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

Researchers tested a new gel treatment containing a drug called 7-NI in mice with autism-like behaviors. Instead of daily injections, they gave one shot under the skin that slowly released the medicine over 10 days. The treated mice showed better memory, improved social behavior, and less anxious behavior. This could lead to easier treatments for autism that don't require daily medication.

This preclinical study tested a novel extended-release gel formulation of 7-nitroindazole (7-NI) in Shank3 mutant mice, an autism model. The PSARA gel was administered subcutaneously as a single dose, releasing the drug over 10 days. Results showed improved memory, social interaction, and reduced anxiety-like behaviors in treated mice, along with decreased nitrosative stress markers in plasma. The gel maintained therapeutic drug levels (~45 μg/ml/day) throughout the treatment period.

This approach represents a potential advancement over daily injections previously required, offering sustained therapeutic effects from a single administration.

This preclinical research suggests potential for developing sustained-release autism treatments targeting nitric oxide pathways. However, extensive human studies are needed before clinical application. The approach could improve treatment adherence if proven safe and effective in humans.

Study conducted only in mouse models; sample size not reported; behavioral testing started only 3 days post-injection; long-term effects beyond 10 days unknown; human safety and efficacy data not available.

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 Shank3and Cntnap2mutant 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.