THERAPY OF AUTISM: PHARMACOKINETIC PROFILE OF CENTRALLY BIOACTIVE PEPTIDES

Carnosine (beta-alanyl-L-histidine, CAR) is a histidine-containing dipeptide particularly abundant in excitable tissues such as nervous system and skeletal muscle. Carnosine acts as a bioactive peptide in the central nervous system (CNS): it has been found to act as neuroprotectant in several animal models of cerebral ischemia, induces an antidepressant-like effect in rats and hyperactivity in chicks. Regarding clinical studies, Chez et al reported beneficial effects of CAR in autistic children in terms of significant improvements in behavior, socialization, and communication, as well as increases in language comprehension, vocabulary tests and biweekly parent reports. Hence CAR is a potential therapeutic agent and its interest is further sustained by considering that it is devoid of any toxicity and that it is contained in a mM concentration range in some food such as meat (appromaximately 2 mg/ 1 gr beef). However, little is known about the ADME properties of CAR in humans, both given as pure compound or as meat, and this is mostly due to the lack of a specific and sensitive analytical method to monitor CAR in biological matrices. We recently set-up and fully validated an LC-ESI-MS/MS method for the quantization of CAR and here applied to determine the pharmacokinetics of the dipeptide after ingesting pure CAR or CAR rich foods. Healthy women (n=4) went through four phases of one dose of either 450 mg CAR (A), 150 g beef (B, 300 mg of CAR), 150 g chicken (C), or chicken broth (CB) from 150 g chicken with >2 wks of wash out period between each phase. Blood samples were collected 0-300 min and urine samples before and after (up to 7 hrs) ingesting the food. No CAR was detected in plasma after ingesting A, B, C or CB (L.O.D. 0.01 nmoles ml-1). Urinary carnosine increased from 2.62±0.62 µM (base level) to 37.07±10.18 µM, and to 42.35±9.42 µM after ingesting B and CB, respectively. Thus, CAR, both as dietary or pure compound, is rapidly hydrolyzed by carnosinase in plasma and excreted only in a minor fraction in urine (5% of the ingested dose within 7 hours). The present results shed some light on the metabolic fate of dietary CAR in humans, which is firstly hydrolyzed to the constitutive aa in plasma, and then re-synthesized in CNS by carnosine synthase. Moreover, urinary CAR, could be useful for drug monitoring studies.