CNS Protection from Hyperammonemia

PIs: Ljubica Caldovic, PhD

Institution: Children's National Health System

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Hyperammonemia, or elevated blood ammonia, ensues when conversion of ammonia into urea is reduced or blocked due to defects in the urea cycle. Ammonia is a product of protein breakdown and an extremely potent neurotoxin. Symptoms of hyperammonemia include a wide range of neuro-cognitive deficits and, in most severe cases, coma and death. Although the brain is the only organ known to be damaged by elevated ammonia none of the current treatments for hyperammonemia focus on protecting the brain from the toxic effects of ammonia. Ammonia is also toxic to fish brain and the mechanism of ammonia toxicity to the brain appears to be similar in fish and humans.

We have created a zebrafish model of hyperammonemia and used it to screen for drugs that can protect the zebrafish from ammonia toxicity. Seven drugs protected zebrafish from ammonia toxicity in a dose dependent manner and we then tested whether pairs of drugs protect zebrafish from ammonia toxicity more efficiently than either drug alone. Two different pairs of drugs were more efficient at protecting zebrafish activity from ammonia toxicity that either drug alone.

We have also created a mouse model of inducible hyperammonemia, the N-acetylglutamate synthase knockout (NAGSko) mouse. This mouse survives and reproduces when treated with a drug N-carbamylglutamate and develops hyperammonemia within hours after withdrawal of the treatment. We have recorded neuronal activity as NAGSko mice develop hyperammonemia; neuronal activity becomes abnormal soon after the withdrawal of N-carbamylglutamate treatment and abnormalities become more severe as hyperammonemia progresses. We will be testing whether drugs identified in the zebrafish screen normalize the neuronal activity of hyperammonemic NAGSko mice.