Yoshitoshi Kasé

Electrophoretic study of pipecolic acid, a biogenic imino acid, in the mammalian brain ☆

Pipecolic acid (PA), one of the imino acids, is a normal constituent in the mammalian brain. It is said that PA is a major intermediate of lysine metabolism in the rat brain. Biochemical studies have suggested that PA may be involved in the regulation of synaptic mechanism in the CNS. Moreover, the pathophysiological significance of PA has been also suggested by some investigators. However, there has so far been no good evidence based on the comprehensive electrophysiological experiments. Using unit recording and microelectrophoretic technique, the action of PA on single neuron activities in the rat brain was examined. PA depressed the firing of 88 out of 115 cortical neurons tested. Only 2 were excited and 25 remained unaffected. All the identified hippocampal pyramidal neurons examined were uniformly inhibited. It has been reported that PA inhibits the uptake of GABA into the brain slices and enhances the release of GABA from the slices. Thus, it is likely that the inhibitory response due to PA may have some connections with GABAergic transmission. On the other hand, it remains to be clarified whether the specific PA sensitive receptors exist in the brain. Our findings provide a clue to the elucidation of the presumed synaptic involvement of PA in the CNS.

Pipecolic acid in the dog brain

Abstract Pipecolic acid is an intermdiary metabolite of lysine and is decarboxylated to produce piperidine, an endogenous synaptotropic substance. In the present study, the existence of pipecolic acid in the dog brain was confirmed. It was present in highest concentration in the cerebellum followed by the diencephalon and caudate nucleus, and this distribution resembles that of piperidine in dog brain. It seems to be evident that pipecolic acid is a precursor of piperidine in the brain.

Effects of cyclodextrins on chlorpromazine-induced haemolysis and central nervous system responses

Cyclodextrins (CyDs) protected the human erythrocytes from haemolysis induced with chlorpromazine (CPZ) in isotonic solution, depending upon the magnitude of the stability constant of CPZ‐CyD complexes (β‐> γ‐> α‐CyD). From the observations of CPZ uptake into erythrocytes and changes in surface activity of CPZ, the protective effects of CyDs in vitro appeared to be due to the decrease in effective haemolytic concentration of CPZ through inclusion complex formation rather than the direct interaction of CyDs with the erythrocyte membrane. The effect of β‐CyD on some central nervous system (c.n.s.) actions of CPZ in rats was also investigated to see if there were any advantages in the use of β‐CyD complexes given by injection. The results suggest that β‐CyD does not alter the time‐course or magnitude of the effects of CPZ on the c.n.s.

Pipecolic acid: a new type of α-amino acid possessing bicuculline-sensiti action in the mammalian brain

Using unit recording and electrophoretic techniques, pharmacological properties of pipecolic acid (PA) were studied in the brain neurons of rats. PA response was blocked by bicuculline more effectively than GABA response but not blocked by strychnine. Stereochemical findings obtained using the HGS-model demonstrated that PA structure is almost the same as a part of bicuculline structure. The present results suggest that PA might be a new type of substance possessing bicuculline-sensitive action. The site of the action of PA was also discussed.

Piperidine in the cerebellum of the dog

LOCKETT, 1949; KAsB, MIYATA and YUIZONO, 1967) and on the central nervous system (CNS). Like acetylcholine and nicotine, it produces central synaptic stimulation in small doses and depression in large doses as indicated by enhancement and reduction in the transcallosal evoked potential. It also produces emesis by acting on the medullary chemoreceptor trigger zone (KAsb, MIYATA, KAMIKAWA and KATAOKA, 1969~). A tranquillizing action has been reported in schizophrenic patients (TASHER, ABOOD, GIBBS and GIBBS, 1960), and the irritability of ‘fighting mice’ and ‘rage’ in rats after extirpation of the olfactory bulbs (KAsB et al., 1969a) Piperidine is a normal constituent of the mammalian brain (HONEGGER and HONEGGER, 1960; PERRY, HANSEN and MACDOUGALL, 1967; KAsB, KATAOKA and MIYATA, 19696), human cerebrospinal fluid (PERRY, HANSEN and JENKINS, 1964) and human urine (EULER, 1944; BLAU, 1961; KASE ef al., 19696). When tritiated piperidine is given intravenously to the rabbit, it is distributed in the brain and is particularly concentrated in the caudate nucleus (ABOOD, RINALDI and EAGLETON, 1961). In mice, intraperitoneal administration of piperidine causes an increase in muscular tone, muscular fasciculation, tremor and convulsions and also potentiates tremorine-induced tremor and is followed by death (KAsk et al., 1969~). On the other hand, a prior intraventricular injection of piperidine prevents the tremor (KAsE et a/., 1969~). Piperidine produces muscle relaxation and weakness, ataxia and the generalized decrease in motor responsiveness in rats (KAsB et a/., 1969a) and rabbits (ABOOD et al., 1961). Piperidine can be produced in oitro from pipecolic acid, which is an intermediate of lysine metabolism and exists in serum, urine (TOMINAGA and HIKAWA, 1957) and the brain (KAsE, KATAOKA and MIYATA, in preparation) of rats, by decarboxylase in the brain tissue

