Effects of extended-release 7-nitroindazole gel formulation treatment on the behavior of Shank3 mouse model of autism

Muhammad Abdel-Haq, Shashank Kumar Ojha, Wajeha Hamoudi, Awanish Kumar, Manish Kumar Tripathi, Igor Khaliulin, Abraham J. Domb, Haitham Amal

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral deficits such as abnormalities in communication, social interaction, anxiety, and repetitive behavior. We have recently shown that the Shank3 mutation in mice representing a model of ASD causes excessive nitric oxide (NO) levels and aberrant protein S-nitrosylation. Further, 10-day daily injections of 7-NI, a neuronal nitric oxide synthase inhibitor, into Shank3Δ4-22 and Cntnap2(−/−) mutant mice (models of ASD) at a dose of 80 mg/kg reversed the manifestations of ASD phenotype. In this study, we proposed an extended release of 7-NI using a novel drug system. Importantly, unlike the intraperitoneal injections, our new preparation of poly (sebacic acid-co-ricinoleic acid) (PSARA) gel containing 7-NI was injected subcutaneously into the mutant mice only once. The animals underwent behavioral testing starting from day 3 post-injection. It should be noted that the developed PSARA gel formulation allowed a slow release of 7-NI maintaining the plasma level of the drug at ∼45 μg/ml/day. Further, we observed improved memory and social interaction and reduced anxiety-like behavior in Shank3 mutant mice. This was accompanied by a reduction in 3-nitrotyrosine levels (an indicator of nitrative/nitrosative stress) in plasma. Overall, we suggest that our single-dose formulation of PSARA gel is very efficient in rendering a therapeutic effect of 7-NI for at least 10 days. This approach may provide in the future a rational design of an effective ASD treatment using 7-NI and its clinical translation.

Original languageEnglish
Pages (from-to)41-49
Number of pages9
JournalNitric Oxide - Biology and Chemistry
Volume140-141
DOIs
StatePublished - 1 Nov 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Funding

The research was partially funded by Beyond Air under the terms of a Research and License agreement. This work was funded by a US Department of Defense (DoD) grant, an Israeli Science Foundation (ISF) grant, an Eagles Autism Foundation grant, a National Institute of Psychobiology in Israel (NIPI) grant, an Israeli Council for Higher Education Maof Grant, and a Berettler Center for Research in Molecular Pharmacology and Therapeutics Grant. The authors also thank the Satell Family Foundation and the Neubauer Family Foundation for their support.

FundersFunder number
Beyond Air
National Institute of Psychobiology in Israel
Satell Family Foundation
U.S. Department of Defense
Neubauer Family Foundation
Eagles Autism Foundation
Israel Science Foundation
Council for Higher Education

    Keywords

    • 7-Nitroindazole (7-NI)
    • Autism spectrum disorder (ASD)
    • Behavioral deficits
    • Neuronal NO synthase (nNOS) inhibition
    • Nitric oxide (NO)
    • PSARA gels

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