Involvement of selective GABA-A receptor subtypes in amelioration of cisplatin-induced neuropathic pain by 2’-chloro-6-methyl flavone (2’-Cl-6MF)

Khan, Imran; Abdelhalim, Abeer; Halim, Sobia Ahsan; Khan, Ajmal; Altaf, Nouman; Ahmad, Waqar; Ghaffar, Rukhsana; Al‐Harrasi, Ahmed

doi:10.1007/s00210-020-02021-x

Cited by 3 publications

(5 citation statements)

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“…On the other hand, pain behavior is also mediated by GABAergic neurons and receptors . Both the NLX (all doses) and PTZ (at the highest dose) blocked the antinociceptive response of the ID, indicating that its antinociceptive response is being mediated by the mechanisms involving opioidergic and GABAergic pathways . We have conducted standard tests regarding the mechanism of action, i.e., antagonism with naloxone (NLX) and antagonism with PTZ.…”

Section: Resultsmentioning

confidence: 99%

“…Since an unknown era, fever has been an essential feature or an indication of the presence of many diseases. The feverish response is controlled by the central nervous system through a multitude of mechanisms. , Fever is mostly accompanied by an ailing state and negative changes in bodily functions, including the immune system. Fever, therefore, is a major determinant of pathogenesis of many illnesses.…”

Section: Resultsmentioning

confidence: 99%

“… 43 Both the NLX (all doses) and PTZ (at the highest dose) blocked the antinociceptive response of the ID, indicating that its antinociceptive response is being mediated by the mechanisms involving opioidergic and GABAergic pathways. 44 We have conducted standard tests regarding the mechanism of action, i.e., antagonism with naloxone (NLX) and antagonism with PTZ. These tests are considered standard because they are well-established and widely used in preclinical research to assess the involvement of these neurotransmitter systems in various physiological and behavioral responses.…”

Section: Resultsmentioning

confidence: 99%

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Involvement of the Opioidergic Mechanism in the Analgesic Potential of a Novel Indazolone Derivative: Efficacy in the Management of Pain, Neuropathy, and Inflammation Using In Vivo and In Silico Approaches

et al. 2023

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Indazolones possess interesting pharmacological activities. The search for indazole and indazolone-containing nuclei as drugs is an important research area of medicinal chemistry. The current work aims to evaluate a novel indazolone derivative against in vivo and in silico targets of pain, neuropathy, and inflammation. An indazolone derivative (ID) was synthesized and characterized using advanced spectroscopic techniques. Well-established animal models of abdominal constriction, hot plate, tail immersion, carrageenan paw edema, and Brewer's yeast-induced pyrexia were employed for evaluating the potential of the ID at different doses (20−60 mg kg −1 ). Nonselective GABA antagonists, opioid antagonist naloxone (NLX) and pentylenetetrazole (PTZ), were employed to assess the potential role of GABAergic and opioidergic processes. The antineuropathic potential of the drug was evaluated using a vincristine-induced neuropathic pain model. In silico studies were performed to assess any possible interactions of the ID with pain target sites like cyclooxygenases (COX-I/II), GABA A , and opioid receptors. This study revealed that the selected ID (doses of 20−60 mg kg −1 ) efficiently hampered chemically and thermally induced nociceptive responses, producing significant anti-inflammatory and antipyretic effects. These effects produced by the ID were dose-dependent (i.e., 20−60 mg kg −1 and p range of 0.001−0.01) and significant in comparison to standards (p < 0.001). Antagonistic studies with NLX (1.0 mg kg −1 ) and PTZ (15.0 mg kg −1 ) revealed the involvement of the opioidergic mechanism rather than the GABAergic mechanism. The ID showed promising anti-static allodynia effects as well. In silico studies revealed preferential binding interactions of the ID with cyclooxygenases (COX-I/II), GABA A , and opioid receptors. According to the results of the current investigation, the ID may serve in the future as a therapeutic agent for the treatment of pyrexia, chemotherapy-induced neuropathic pain, and nociceptive inflammatory pain.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Involvement of the Opioidergic Mechanism in the Analgesic Potential of a Novel Indazolone Derivative: Efficacy in the Management of Pain, Neuropathy, and Inflammation Using In Vivo and In Silico Approaches

et al. 2023

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“…Moreover drugs that enhance GABAergic neurotransmission such as pregabalin and gabapentin are commonly used in the treatment of different categories of neuropathy [ 27 ].The findings of the current study revealed a complete reversal of the protective effect of 3',4'-dihydroxyflavonewith bicuculline pre-treatment against paclitaxel induced neuropathic manifestations. Earlier studies have reported the anti-neuropathic effect of synthetic flavone compounds involving the a2 subunit containingGABA A receptors [ 11 , 13 ]. Thus, the present observation clearly demonstrates that the modulation of GABA A receptors plays an important role in the anti-neuropathic effect of 3',4'-dihydroxyflavone.…”

