Early and delayed neurotoxicity of mitoxantrone and doxorubicin following subarachnoid injection.

Abstract

Doxorubicin (DXR) and Mitoxantrone (MXN) were administered into the subarachnoid space of mice or the ventricular system of rats. The maximal non-toxic systemic single dose (zero mortality = LDo) of DXR or MXN was used as reference for planning drug doses for CSF administration. LDo in mice were: 8 mg/kg DXR and 6 mg/kg MXN; in rats: 6 mg/kg DXR and 4.5 mg/kg MXN. Signs of neurotoxicity were remarkably similar in DXR or MXN treatment animals and included: head tremor, atactic-dystonic posture and circling behavior. The toxicity was dose dependent. Doses of greater than or equal to 10% the LDo caused early appearance of clinical signs: a dose of 10% LDo caused neurotoxicity in 90% of DXR treated mice and in only 15% of MXN-treated animals. Treatment with 25% LDo MXN caused neurotoxicity in 30% of treated animals. Doses of less than or equal to 5% the LDo caused a delayed onset of DXR neurotoxicity in one third of treated mice (after 60-90 days). In rats, neurotoxicity was of an early onset and augmented severity following doses of greater than or equal to 5% LDo. Abnormal histopathological findings were detected only in symptomatic animals with early toxicity and were usually restricted to superficial cortical layers in mice or the basal surface of the brainstem in rats. Brains of mice with delayed toxicity were unremarkable. The levels of monoamine neurotransmitters and their metabolites (DA, DOPAC, HVA, NE, 5HT) in the striatum, cortex and cerebellum of mice with early and delayed DXR neurotoxicity did not differ from normal brains.(ABSTRACT TRUNCATED AT 250 WORDS)