Cytotoxic effects of adriamycin on the central nervous system of the mouse--cytofluorescence and electron-microscopic observations after various modes of administration.

Adriamycin (doxorubicin) is commonly used in the treatment of malignant tumours. Adverse effects on the CNS have not been described so far, but the patients may suffer from a dose-related myocardial toxicity. Lesions have previously been observed in peripheral ganglia of experimental animals. Using a direct fluorescence microscopic method we have investigated the distribution of adriamycin in the CNS of normal mice after various modes of administration. Adriamycin, after intravenous (i.v.) injection, did not pass into the brain generally but entered the choroid plexus and circumventricular organs, namely the median eminence, postremal area, subfornical organ, organum vasculosum of the lamina terminalis, pineal gland, and neurophypophysis. After a single i.v. injection of the drug, the animals showed distinct morphological changes in three regions examined thus far, the neurohypophysis (NH), median eminence (ME), and postremal area (PA). In the NH and ME many degenerated neurosecretory axon terminals were observed. In addition, nuclear and cytoplasmic changes were seen in the pituicytes and glial cells of the ME. The PA showed severe neuronal alterations which included nucleolar segregation, rarefaction of the nuclear chromatin, and cytoplasmic changes. When the blood-brain barrier was circumvented by direct microinjection into the cerebral ventricles, the drug passed into the surrounding brain parenchyma, being detected in the nuclei of both neurons and glia. It can therefore be assumed that, when adriamycin is given to patients with a disturbance of the blood-brain barrier, the drug may spread into the brain in the same way. The blood-brain barrier can also be bypassed by injecting a substance intramuscularly or/and intradermally and letting it pass into the spinal cord or brain-stem by retrograde axonal transport. In model experiments, adriamycin was injected into the tongue and six hours later its fluorescence could be detected in the hypoglossal neurons. Animals allowed to survive for a longer period, showed selective damage to these neurons as evidenced by early nuclear changes followed by alterations in the cytoplasm.(ABSTRACT TRUNCATED AT 400 WORDS)