Proposed link between cytokines, nitric oxide and human cerebral malaria.

Nitric oxide (NO), also known as endothelial-derived relaxing factor (EDRF), is generated by a range of cell types including endothelial cells, smooth muscle cells and neurons, and mediates a range of different physiological functions, such as maintenance of vascular tone and neuro-transmission. In this article, Ian Clark, Kirk Rockett and Bill Cowden propose that when vascular generation of NO is particularly high (for example, if local intravascular levels of tumour necrosis factor (TNF) are markedly increased) this mediator could diffuse to nearby neurons, be misinterpreted as being of synaptic origin and thus interfere with orderly neuro-transmission. NO of vascular origin could also, through vasodilation of cerebral vessels, contribute to increased intracranial pressure and thus to certain of the clinical signs seen in cerebral malaria. As well as contributing to cerebral malaria, these phenomena could also lead to the neurological changes observed in certain other systemic diseases.