Shehla Akbar1, Fazal Subhan2, Nasiara Karim3, Muhammad Shahid4, Nisar Ahmad5, Gowhar Ali6, Wajahat Mahmood7, Khwaja Fawad8. 1. Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: naina.akbar@yahoo.com. 2. Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: fazal_subhan@upesh.edu.pk. 3. Department of Pharmacy, University of Malakand, Chakdara, Pakistan. Electronic address: nasiara.karim@hotmail.com. 4. Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: shahidsalim_2002@hotmail.com. 5. Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: nisarahmadsatal@yahoo.com. 6. Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: gohar.pharmacist@gmail.com. 7. Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan. Electronic address: wmahmood@cit.net.pk. 8. Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: fawad.khwaja@yahoo.com.
Abstract
BACKGROUND: Diabetic neuropathy is the most prevalent, persistent and debilitating complication of diabetes mellitus often coupled with vulvodynia that may present as an isolated symptom or as a part of constellation of other neuropathic abnormalities. OBJECTIVE: Flavonoids have selective affinity for GABA receptors and 6-methoxyflavanone (6-MeOF) is a positive allosteric modulator of GABA responses at human recombinant GABAA receptors. GABAergic and opioidergic system inhibition have been shown to facilitate neuropathic pain. METHODS: 6-MeOF was evaluated for analgesic effect in the hot plate test and streptozotocin-induced diabetic neuropathic pain in female rats using von Frey hairs. The possible involvement of opioidergic and GABAergic mechanisms was investigated using naloxone and pentylenetetrazole (PTZ) antagonists, respectively. The biodistribution of 6-MeOF in plasma and CNS was examined using a validated HPLC/UV analytical method. The binding affinity of 6-MeOF with opioid and GABA receptors was studied using molecular docking simulation approach. RESULTS: 6-MeOF (10 and 30mg/kg) attenuated the acute phasic thermal nociception in the hot plate test while in the case of streptozotocin-induced diabetic neuropathy model, 6-MeOF (10 and 30mg/kg) produced static/dynamic anti-allodynic (increased paw withdrawal threshold and latency) as well as static/dynamic anti-vulvodynic effects (increased flinching response threshold and latency), when compared to the vehicle and standard gabapentin (75mg/kg). In silico studies depicted the preference of 6-MeOF for the delta- and kappa-opioid and GABAA receptors. Moreover, the pharmacokinetic profile revealed a quick appearance of 6-MeOF in the systemic circulation and brain areas with maximum concentration observed after 30min in the amygdala, brain stem and cerebral cortex. CONCLUSION: 6-MeOF readily crosses the blood brain barrier and may be effective in attenuating the diabetes-induced allodynia as well as vulvodynia, probably through interactions with the GABAergic and opioidergic systems.
BACKGROUND:Diabetic neuropathy is the most prevalent, persistent and debilitating complication of diabetes mellitus often coupled with vulvodynia that may present as an isolated symptom or as a part of constellation of other neuropathic abnormalities. OBJECTIVE:Flavonoids have selective affinity for GABA receptors and 6-methoxyflavanone (6-MeOF) is a positive allosteric modulator of GABA responses at human recombinant GABAA receptors. GABAergic and opioidergic system inhibition have been shown to facilitate neuropathic pain. METHODS:6-MeOF was evaluated for analgesic effect in the hot plate test and streptozotocin-induced diabetic neuropathic pain in female rats using von Frey hairs. The possible involvement of opioidergic and GABAergic mechanisms was investigated using naloxone and pentylenetetrazole (PTZ) antagonists, respectively. The biodistribution of 6-MeOF in plasma and CNS was examined using a validated HPLC/UV analytical method. The binding affinity of 6-MeOF with opioid and GABA receptors was studied using molecular docking simulation approach. RESULTS:6-MeOF (10 and 30mg/kg) attenuated the acute phasic thermal nociception in the hot plate test while in the case of streptozotocin-induced diabetic neuropathy model, 6-MeOF (10 and 30mg/kg) produced static/dynamic anti-allodynic (increased paw withdrawal threshold and latency) as well as static/dynamic anti-vulvodynic effects (increased flinching response threshold and latency), when compared to the vehicle and standard gabapentin (75mg/kg). In silico studies depicted the preference of 6-MeOF for the delta- and kappa-opioid and GABAA receptors. Moreover, the pharmacokinetic profile revealed a quick appearance of 6-MeOF in the systemic circulation and brain areas with maximum concentration observed after 30min in the amygdala, brain stem and cerebral cortex. CONCLUSION:6-MeOF readily crosses the blood brain barrier and may be effective in attenuating the diabetes-induced allodynia as well as vulvodynia, probably through interactions with the GABAergic and opioidergic systems.
Authors: Nisar Ahmad; Fazal Subhan; Nazar Ul Islam; Muhammad Shahid; Naseem Ullah; Rahim Ullah; Muhammad Khurram; Muhammad Usman Amin; Shehla Akbar; Ihsan Ullah; Robert D E Sewell Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2021-07-12 Impact factor: 3.000