Neuropathology & pathogenesis of experimental fenfluramine toxicity in young rodents

The anorectic compound fenfluramine hydrochloride was injected into young Holtzman strain rats (from days 6 to 40 of life), at the dose of 75 mg/kg body weight. Intralysosomal lamellar bodies (LBs) were seen in the endothelial cells, pericytes, the perivascular astrocyte processes and occasionally in the lumen. The pathology of myelinated fibres varied from thinning of myelin to complete demyelination and, at times, presence of dense bodies in the axons, the changes perhaps being a result of the oligodendroglia damage. A small group of adult mice was administered three oral doses each of Ponderax equivalent to 5 mg of fenfluramine. The brain stem and cerebellar neurons of these mice showed abnormal dark cytoplasm, without lamellar bodies. Even in this short-term experiment, there was formation of a few LBs in the neuropil, the prominence of dark glial cells, probably oligodendroglia, and some perivascular intracytoplasmic oedema. The earliest detection of dense bodies in the undistended astrocyte processes before they were observed in the cell perikarya, both in the younger rats and the adult mice, suggested the perivascular astrocyte to be the first CNS constituent to come in contact with the toxic agent as it passes the blood-brain barrier. On the basis of our observations, it also appears that the 'myelinosomes' or lamellar phagolysosomes developing due to failure of degradation of drug-phospholipid interaction product, accumulate in different cells of the CNS.