Exploring the potential therapeutic benefits of 7-methoxy coumarin for neuropathy pain: an in vivo, in vitro, and in silico approach.

BACK GROUND: 7-Methoxycoumarin (7-MC) is well recognized for its anti-inflammatory and anti-nociceptive actions. Its capacity to lessen neuropathic pain hasn't been documented yet. Hence the impact of 7-MC on vincristine-induced peripheral neuropathic pain in rodents was investigated. The investigation also looked at the impact of 7-MC in reducing neuropathic pain via voltage-gated calcium channels and phospholipase enzyme inhibition using pertinent in vitro and in silico methods. METHODS AND RESULTS: Vincristine (0.1 mg/kg, i.p., daily) was administered continuously for 7 days to induce peripheral neuropathic pain in mice, with cold allodynia and thermal hyperalgesia and evaluated on the 8th day using the acetone bubble test and hot water tail immersion test. In order to derive the mechanistic approach for ameliorating neuropathic pain, the role of 7-MC in the inhibition of the phospholipase enzyme, gene expression studies on voltage-gated calcium channels using mouse BV2 microglial cells and in silico studies for its calcium channel binding affinity were also performed. The test compounds reduced vincristine-induced cold allodynia and thermal hyperalgesia in mice in a dose-dependent experiments. In vitro studies on phospholipase inhibition by 7-MC showed an IC50 of 27.08 µg/ml and down-regulated the gene expression of calcium channels in the BV2 microglial cell line. In silico docking scores for 7-MCwere higher than the standard drug gabapentin. CONCLUSION: The compound 7-MC has shown promise in alleviating vincristine-induced peripheral neuropathicin mice. Studies conducted in parallel, both in silico and in vitro have demonstrated that 7-MC effectively reduces neuropathic pain. This pain reduction is achieved through two mechanisms: inhibiting the phospholipase enzyme and blocking voltage-gated calcium channels.

3', 4'-dihydroxyflavone ameliorates paclitaxel model of peripheral neuropathy in mice by modulating KATP channel, adenosine (A3) and GABAA (α2 subunit) receptors.

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.

A Comprehensive Analysis of Phytochemical Composition, Acute Toxicity Assessment, and Antioxidant Potential of Ethanolic Extract of Carica Papaya Seeds.

BACKGROUND: Carica papaya seeds are rich in phytochemicals with potential health benefits, warranting safety and antioxidant assessments. This study comprehensively examined the ethanolic extract of Carica papaya seeds (EECPS) to elucidate its phytochemical composition, acute toxicity profile, and antioxidant activity. METHODS: Phytochemical analysis of EECPS revealed the presence of various bioactive compounds, including flavonoids, tannins, phenols, alkaloids, proteins, glycosides, and saponins. Additionally, the presence of sulfuric acid was confirmed. Acute toxicity assessment involved oral administration of EECPS at 2000mg/kg body weight to Wistar rats, with a 14-day observation period. General parameters, body weight changes, and histopathological examination of kidney and liver tissues were evaluated. Antioxidant activity was assessed using the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) assay, and the half-maximal inhibitory concentration (IC50) value of EECPS was compared to that of gallic acid. RESULTS: Phytochemical analysis confirmed the diverse composition of EECPS, suggesting its potential health benefits and biological activity. Acute toxicity assessment revealed no adverse effects, with rats exhibiting normal behavior, weight stability, and no histopathological abnormalities in vital organs. The gallic acid IC50 value was determined to be 5.73±0.02 µg/mL, indicating its antioxidant potency. EECPS exhibited antioxidant properties in a dose-dependent manner, with higher concentrations demonstrating increased DPPH free radical quenching capacity. The IC50 value for EECPS was calculated from the dose-response curve to be 39.41±1.61 µg/mL (expressed as mean ± standard error of the mean (SEM)). CONCLUSION: The phytochemical analysis of EECPS highlights its diverse composition and potential health benefits. Acute toxicity studies in rats confirm its safety for oral administration, with no adverse effects observed. EECPS exhibits significant antioxidant activity, as indicated by its IC50 value. These findings suggest that EECPS holds promise for therapeutic use and health applications. However, further research is needed to determine its precise antioxidant potential. Subchronic and chronic toxicity studies are recommended to establish its safety profile definitively and unlock its full potential for healthcare and nutrition.

