Experimental neurotoxicity of the anorectic fenfluramine. I. A fine structural model for cerebral lysosomal storage and neuroglial reaction.
Fenfluramine, an amphophilic compound which is a halogenated derivative of amphetamine, is still used as an anorectic agent for weight reduction, as it acts on the satiety center of the hypothalamus. Holtzman strain rats aged 6 days were daily injected s.c. fenfluramine hydrochloride at the dose of 75 mg/kg body weight. The animals were killed at different time intervals between days 7 and 40, and different parts of the brain were examined by light and electron microscopy. About half of the animals showed intralysosomal membrano-cytoplasmic bodies in the oligodendroglia, neurons, and neuropil, maximally in the animals receiving 8-19 injections. They were seen as concentrically arranged, single-layered lamellae; small dense bodies; or larger heterogeneous bodies. The mechanism of production of such inclusions could be the formation of complexes of this amphophilic compound with tissue phospholipids, or some enzyme-inhibiting action. A marked prominence of dark cells, predominantly oligodendroglia, was also noticed in the brains of experimental animals. Some of these cells appeared to be dark neurons, probably resulting from the serotonin-depleting effect of fenfluramine. A few dark cells were identified as resting microglial cells, while macrophagic "reactive microglia" were detected in the brains of very young animals. Fenfluramine appears to provide a model for studying neuroglial reactions.
D000818:Animals; D001067:Appetite Depressants / Q000506:poisoning*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D005277:Fenfluramine / Q000506:poisoning*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008854:Microscopy, Electron; D009457:Neuroglia / Q000187:drug effects* / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains
D001067:Appetite Depressants; D005277:Fenfluramine