Neurotoxicity of Paclitaxel and Rapamycin in Rat Model with Transient Blood-Brain Barrier Disruption

Abstract

Background: Drug-eluting stents and balloons are occasionally used for patients with medically intractable intracranial atherosclerotic stenosis to reduce postprocedural restenosis. However, neurotoxicity by the drugs are not clear yet. Objective: The authors aim to find out whether drugs impregnated in stents and balloons cause neurotoxicity in a rat model with brain-blood barrier (BBB) disruption Methods: A rat model was made with intra-arterial catheter indwelling at the right common carotid artery for drug administration. Optimal time interval was searched for transient BBB opening after mannitol administration. Paclitaxel and rapamycin in different doses equivalent to human doses of 600, 1200 and 2400 μg were administered via intra-arterial catheter in an optimal time interval from mannitol injection, respectively. Brain tissues were obtained at 24 hours and 14 days after drug administration for a total of 60 rats, consisting of 6 groups per drug and 5 rats per group. Additionally, a total of 10 brain tissues were obtained from 2 sham groups of each 5 rats in 24 hours and 14 days after drug administration. All the rats were evaluated in terms of neurological status and histological findings for neuron damage and inflammation. Results: Optimal time interval for BBB disruption was determined as 10 minutes after mannitol administration. Injecting each drugs in 10 minutes after mannitol administration via the intra-arterial catheter, there were no significant findings of neuronal damage and inflammation in all the cases, irrespective of the type of drugs, drug concentration and time interval between drug injection and histologic examination. None showed neurological deficits. Conclusion: Intra-arterial injection of paclitaxel and rapamycin, ranging from the original to quadruple doses equivalent to human, did not cause neurotoxicity in rats with transient BBB disruption. This animal data is expected to be applicable in the human condition.