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

Peripheral neuropathy induced by chemotherapeutic agents is the most common dose-limiting adverse effect observed in patients during and after treatment of malignancies. Many flavones have been reported to ameliorate neuropathy of different origin in experimental animals and their possible mode of action explored. The present study aims to investigate 7,3'-dihydroxyflavone for its anti-neuropathic effect against paclitaxel induced peripheral neuropathy in mice by employing behavioural tests such as mechanical allodynia, cold allodynia and thermal hyperalgesia. The possible involvement of GABAA, KATP channels and adenosine receptors in the anti-neuropathic effect of 7,3'-dihydroxyflavone was also studied by employing suitable interacting drugs. Treatment with 7,3'-dihydroxyflavone (50, 100 or 200 mg/kg, s.c) significantly and dose-dependently reduced the 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. Pre-treatment with glibenclamide (10 mg/kg, i.p), caffeine (50 mg/kg, i.p) or bicuculline (2 mg/kg, i.p) significantly reversed the anti-neuropathic effect of 7,3'-dihydroxyflavone in behavioral tests. In conclusion, the present investigation identified 7,3'-dihydroxyflavone as a potential candidate with anti-neuropathic effect against paclitaxel induced peripheral neuropathy involving KATP channels, adenosine and GABAA receptors.

Anxiolytic-like activity of 5-methoxyflavone in mice with involvement of GABAergic and serotonergic systems - in vivo and in silico evidences.

Anxiety disorders are common worldwide and novel compounds are investigated for anxiolytic effect. A few studies have demonstrated the anxiolytic-like activity of natural and synthetic flavonoids. 5-methoxyflavone, a synthetic flavone derivative, has been reported to exhibit central nervous system depressant (sedative-hypnotic) effect in an earlier study. The present study was designed to investigate whether 5-methoxyflavone possesses anxiolytic-like activity in mice by employing two unconditioned models of anxiety such as elevated plus maze and light-dark box test. The possible role played by GABAergic (GABAA) and serotonergic (5HT1A) systems in the anxiolytic-like effect of 5-methoxyflavone was also investigated in the elevated plus maze test. Molecular docking studies were performed to ascertain the interaction of 5-methoxyflavone with GABAA (α2 subunit-containing) and 5HT1A receptors. 5-methoxyflavone treatment in mice (10, 20 or 40 mg/kg, i.p) increased the number of entries and time spent in the open arms in an elevated plus maze (p < 0.001). In the light-dark box test a significant increase in the time spent in light compartment (p < 0.001) and prolonged latency to enter the dark compartment (p < 0.01) were also observed. Pretreatment of mice with 5HT1A antagonist pindolol (10 mg/kg, i.p) or GABAA antagonist bicuculline (2 mg/kg, i.p) significantly attenuated the effect of 5-methoxyflavone in the elevated plus maze test. In silico studies provided evidences for good binding affinity of 5-methoxyflavone towards GABAA (α2 subunit-containing) and serotonergic (5HT1A) receptors by H-bond interactions. In conclusion, the present study identified a novel anxiolytic-like effect of 5-methoxyflavone involving GABAergic and serotonergic mechanisms.

Antinociceptive effect of flavonol and a few structurally related dimethoxy flavonols in mice.

