Abstract

Domoic acid (DA) is a potent neurotoxin which, when ingested, can cause neurological dysfunction and cardiotoxicity by binding to glutamate receptors and causing excitotoxic effects. Over-excitation of glutamate receptors results in continuous cellular activation and secondary oxidative damage, followed by cell death and tissue necrosis. Clinical signs of toxicosis include disorientation, seizures, and coma which can be managed with anti-seizure medication; however, there are no treatments available to block the effects of domoic acid on glutamate receptors. As the time between animal exposure and presentation to medical facilities can be lengthy, therapy should target the secondary oxidative damage caused by continued cellular activation. Alpha lipoic acid (ALA) is an important precursor for glutathione - a highly potent anti-oxidant. ALA is able to cross the blood-brain barrier and reach therapeutic levels in the brain, thus increasing local antioxidant availability; however, dosing recommendations vary widely among animal species and have never been assessed in marine mammals. Hundreds of stranded California sea lions are diagnosed annually with DA toxicosis throughout California, thus are an appropriate animal in which to establish dosing guidelines and efficacy of parenteral ALA administration. Stranded California sea lions that had undergone rehabilitation at The Marine Mammal Center that had not received any medications for at least one week and were deemed healthy, were administered 10 mg/kg ALA subcutaneously. A blood sample was collected immediately prior to ALA administration to serve as a control, and samples were collected at 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, 18 and 24 hours post-administration. Samples were processed within 10 minutes of collection and serum was frozen at -80°C until evaluation by liquid chromatography-mass spectrometry. A population pharmacokinetic profile was established by collecting two samples from each of 15 animals, and 3 data sets were created for each time point. ALA concentration peaked within 0.25 h with a Cmax of 942.5 ng/ml. ALA was still measurable in serum 24 hours post-administration (6.43 ng/ml). One sea lion had a small amount of bleeding at the injection site immediately post-administration, consistent with puncture of a superficial blood vessel; however, no other negative effects were noted in any animal. While an effective therapeutic dose is unknown for most species, these results suggest that in California sea lions, a subcutaneous dose of 10 mg/kg once every 24 hours may be sufficient to achieve therapeutic levels. ALA (10 mg/kg SID for 5–7 days) is currently being utilized as supportive treatment of sea lions suffering from DA toxicosis, and evaluation of repeated dosing is currently underway.