Sadao Kano

Mechanism of paraquat-stimulated lipid peroxidation in mouse brain and pulmonary microsomes

Abstract— Paraquat‐stimulated NADPH‐dependent lipid peroxidation in mouse brain and pulmonary microsomes was inhibited by superoxide dismutase and singlet oxygen quenchers, but not by catalase or hydroxyl radical scavengers. MnCl2, which might form a salt with unsaturated lipid, inhibited the lipid peroxidation in brain microsomes, but not that in pulmonary microsomes. These findings suggest that activated oxygen species, especially superoxide and singlet oxygen, may play a major role in the stimulation of microsomal lipid peroxidation by paraquat in both brain and lung, and that the nature of the lipids exposed to peroxidative attack may be different in microsomes of the two organs.

Distinct effects of Nω-nitro-l-arginine on seizures induced by several drugs in mice

Abstract A potent nitric oxide (NO) synthase inhibitor, Nω-nitro- l -arginine ( l -NA), suppressed tonic seizure elicited by pentylenetetrazol (PTZ; 100 mg/kg, SC) in a dose-related manner (25 to 100 mg/kg, IP), but had no effect on clonk seizure. The effect was most potent at 1 h after the administration of l -NA. l -NA (100 mg/kg, IP) suppressed clonic seizure as well as tonic seizure in bicuculline-treated (3.0 or 4.5 mg/kg, SC) mice. However, it did not affect seizures elicited by picrotoxin (2.0 to 6.0 mg/kg, SC). On the other hand, N -methyl-DL-aspartate (NMDLA; 300 mg/kg or 350 mg/kg, IP) induced clonic seizure, but tonic seizure was not always noted. All mice with clonic and tonic seizures died, and some mice with clonic seizure died without accompanying tonic seizure. l -NA did not influence NMDLA-induced seizures, but it appeared to enhance NMDLA lethality, though without statistical significance. These findings suggest distinct roles of NO in seizures induced by different drugs in mice.

Local changes in oxygen tension and blood flow in the brain under hyperthermia induced by intracerebroventricular NMDA in rats

Intracerebroventricular administration of N-methyl-D-aspartate (NMDA; 100 nmol) to rats increased oxygen tension and blood flow of the caudate putamen and the ventral hippocampus. The regional differences in the increase in oxygen tension could not be explained in terms of those in the blood flow. NMDA also increased the temperature of the two brain regions to a similar extent, and these increases preceded that in the rectum. These findings suggest that NMDA receptor stimulation leads to exposure of the brain to a higher oxygen level and higher temperature, which might be involved in NMDA neurotoxicity.

DISTINCT EFFECTS OF MK-801 AND ()-2-AMINO-5-PHOSPHONOPENTANOIC ACID ON N-METHYL-D-ASPARTATE-INDUCED RISE OF BRAIN TEMPERATURE IN RATS

Intracerebroventricular (i.c.v.) administration of N-methyl-D-aspartate (NMDA) caused a biphasic rise of brain temperature, namely, a rapid, early rise and a larger, late rise, in urethane-anesthetized rats. I.c.v. pretreatment with a noncompetitive NMDA receptor antagonist, MK-801, attenuated the late rise of the brain temperature, but had no effect on the early rise, whereas i.c.v. pretreatment with a competitive NMDA receptor antagonist, (+/-)-2-amino-5-phosphonopentanoic acid (AP-5), attenuated both rises. AP-5 per se caused a rise in brain temperature without any rise of rectal temperature, whereas MK-801 per se caused no significant change of the brain or rectal temperature. This rise by AP-5 was suppressed by MK-801, suggesting an agonistic effect of AP-5 on NMDA receptors in rat brain in vivo.

Characterization of temperature rise of the brain and the rectum following intracerebroventricular administration of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and kainate in rats

Intracerebroventricular administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) or kainate caused a rise of the temperature of the brain and the rectum in urethane-anesthetized rats. An AMPA-kainate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), significantly suppressed the AMPA- and kainate-induced rises of brain and rectal temperatures. An N-methyl-d-aspartate receptor antagonist, MK-801, also suppressed the rises of the brain and rectal temperatures induced by AMPA or kainate, but the profiles of the suppressive effects of MK-801 were different between rats treated with AMPA and kainate. An antipyretic agent, indomethacin, completely suppressed the AMPA-induced rises of brain and rectal temperatures. Although indomethacin completely suppressed the kainate-induced rise of the rectal temperature as well, the brain temperature was still raised. These findings suggest that distinct mechanisms may be involved in the temperature rise of the brain and the rectum mediated through AMPA and kainate receptor stimulation.