Previous reports suggest flavonoids as potent analgesic compounds. Based on these observations, the present study investigated the antinociceptive action of flavonol, 3', 4'-dimethoxy flavonol, 6, 3'-dimethoxy flavonol, 7, 2'-dimethoxy flavonol, and 7, 3'-dimethoxy flavonol and the possible mechanisms involved in these effects. The antinociceptive effect of the investigated compounds in doses of 25, 50, 100, and 200 mg/kg was evaluated in male Swiss albino mice using the acetic acid test, formalin-induced nociception, and hot water tail immersion test. The role of opioid, tryptaminergic, adrenergic, dopaminergic, GABAergic, and K+ATP channels in producing the antinociceptive effect was also studied using appropriate interacting agents. Treatment with flavonol and dimethoxy flavonols resulted in a significant reduction in the number of abdominal constrictions in the acetic acid test, a significant inhibition of the paw-licking/biting response time in both the phases of formalin nociception and also a significant increase in mean reaction time in the hot water tail immersion test. These observations revealed the antinociceptive effect of dimethoxy flavonols. The role of opioid, serotonergic (5HT3), and dopaminergic system was identified in the antinociceptive effect of flavonol and all dimethoxy derivatives investigated. In addition, the role of GABAergic, K+ATP channel, and α-2 adrenergic mechanisms were also observed in the antinociceptive action of some of the investigated compounds. The present study identified the antinociceptive effect of flavonol and dimethoxy flavonols in mice acting through different neuronal pathways.

Sedative-hypnotic like effect of 5-methoxyflavone in mice and investigation on possible mechanisms by in vivo and in silico methods.

Flavonoids have been shown to possess central nervous system (CNS) depressant effect mediated through the ionotropic GABAA receptors. In the present study, 5-methoxyflavone was evaluated for sedative-hypnotic like activity in mice and the mechanisms involved by employing a battery of tests including molecular docking studies. In the open field test, 5-methoxyflavone in various doses (50, 100 and 150 mg/kg, i.p) exhibited a significant and dose-dependent reduction in the spontaneous locomotor activity (F (530) = 87.17 P < 0.001). Pretreatment with 5-methoxyflavone decreased the latency to sleep induction after pentobarbitone or ether administration and also significantly increased the duration of sleep (p < 0.001). A significant and dose-dependent myorelaxant effect was observed with 5-methoxyflavone in the inclined plane, horizontal wire test and rota rod test. Pretreatment with picrotoxin, bicuculline, glycine, caffeine or NMDA either decreased or completely abolished the hypnotic effect of 5-methoxyflavone in mice. The above results revealed the involvement of GABAA, adenosine, glycine and NMDA receptors in the hypnotic effect of 5-methoxyflavone. The results of in silico studies indicated that, 5-methoxyflavone exhibits good binding affinity towards these receptors by H-bond interactions. In conclusion, the present study identified a novel and potential sedative-hypnotic like effect of 5-methoxyflavone involving multiple mechanisms.

Effect of certain trimethoxy flavones on paclitaxel - induced peripheral neuropathy in mice.

BACKGROUND: The anti - nociceptive effect of 7, 2', 3' - trimethoxy flavone, 7, 2', 4' - trimethoxy flavone, 7, 3', 4' - trimethoxy flavone and 7, 5, 4' - trimethoxy flavone against inflammatory, neurogenic and thermal pain in mice was reported earlier. The present study was designed to investigate the effect of the above trimethoxy flavones in amelioration of peripheral neuropathy induced by paclitaxel. METHODS: Peripheral neuropathy was induced in mice by administration of a single i.p. dose (10 mg/kg) of paclitaxel. The manifestations of peripheral neuropathy such as tactile allodynia, cold allodynia and thermal hyperalgesia were assessed 24 h later by employing hair aesthesiometer test, acetone bubble test and hot water tail immersion test respectively. Further, the role of inflammatory cytokines like TNF - α, IL - 1ß and free radicals in the action of trimethoxy flavones was investigated using in vitro assays. RESULTS: The test compounds dose dependently attenuated paclitaxel - induced tactile allodynia, cold allodynia and thermal hyperalgesia in mice. The test compounds inhibited TNF - α, IL - 1ß and free radicals in a concentration dependent manner. CONCLUSION: The investigated trimethoxy flavones attenuated paclitaxel - induced peripheral neuropathy in mice. The inhibition of cytokines and free radicals in addition to many neuronal mechanisms reported earlier may contribute to this beneficial effect.

