Increased plasma levels of histidine and histamine in falciparum malaria: relevance to severity of infection

Severe falciparum malaria, with its associated hyperpyrexia, distorts plasm a levels of large neutral amino acids (NAA) and consequently, brain uptake of individual NAA. Since brain levels of NAA determine cerebral synthesis o f monoamines (serotonin, histamine, catecholamines), we measured plasma con centrations of NAA, and also plasma histamine (Hm) in children with falcipa rum malaria and in uninfected controls. Malaria elicited a marked (P < 0.02 5) increase in plasma histidine (His) with a 5-fold significant (P < 0.001) elevation in histamine, as well as a 2.5-fold increase (P < 0.005) in plas ma phenylalanine (Phe), with no changes in the other NAA. Using kinetic par ameters of NAA transport at human blood-brain barrier (BBB), we showed that malaria significantly altered calculated brain uptake of His (+30%), Phe ( +96%), Trp (-30%) and Ile (-27%), with no change in the other NAA, compared with controls. Our data suggested enhanced cerebral synthesis of Hm with i mpaired production of serotonin and the catecholamines in the patients, and therefore, the need to evaluate the encephalopathy in severe malaria withi n the context of abnormalities in metabolism of Hm and other monoamines res ulting from imbalance in plasma levels of the large neutral amino acids. Of clinical relevance also is the impaired inactivation of increased brain Hm by antimalarials such as the widely used aminoisoquinolines leading to ele vated brain levels of imidazole-4-acetic acid (IAA), a potent inducer of a sleep-like state often accompanied by seizures, analgesia, decreased blood pressure and other effects.