Section: Discussionmentioning

confidence: 99%

“…It is pertinent to mention that, flavone derivatives have been found to interact with several neurotransmitters and ion channels which are implicated in CIPN. Recently, studies have reported the anti-neuropathic effect of a synthetic flavone involving a2 subunit containing GABA A receptors in cisplatin model of peripheral neuropathy in mice [ 13 ]. Studies have also demonstrated the involvement of ion channels such as K V and K ATP channels in the induction of peripheral neuropathy with paclitaxel [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

3′, 4′-dihydroxyflavone ameliorates paclitaxel model of peripheral neuropathy in mice by modulating KATP channel, adenosine (A3) and GABAA (a2 subunit) receptors

Ramasamy

2023

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Paclitaxel is a widely used cancer chemotherapeutic agent for many solid tumors; but peripheral neuropathy is a major limitation for its clinical use. Studies have demonstrated the usefulness of flavone derivatives in chemotherapy induced peripheral neuropathy. The present study evaluates the anti-neuropathic effect of 3′, 4′-dihydroxyflavone on paclitaxel-induced peripheral neuropathy and the underlying mechanisms. Paclitaxel was administered to mice in a single dose of 10 mg/kg, i.p.The neuropathic behavioural parameters such as mechanical allodynia, cold allodynia and thermal hyperalgesia were assessed 24 h later. The test compound 3′, 4′-dihydroxyflavone (50,100 or 200 mg/kg,s.c) was administered 30 min prior to the assessment of behavioral parameters. The possible mechanisms involving KATP channels, adenosine and GABAA receptors were explored by employing suitable interacting drugs. Molecular docking studies to predict the binding interactions of 3′, 4′-dihydroxyflavone at the above targets were also carried out. The test compound 3′, 4′-dihydroxyflavoneexhibited a significant reduction in paw withdrawal response score in both mechanical and cold allodynia and also increased the tail flick response time in thermal hyperalgesia due to paclitaxel-induced neuropathy. The anti-neuropathic effect of 3′, 4′-dihydroxyflavonewas significantly reversed by pre-treatment with glibenclamide, caffeine or bicuculline revealing the involvement of KATP channels, adenosine and GABAA receptors respectively. Furthermore, the molecular docking studies indicated a favourable binding affinity and good H-bond interaction of 3′, 4′-dihydroxyflavone at these targets. The findings of the present study suggests that, 3′, 4′-dihydroxyflavone has anti-neuropathic effect against paclitaxel-induced peripheral neuropathy through mechanisms that involve KATP channels, adenosine (A3) and GABAA (α2 subunit) receptors.

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Anti-neuropathic effect of 7,3′-dihydroxyflavone in paclitaxel induced peripheral neuropathy in mice involving GABAA, KATP channel and adenosine receptors

Ramasamy

Shanmugasundaram

Rajesh

et al. 2022

Neurochemistry International

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Involvement of selective GABA-A receptor subtypes in amelioration of cisplatin-induced neuropathic pain by 2’-chloro-6-methyl flavone (2’-Cl-6MF)

Cited by 3 publications

References 35 publications

Involvement of the Opioidergic Mechanism in the Analgesic Potential of a Novel Indazolone Derivative: Efficacy in the Management of Pain, Neuropathy, and Inflammation Using In Vivo and In Silico Approaches

Involvement of the Opioidergic Mechanism in the Analgesic Potential of a Novel Indazolone Derivative: Efficacy in the Management of Pain, Neuropathy, and Inflammation Using In Vivo and In Silico Approaches

3′, 4′-dihydroxyflavone ameliorates paclitaxel model of peripheral neuropathy in mice by modulating KATP channel, adenosine (A3) and GABAA (a2 subunit) receptors

Anti-neuropathic effect of 7,3′-dihydroxyflavone in paclitaxel induced peripheral neuropathy in mice involving GABAA, KATP channel and adenosine receptors

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