Neurotoxicity of adriamycin passed through the transiently disrupted blood-brain barrier by mannitol in the rat brain.
Neurotoxicity of adriamycin (ADM) was investigated following the transient disruption of the blood-brain barrier (BBB) in rats. The BBB disruption by the hyperosmotic agent (1.4 M mannitol) was confirmed by the leakage of ADM and Evans blue administered intravenously. Neuropathological changes due to the toxicity of ADM were found as early as day 4. The neurons in the cerebral cortex and nucleus caudatus-putamen showed focal clearing of the nuclear chromatin, increased dense bodies in the cytoplasm and dilatation of the cisternae of the rough endoplasmic reticulum (r-ER) and Golgi apparatus. By day 7, nucleolar segregation and irregular membranous structures appeared in the nuclei with the progression of cytoplasmic changes. By day 10, the cytoplasm of many neurons was vacuolated. Electron-microscopically, the cisternae of the r-ER and Golgi apparatus were prominently dilated in these neurons. Neuronal microtubules were increased in number, in particular in the perinuclear region. Numerous whorl-like membranous structures and separation of nuclear membrane were also observed. Some astrocytic processes surrounding the blood vessels revealed loss of organelles and a few pericytes showed an increased number of lysosomes on days 7 and 10. This experiment clearly demonstrates that ADM has strong neurotoxic effects in the central nervous system when the BBB is disrupted, and provides the warning for the possibilities of neurotoxic side effects when ADM is administered, in combination with a hyperosmotic agent, for the treatment of human malignant tumors, including brain tumors.
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D004317:Doxorubicin / Q000506:poisoning*; D005070:Evans Blue; D008297:Male; D008353:Mannitol / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D051381:Rats; D011919:Rats, Inbred Strains
D008353:Mannitol; D005070:Evans Blue; D004317:Doxorubicin