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The changes in mental status during cerebral malaria, heat stroke, and recovery from major surgery are clinically similar, and are associated with high circulating concentrations of cytokines that can induce nitric oxide generation in vascular walls. This vascular nitric oxide could diffuse across the blood brain barrier, causing functional changes that include inhibition of glutamate-induced calcium entry, reduced activity of the calcium-dependent nitric oxide synthase, and thus reduced nitric oxide formation, in post-synaptic neurons. Certain general anaesthetics and ethanol reduce glutamate-induced calcium entry into post-synaptic cells, and so would also reduce the rate of formation of neuronal nitric oxide. In view of the apparent importance of glutamate-induced nitric oxide in excitatory neurotransmission, a reduction in neuronal nitric oxide could help explain why these otherwise unrelated influences alter central nervous system function in a similar manner. In particular, this reduction could rationalise why heat stroke, ethanol excess, morphine poisoning, and conditions with high blood ammonia concentrations are easily confused clinically with cerebral malaria.

Original publication




Journal article


Lancet (London, England)

Publication Date





894 - 896


Division of Biochemistry and Molecular Biology, School of Life Sciences, Australian National University, Canberra.


Brain, Humans, Malaria, Cerebral, Heat Exhaustion, Calcium, Nitric Oxide, Ammonia, Ethanol, Morphine, Amino Acid Oxidoreductases, Receptors, N-Methyl-D-Aspartate, Cytokines, Immunotherapy, Anesthesia, General, Nitric Oxide Synthase