Cerebral photosensitisation by haematoporphyrin derivative. Evidence for an endothelial site of action

Abstract

Exposure of the cranium to white light in mice that had been given haematoporphyrin derivative (HpD) led to a rapid onset of vasogenic cerebral oedema, cerebral necrosis, coma and death. Selectivity of the initial damage for endothelium was suggested by (a) early breakdown (less than 1 h) of the blood-brain barrier (BBB) as shown by increased permeability to Evans blue (b) separation and increased vesiculation of endothelial cells at 2 h and (c) endothelial cell pyknosis at 3--4 h in small vessels next to apparently undamaged neurones and neuroglia. There was no damage to myelin sheaths, and astrocytes showed only end-feet oedema, a reaction to exudation of protein-rich fluid. Within a few hours of illumination, most cells in the illuminated area were necrotic. Cerebral photosensitivity persisted for at least 12 weeks after a single injection of HpD. Our results suggest that the primary site of damage in the brain is the endothelium of small vessels, and that HpD remains associated with this for a remarkably long time. These findings are relevant to the mechanisms by which photodynamic therapy damages other tissues, including neoplasms, and particularly to the possible application of this treatment to brain tumours.