Detection of platinum in the brain of mice treated with cisplatin and subjected to short-term hypoxia.
Cisplatin is widely used for cancer treatment but has strong side-effects, including nephrotoxicity. Neurotoxicity has been thought to be limited to peripheral damage because the blood-brain barrier is thought to be impervious to hydrophilic substances such as cisplatin. Because anoxic ischaemia has been associated with lesions of the barrier, inductively coupled plasma mass spectrometry has been used to monitor the accumulation of platinum in the brains of mice treated with cisplatin and exposed to oxygen-deficient atmospheres. Platinum was detected in the cerebral cortex of mice 24 h after the administration of cisplatin (3 mg kg-1) followed by exposure for 60 s to an atmosphere containing 7% oxygen, but not in the cerebral cortex of mice exposed to normal atmospheres. Platinum was also observed in the cerebral cortex after exposure for 120 s to an atmosphere containing 14% oxygen, and platinum levels increased as the concentration of oxygen was reduced. The highest platinum levels were obtained 10 h after administration of cisplatin and exposure for 120 s to an atmosphere containing 7% oxygen. Platinum was still retained in the cerebral cortex one week after administration. In contrast, platinum levels in the blood and kidney decreased with time. Platinum levels were measured in seven regions of the brain: the right and left cerebral cortices, the basal ganglia, the thalamus and hypothalamus, the bulbus olfactorius, the cerebellum, and the mesencephalon. When cisplatin was administered to mice not subjected to hypoxia, platinum was not detected in the right and left cerebral cortices, basal ganglia or the thalamus and hypothalamus, but was detected in the bulbus olfactorius, cerebellum and mesencephalon. When such mice were exposed to low levels of oxygen, however, platinum was detected in the right and left cerebral cortices, the basal ganglia and the thalamus and hypothalamus. Platinum levels in the cerebellum and mesencephalon of mice exposed to low levels of oxygen were higher than those of mice exposed to normal air. In addition, platinum levels in the bulbus olfactorius were significantly higher than those in the other regions, although the platinum content of the bulbus olfactorius was not affected by hypoxia. From these observations, it is concluded that platinum is easily accumulated in the bulbus olfactorius after the administration of cisplatin, and that after exposure to atmospheres containing low levels of oxygen, platinum easily passes through the blood-brain barrier and accumulates in all parts of the brain.
Minami
T
T
Faculty of Pharmaceutical Sciences, Kinki University, Osaka, Japan.
Ichii
M
M
Okazaki
Y
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010984:Platinum / Q000097:blood / Q000378:metabolism*; D013997:Time Factors
D000970:Antineoplastic Agents; D010984:Platinum; D002945:Cisplatin