Yoshiki Matsui

Monoamine oxidase inhibitors prevent striatal neuronal necrosis induced by transient forebrain ischemia

Seven days after 30 min of ischemia, neuronal necrosis was observed in the striatum. Pretreatment with type A monoamine oxidase (MAO-A) inhibitors, clorgyline and RS-8359 ((+)-4-(4-cyanoanilino)-7-hydroxycyclopenta (3,2-e) pyrimidine) decreased significantly the number of necrotic neurons and inhibited changes in the dopamine metabolite contents during and after transient ischemia. An MAO-B inhibitor, deprenyl also decreased the neuronal necrosis, but it inhibited only the changes in 3,4-dihydroxyphenylacetic acid (DOPAC) content after reperfusion. The results suggest that the activation of dopamine metabolism after transient ischemia was mainly mediated by MAO-A and partly by MAO-B and suggest a possible role of dopamine deamination by MAO in the development of ischemic neuronal necrosis.

Output, Tissue Levels, and Synthesis of Acetylcholine During and After Transient Forebrain Ischemia in the Rat

Abstract: Biochemical changes in the rat brain cholinergic system during and after 60 min of ischemia were studied using a four‐vessel occlusion model. Extracellular acetylcholine (ACh) concentrations in the unanesthetized rat hippocampus markedly increased during ischemia and reached a peak (about 13.5 times baseline levels) at 5–10 min after the onset of ischemia. At 2–5 h after reperfusion, extracellular ACh concentrations were reduced to 64–72% of the levels of controls. ACh levels in the hippocampus, striatum, and cortex decreased significantly during ischemia and exceeded their control values just after reperfusion. A significant increase in hippocampal ACh level after 2 days of reperfusion and a decrease in [14C]ACh synthesis from [14C]glucose in hippocampal slices excised at 2 days after reperfusion were observed. The extracellular concentrations and tissue levels of choline markedly increased after ischemia. These results show that ACh is markedly released into the extracellular space in the hippocampus during ischemia, and they suggest that ACh synthesis is activated just after reperfusion and that cholinergic activity is reduced after 2–48 h of reperfusion in the hippocampus.

S-adenosyl-L-methionine prevents ischemic neuronal death

The effect of S-adenosyl-L-methionine (SAM) on neuronal degeneration induced by transient forebrain ischemia was studied in rats. Bilateral occlusion of the common carotid arteries for 30 min in a 4-vessel occlusion model caused degeneration of CA1 neurons of the hippocampus. When SAM-HCl or SAM sulphate tosylate (SAM-ST, 100 mg/kg as the free form of SAM, i.p.) was administered just after recirculation and every hour for 5 h after recirculation, the degeneration and loss of pyramidal cells were prevented. However, adenosine, a metabolite of SAM, and glycerol, which has the same osmotic pressure as the solution of SAM-ST, did not show any effects on the neuronal damage. The results showed that SAM has a beneficial effect on neuronal damage induced by ischemia.

Cataleptic and anticataleptic effects of muscimol and gabaculine injected into globus pallidus and substantia nigra, and interactions with haloperidol or benzodiazepines

SummaryIntranigral injection of muscimol induced hyperactivity in rats and antagonized haloperidol-induced catalepsy. Intranigral injection of gabaculine, an inhibitor of GABA transaminase, induced similar effects 5 h after injection, when the nigral GABA content was increased 7-fold. On the other hand, injections of muscimol (30 ng) into the globus pallidus potentiated the cataleptic effect of haloperidol, and muscimol alone in high doses (100 and 200 ng) induced catalepsy. Gabaculine also induced catalepsy of medium intensity and potentiated the effect of haloperidol 24 h after injection, when GABA was increased in the globus pallidus as well as in the substantia nigra. Injections of muscimol into either the globus pallidus or substantia nigra increased striatal HVA and enhanced haloperidol-induced elevation of HVA.Three benzodiazepines, nitrazepam, diazepam and chlordiazepoxide administered orally, potentiated the effect of muscimol (30 ng) injected into the globus pallidus and induced catalepsy. A similar effect was not obtained with phenobarbital.It is suggested that stimulation of GABA receptor or increase of GABA content in the sustantia nigra antagonize haloperidol-induced catalepsy by activation of nigral dopaminergic system, and that enhancement of pallidal GABA function induces catalepsy by non-dopaminergic mechanisms. Potentiation of haloperidol-induced catalepsy by benzodiazepines may be due to enhancement of GABA-ergic transmission within the globus pallidus.

