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

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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

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Data availability

The majority of experimental data are included in the Supplementary data. Additional datasets generated during the current study are available from the corresponding author upon reasonable request.

Abbreviations

AEA:

Anandamide

2-AG:

2-Arachidonoyl glycerol

CB1/2:

Cannabinoid receptor 1/2

CCI:

Chronic constrictive injury

CAT:

Catalase

ECS:

Endocannabinoid system

FAAH:

Fatty acid amide hydrolase

GSH:

Glutathione

MAGL:

Monoacylglycerol lipase

MDA:

Malonaldehyde

MTDL:

Multi-target directed ligands

NP:

Neuropathic pain

ROS:

Reactive oxygen species

SNL:

Spinal nerve ligation

SOD:

Superoxide dismutase

SGOT:

Serum glutamic-oxaloacetic transaminase

SGPT:

Serum glutamic-pyruvic transaminase

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Funding

This work was supported by IIT (BHU) Varanasi as a teaching assistantship to Shivani J.

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Authors and Affiliations

  1. Pharmaceutical Chemistry Research Laboratory II, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, UP, 221005, India

    Shivani Jaiswal & Senthil Raja Ayyannan

  2. Institute of Pharmaceutical Research, GLA University, Mathura, UP, 281406, India

    Shivani Jaiswal

  3. Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, UP, 221005, India

    Akhilesh & Vinod Tiwari

Authors
  1. Shivani Jaiswal
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  2. Akhilesh
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  4. Senthil Raja Ayyannan
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Contributions

Conceptualization: SJ, SRA; investigation: SJ, A; data analysis: SJ, A, VT; original draft preparation: SJ; review and editing: SRA, VT.

Corresponding author

Correspondence to Senthil Raja Ayyannan.

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Jaiswal, S., Akhilesh, Tiwari, V. et al. Anti-nociceptive potential of an isatin-derived dual fatty acid amide hydrolase-monoacylglycerol lipase inhibitor. Pharmacol. Rep 75, 737–745 (2023). https://doi.org/10.1007/s43440-023-00468-2

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  • DOI: https://doi.org/10.1007/s43440-023-00468-2

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