Anti-nociceptive Effect of 7-methoxy Coumarin from Eupatorium Triplinerve vahl (Asteraceae).

AIM: To evaluate the anti-nociceptive activity of 7-methoxy coumarin isolated from ethyl acetate fraction of the alcoholic extract of Eupatorium triplinerve Vahl. MATERIALS AND METHODS: The shade dried leaves of E. triplinerve were extracted with ethyl alcohol and the extract was condensed. This extract was fractionated with n-hexane, ethyl acetate, and n-butanol. The ethyl acetate fraction was subjected to column chromatography which yielded a crystalline compound-A, which was investigated for spectral characteristics. PHARMACOLOGICAL STUDIES: The isolated compound-A was subjected to behavioral studies and anti-nociceptive evaluation in mice by acetic acid induced writhing and formalin induced nociception. RESULTS: The spectral studies indicated that the structure of compound-A complies with 7- methoxy coumarin. Pre-treatment with 7-methoxy coumarin reduced the number of abdominal constrictions in mice and decreased the time spent in paw licking and biting response in formalin assay. There were no significant behavioral changes. CONCLUSION: A dose dependent anti-nociceptive action of 7- methoxy coumarin was revealed by the present experiments which support the traditional use of E. triplinerve in pain and inflammatory disorders. SUMMARY: Bio-guided fractionation of alcoholic extract of E. triplinerve yielded 7-methoxy coumarin.7-methoxy coumarin was evaluated for its anti-nociceptive potential by acetic acid induced writhing and formalin induced nociception assays.7-methoxy coumarin exhibited significant inhibition of acetic acid induced writhing response and the second phase of formalin nociception.The anti-nociceptive action of 7-methoxy coumarin revealed by the present experiments supports the traditional use of E. triplinerve in pain and inflammatory disorders. Abbreviation used: TLC-Thin layer chromatography, Kg-kilogram, g-gram, TXB2-Thromboxane B2, UV-Ultraviolet, IgE-Immunoglobulin E, s.c-subcutaneous, p.o-oral route.

Anti-nociceptive activity of a few structurally related trimethoxy flavones and possible mechanisms involved.

BACKGROUND: The present study was designed to investigate the anti-nociceptive activity of a few structurally related trimethoxy flavones (7,2',3'-TMF, 7,2',4'-TMF, 7,3',4'-TMF and 7,5,4'-TMF) and the possible mechanisms involved. METHODS: Anti-nociceptive activity was evaluated in mice by employing acetic acid-induced writhing, formalin-induced nociception and hot water tail immersion methods. The involvement of opioid, GABAergic, tryptaminergic, adrenergic and dopaminergic mechanisms and K+ATP channels in the anti-nociceptive activity of trimethoxy flavones was investigated using suitable interacting chemicals. RESULTS: Trimethoxy flavones exhibited a significant and dose-dependent inhibition of acetic acid writhing. The paw-licking response time was reduced both in the early and late phases of formalin nociception in a dose-dependent manner by trimethoxy flavones. A significant increase in tail withdrawal latency time was also observed after trimethoxy flavones treatment. These observations revealed the potential anti-nociceptive action of the investigated trimethoxy flavones. Pretreatment with naloxone and bicuculline significantly attenuated the reduction of abdominal constrictions produced by all the tested trimethoxy flavones indicating a definite role of opioid and GABAergic mechanisms in the anti-nociceptive effect of trimethoxy flavones. The anti-nociceptive action elicited by various trimethoxy flavones was differently modulated by glibenclamide, ondansetron, yohimbine and sulpiride. CONCLUSIONS: The investigated trimethoxy flavones exhibited promising anti-nociceptive activity in various nociceptive models, and multiple mechanisms are involved in the anti-nociceptive activity of these compounds.