Enhancement of the analgesic effect of morphine by sodium diethyldithiocarbamate in rats

Nach DDC-Vorbehandlung wurde bei männlichen Ratten eine deutliche Potenzierung der Morphinanalgesie beobachtet. Es konnte nachgewiesen werden, dass dieses Phänomen nicht durch die nach DDC-Gabe auftretende Veränderung des CA-Gehaltes im Gehirn bedingt ist.

Accumulation of copper in the central nervous system on prolonged administration of sodium diethyldithiocarbamate to rats

Summary Prolonged administration of sodium diethyldithiocarbamate (DDC) to rats caused accumulation of copper in the cerebral cortex, brain stem and spinal cord, but not cerebellum. The serum copper and ceruloplasmin levels were not affected by DDC. The results are discussed in connection with the mechanism of potentiation of morphine analgesia by DDC in rats.

Potentiation of muscimol‐induced hyperactivity by benzodiazepines

When GABA-mimetic agents, inhibitors of GABAtransaminase or GABA agonists, are administered systemically, animals show catalepsy, sedation and hypokinesia (Naik et a1 1976; Benton & Rick 1976; Matsui & Deguchi 1977). However, when these drugs are injected intracerebrally, animals show varying behaviour according to the injection site; for example, pallidal injection induces akinesia (Pycock & Horton 1976) while nigral injection induces hyperactivity (Scheelu i iger et a1 1977; Matsui & Kamioka 1978a). Benzodiazepines are thought to bring about their various effects by facilitation of GABA-ergic transmission in the central nervous system (Haefely et al 1975) and potentiating the effect of GABA-mimetic agents (Polc et al 1974; Naik et a1 1976). We have found that benzodiazepines potentiate the effect of the GABA agonist, muscimol, injected into the globus pallidus to induce catalepsy (Matsui & Kamioka 1978b). In this paper, we examine whether benzodiazepines also potentiate the hyperactivity induced by muscimol injected into the substantia nigra. Non-anaesthetized male Wistar-Imamichi rats (250300 g) were injected with muscimol (0.5 p1/10 s) bilaterally into the substantia nigra through guide cannulae (0.d. 0.7 mm), which were stereotaxically implanted under sodium pentobarbitone (Abbott laboratories, 40 mg kg-l, i.p.) 4 days before injection, using stainless steel needles (0.d. 0.35 mm) and the stereotaxic atlas of Pellegrino & Cushman (1967). The muscimol was given 60 min after rats were placed singly in a Perspex box on the Valimex (Columbus Instruments, Ohio). The rats were returned immediately to the Perspex box and locomotor activity recorded cumulatively over 60 min. Nitrazepam (Sankyo Co., Ltd.), diazepam (Takeda pharmaceutical Ind., Ltd.) or chlordiazepoxide (Takeda) were suspended in 1 % carboxymethyl cellulose (CMC) and administered orally 30 min before injection of muscimol. Muscimol was synthesized in our laboratories. The brains were later examined histologically and data obtained from rats with placement errors were discarded. Fig. 1 shows the effects of intranigral injection of muscimol on locomotor activity and the interaction with benzodiazepines. When 3 ng of muscimol was injected into the substantia nigra, rats showed continuous sniffing and headmovements and the counts measured on the Valimex increased significantly compared with those of the saline-injected group. Muscimol, 10 and 30 ng, further increased the hyperactivity. Nitrazepam, 0.3 mg kg-l, diazepam, 1 mg kg-I, and

Plasma copper levels and their significance in morphine analgesia and tolerance.

Abstract Morphine lowered plasma copper content. However after of sodium diethyldithiocarbamate, which decreased the copper level markedly and potentiated morphine analgesia, it caused no further decrease. This action of morphine was antagonized by levallorphan which elevated plasma copper concentration. In morphine tolerant rats, there was a marked increase in plasma copper level which was partially reversed by morphine withdrawal. When sodium diethldithiocarbamate was administered to the morphine tolerant animals, morphine analgesia reappeared, and the elevated copper level was markedly decreased. These results indicate that the changes in copper level in plasma, or the mechanisms mediating these alterations and/or the results caused by these fluctuations may be related to the manifestation of morphine analgesia and tolerance.

Change of copper concentration in the central nervous system after morphine treatment and effect of copper on morphine analgesia in rats

Summary Morphine increased the concentration of copper in the spinal cord. This was antagonized by simultaneous injection of levallorphan, which injected alone did not influence the copper content of nervous tissues. In morphine tolerant rats, the copper content of the cerebral cortex was lower than that of control animals 4 hr after the last injection of morphine. Intraperitoneal injection of copper sulphate enhanced the analgesic action of morphine as evidenced by a rise in the threshold tail clip pressure. The relations of morphine analgesia, morphine tolerance and copper metabolism are discussed.