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.
Bibliographical noteFunding Information:
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.
© 2023 Elsevier Inc.
- 7-Nitroindazole (7-NI)
- Autism spectrum disorder (ASD)
- Behavioral deficits
- Neuronal NO synthase (nNOS) inhibition
- Nitric oxide (NO)
- PSARA gels