Anti-nociceptive potential of an isatin-derived dual fatty acid amide hydrolase-monoacylglycerol lipase inhibitor

Abstract

Background: Recently, we have reported an isatin-derived carbohydrazone, 5-chloro-N'-(6-chloro-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (SIH 3) as dual nanomolar FAAH (fatty acid amide hydrolase)-MAGL (monoacylglycerol lipase) inhibitor with good CNS penetration and neuroprotective activity profile. In this study, we further investigated the pharmacological profile of compound SIH 3 in the neuropathic pain model along with acute toxicity and ex vivo studies. Methods: Chronic constrictive injury (CCI) was used to induce neuropathic pain in male Sprague–Dawley rats and the anti-nociceptive activity of the compound SIH 3 was investigated at 25, 50, and 100 mg/kg ip. Subsequently, locomotor activity was measured by rotarod and actophotometer experiments. The acute oral toxicity of the compound was assessed as per the OECD guidelines 423. Results: Compound SIH 3 showed significant anti-nociceptive activity in the CCI-induced neuropathic pain model without altering the locomotor activity. Furthermore, compound SIH 3 showed an excellent safety profile (up to 2000 mg/kg, po) in the acute oral toxicity study and was also non-hepatotoxic. Further, ex vivo studies revealed that the compound SIH 3 produces a significant antioxidant effect in oxidative stress induced by CCI. Conclusion: Our findings suggest that the investigated compound SIH 3 has the potential to be developed as an anti-nociceptive agent. Graphical abstract: [Figure not available: see fulltext.] © 2023, The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.