodium-Induced Acute Intestinal Inflammation in Mice

Dissociable contributions of the amygdala to the immediate and delayed effects of emotional arousal on memory

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