Chemical events behind leukoaraiosis: medicinal chemistry offers new insight into a specific microcirculation disturbance in the brain (a chemical approach to a frequent cerebral phenotype).

Leukoaraiosis (LA), one of the most frequent causes of cognitive disturbances, is presumed to involve vascular demyelinization and cerebral small-vessel diseases. Although it has been suggested that the development of LA is associated with cerebral circulatory disturbances, the pathomechanism of this circulatory problem is not completely understood. Extensive debate is continuing as regards the detailed features of the circulatory disturbances in LA. An endothelial dysfunction may lead to breakdown of the blood-brain barrier, thereby resulting in chronic toxic edema in the perivascular areas. This can then cause the slow development of LA. Endothelial dysfunctions may also give rise to molecular events involving a shift in the O(2) and CO(2) trafficking system in the red blood cells, which will result in special complex microcirculation disturbances in the white matter of the brain; these molecular phenomena may therefore account for chronic slight hypoxia leading to the development of LA. This article discusses these hypothetical alternative molecular events behind LA. The review also illustrates how medicinal chemistry can offer new insight into a common, but still mysterious cerebral phenotype.