Beta-Carotene derivatives as novel therapy for the prevention and treatment of autistic symptoms.

Autistic Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by impaired social interaction & communication as well as restricted and repetitive behavior. The currently reported incidence of ASD is 1-2%, and it increases dramatically to 10-20% in families predisposed to ASD. To date, there is no effective way to treat or prevent ASD, and only symptomatic treatment with limited efficacy is available. Oxytocin (Oxt) enhances affiliative behavior and improves social cognition. Social deficits characteristic of autism may be related to dysfunctional Oxt neurotransmission. Thus, administration of Oxt may relieve ASD, however it has a short plasma half-life and poor Blood Brain Barrier (BBB) permeability. CD38, a multifunctional ecto-enzyme expressed in brain and immune cells, was found to be critical for social behavior via regulation of Oxt secretion. All-trans retinoic acid (ATRA) is a potent inducer of CD38 and improves social behavior, but it is toxic and teratogenic. We have shown that beta-carotene has a similar therapeutic effect. The present study aimed to investigate the activity of novel beta-carotene derivatives in rescuing low sociability found in BTBR mice, providing an in vivo "proof of principle" that beta-carotene derivatives are potential agents to prevent/ameliorate the reappearance of ASD in high-risk populations for ASD. Beta-carotene and its synthetic analogs were administered orally to newborn BTBR mice with ASD associated like behavior. After 2 months, they were tested (at dosages of 0.1 and 1.0 mg/kg) by cognitive (T-maze spontaneous alteration and neurological score) and behavioral tests (reciprocal social interaction, repetitive grooming / bedding behavior), previously shown as indicators for autistic behavior. The following biochemical and molecular biology parameters were also examined: serum Oxt; gene expression in hippocampus and hypothalamus of CD 38, Oxt, Oxt receptor, BDNF, and retinoic acid receptor. The new compounds were significantly more effective than control. The most effective compounds, both in the behavioral tests and in their biochemical effects, were (3R,3'R)-astaxanthin bis(N-Cbz-l-alanine ester) (3B(and (3S,3'S)-astaxanthin bis(N,N-dimethylglycine ester (5). They did not exert any neurological symptoms. Thus, beta-carotene derivatives may have the potential to prevent and/or ameliorate autistic symptoms when administered orally after birth to newborns of families predisposed to autism.

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