Hideko Kawaki

Roles of nitric oxide and prostaglandins in the increased permeability of the blood-brain barrier caused by lipopolysaccharide.

We investigated the involvement of nitric oxide (NO) and prostaglandins (PGs) in the damage to the blood-brain barrier (BBB) induced by lipopolysaccharide (LPS), using fluorescein as a tracer in mice. Aminoguanidine, a competitive inhibitor of inducible NO synthase (iNOS), when administered s.c. at 5 mg/kg, but not 500 mg/kg, reduced significantly the increase in brain fluorescein level after its i.v. injection in LPS-treated mice. When 1000 mg/kg of l-arginine, a substrate of NOS, were co-administered with 5 mg/kg of aminoguanidine to LPS-treated mice, the inhibitory effect of aminoguanidine on the increased fluorescein level disappeared. N(G)-Nitro-l-arginine methyl ester (l-NAME), a non-isoenzyme-selective NOS inhibitor, when administered s.c. at 5 mg/kg, only slightly reduced the LPS-induced increase in the brain fluorescein level. A pretreatment with dexamethasone, which suppressed the induction of both iNOS and cyclooxygenase 2 (COX-2), tended to decrease the brain fluorescein level in LPS-treated mice. Indomethacin, a COX inhibitor, at 5 mg/kg, but not 10 mg/kg, suppressed significantly the LPS-induced increase in the brain fluorescein level. These results involve that both the NO produced by iNOS and the PGs produced by COX contribute to enhance BBB permeability in LPS-administered mice.

Free Radical Scavengers Suppress the Accumulation of Platinum in the Cerebral Cortex

We investigated whether free radical scavengers and antioxidants inhibit the accumulation of platinum (Pt) in the cerebral cortex. Pt was detected in the cerebral cortex of mice afters administration of cisplatin and exposure to short-term hypoxia. When mice were treated with either allopurinol (20 mg/kg) or catalase (100 mg/kg) before cisplatin administration and low oxygen exposure, Pt was not detected in the cerebral cortex. However, Pt was detected in the cerebral cortex of mice pretreated with either a low dosage of allopurinol or heat-denatured catalase. Furthermore, Pt was detected in the cerebral cortex of mice preadministered vitamin C, vitamin E, or deferoxamine. Lipid peroxide levels in the cerebral cortex increased 10 min after the treatment of hypoxia, and peaked 30 min after the treatment. These results suggested that short-term hypoxia produces free radicals, which allows Pt to pass through the blood-brain barrier and accumulate in the cerebral cortex, and that the production of free radicals is reduced by the administration of either allopurinol or catalase, which prevents Pt from passing through the barrier.

Lipopolysaccharide-induced platinum accumulation in the cerebral cortex after cisplatin administration in mice: Involvement of free radicals

The relationship between the accumulation of platinum in the cerebral cortex following cisplatin administration and injury to the blood-brain barrier after lipopolysaccharide (LPS) treatment was investigated. The appearance of intravenously injected fluorescein in the brain was significantly increased 10-24 h after LPS treatment, the effect being dose-dependent. Platinum was detectable in the cerebral cortex of cisplatin-treated mice 24 h after LPS treatment, but not without LPS treatment. In mice pretreated with α-tocopherol, LPS administration did not significantly augment fluorescein penetration into the brain, whereas pretreatment with either allopurinol or ascorbic acid did not modify the LPS-induced increase in fluorescein penetration. In contrast, platinum in the cerebral cortex after cisplatin administration was still detectable in the allopurinol-, ascorbic acid-, and α-tocopherol-pretreated groups, and the levels of platinum in these groups were not significantly different from those in the group treated with LPS only. Administration of superoxide dismutase (SOD), but not of catalase, tended to inhibit the penetration of fluorescein. Both SOD and catalase significantly lowered platinum content in the cerebral cortex following cisplatin administration in mice treated with LPS. Thus, free radicals may injure the blood-brain barrier in mice challenged with LPS, and allow cisplatin to penetrate into the cerebral cortex, resulting in platinum accumulation.

The polarographic behavior of adenine nucleotides in unbuffered 75% dioxane solution☆

Abstract The polarogaphic behavior of phosphoric acid and nucleotides in unbuffered aqueous and 75% dioxane solution was investigated. It seems reasonable to assume that the half-wave potentials and wave heights of nucleotides depend largely on their dissociation constants and also on the inductive character of their phosphatic part. From the polarographic behavior, circular dichroism and nuclear magnetic resonance spectra, the different behavior due to interaction of theophylline and of nicotinic acid, or imidazole, with cyclic AMP was found to depend on the conformation change of cyclic AMP due to the formation of pyridinium or imidazolium ion. The polarographic behavior of the enzymatic destruction of ATP by apyrase was investigated, and it was found that simultaneous identification of the enzymatic reaction products is possible in unbuffered 75 % dioxane solution.