Inhibition of NMDA-induced increase in brain temperature by N-ω-nitro-l-arginine and indomethacin in rats

Intracerebroventricular administration of N-methyl-D-aspartate (NMDA) caused an increase in brain temperature, which appeared rapidly and preceded that in rectal temperature, in urethane-anesthetized rats. The increase in brain temperature was divided into two phases, an early increase and a late increase. Intracerebroventricular indomethacin, a cyclooxygenase inhibitor, completely abolished the NMDA-induced late increase, but not the early increase, in brain temperature. On the other hand, intracerebroventricular N-omega-nitro-L-arginine, a potent inhibitor of nitric oxide synthase, strongly suppressed both the early and the late increases. These findings suggest that both nitric oxide and prostaglandins may be involved in the increase in brain temperature after NMDA receptor activation.

Suppression of paraquat-induced wet dog shakes by nitric oxide synthase inhibitors in rats.

We have found that paraquat (PQ), a widely used herbicide, causes wet dog shakes (WDS), which involve the central opioid system, in rats. A non-selective nitric oxide (NO) synthase (NOS) inhibitor, N(omega)-nitro-L-arginine (L-NA), but not its less active enantiomer, N(omega)-nitro-D-arginine, decreased the PQ-induced WDS in a dose-related manner. A selective neuronal NOS inhibitor in vivo, 7-nitroindazole, also decreased the PQ-induced WDS. Although an opioid receptor antagonist, naloxone, reversed the suppressive effect of these NOS inhibitors on the PQ-induced WDS, L-arginine, an NO precursor, had no effect on it. These findings suggest that the suppression of the PQ-induced WDS by NOS inhibition is associated with the central opioid system and is insusceptible to exogenous L-arginine.

Sudden death caused by tension pneumothorax after rupture of a thoracic aortic aneurysm. Case report.

A rare case of fatal tension pneumothorax is reported. An aged Japanese man with marked subcutaneous emphysema of the neck was found collapsed in a betting office. He was ascertained to have left tension pneumothorax, based on radiographic examinations carried out before his death. At autopsy, severe pneumomediastinum was observed, and the descending thoracic aorta with a ruptured dissecting aneurysm was closely adhered to the left lung pleura. The hemorrhage spread into the pulmonary parenchyma and finally spouted out from the surface of the lung apex. Because the blood loss itself was not fatal in quantity, it is concluded that the patient died of tension pneumothorax caused by a lung penetration from the rupture of an aortic aneurysm.

Postmortem changes in the levels of monoamine metabolites in human cerebrospinal fluid

Four monoamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA), were determined in the cerebrospinal fluid (CSF) of cadavers, whose causes of death had been suicidal hanging (SH) or ischemic heart failure (IHF). The concentration of DOPAC increased in parallel with the increment of the postmortem interval (PMI) (r = 0.626), whereas the concentrations of HVA, MHPG and 5-HIAA did not. The correlation coefficient was further increased by considering each cause of death separately: i.e., SH, r = 0.761; IHF, r = 0.705. These findings suggest the possible usefulness of the DOPAC level in CSF for estimating PMI.

Effects of MPTP, MPP+, and paraquat on NADPH-dependent lipid peroxidation in mouse brain and lung microsomes

Both MPTP and MPP+ inhibited the NADPH-dependent microsomal LPO in mouse brain and lung. On the other hand, PQ significantly stimulated the LPO in brain microsomes in a dose-dependent manner. The herbicide, however, stimulated lung microsomal LPO only in a narrow concentration range, despite much higher P450 reductase activity in lung microsomes than that in brain microsomes. These findings suggest that the effect of PQ on microsomal LPO is different from those of the analogous neurotoxins, MPTP and MPP+, and is not uniform in brain and lung.