Simultaneous analysis of pipecolic acid with proline in the brain by selected ion-monitoring technique

Abstract A method for the simultaneous analysis of pipecolic acid and proline in the brain is developed. The qualification and quantification of pipecolic acid and proline are accomplished with gas chromatography/mass spectrometry including a selected ion-monitoring technique by using deuterium-labeled proline as an internal standard, after the amino and carboxylic groups of these cyclic amino acids are derivatized with boron trifluoride methanol complex and heptafluorobutyric anhydride. The lower limit of quantification for the method is picomole levels and the concentration of pipecolic acid and proline in rat whole brain is determined to be 1.05 and 71.50 nmol/g of tissue, respectively.

Effects of intracerebral administration of piperidine on EEG and behavior

Summary Effects of intracerebral administration of piperidine, a normal constituent of the mammalian brain, on EEG and behavior were examined in freely moving cats. 1) Administration into hippocampus or amygdalae caused resting and calmness in small doses, and seizure discharge accompanied by hyperemotionality in large doses. 2) Administration into pontine reticular formation induced slow wave and fast wave sleeps. 3) Administration into cerebellum caused remarkable changes in the extrapyramidal function. The findings seem to support our presumption that piperidine affects neural mechanisms serving regulation of emotional behavior, sleeping and extrapyramidal function.

Analysis of physiological variations of piperidine levels in tissues by mass fragmentography

Abstract By use of a mass fragmentographic technique the distribution of piperidine in tissues and changes in levels under physiological conditions were examined. Only trace amounts of piperidine existed in the brain of several animal species, although higher concentrations were detected in other species. In the brain of rats and rabbits, some regional differences were seen and high concentrations were found in the striatum. Piperidine levels in the brain and adrenal gland similarly showed the daily and seasonal rhythmic fluctuations.

Influence of cerebral cortex stimulation upon cough-like spasmodic expiratory response (SER) and cough in the cat

In 27 pentobarbitalized cats, the influence of electrical stimulation of the cerebral cortex upon the spasmodic expiratory response (SER) was studied and compared with cortical influences on coughing induced by stimulation of the superior laryngeal nerve (sup. laryngeal N.). This cortical influence was evoked by electrical stimulation of the cortical nucleus of amygdala (Aco), and was very similar to coughing accompanying changes in emotional behavior and was depressed more effectively by psychotropics than by centrally acting antitussives like codeine. When anterior cingulate gyrus (ant. cingulate G.) or orbital gyrus (orbital G.) were stimulated simultaneously with Aco or sup. laryngeal N., weak stimulation was sufficient to inhibit SER, while stronger stimuli were needed for the suppression of cough. If the same cortical regions were stimulated after initiation of SER or cough, SER was markedly suppressed but cough little affected. Production of SER was facilitated by simultaneous stimulation of the piriform lobe (piriform L.) or olfactory tract (olfactory T.), whereas cough production was facilitated by simultaneous stimulation of the suprasylvian gyrus. These results suggest that SER and coughing are differently controlled by the cerebral cortex, and that SER is modulated by the limbic cortex, in particular, by ant. cingulate G., orbital G. and piriform L. The mechanism of modulation for SER is discussed.

Pipecolic acid enhancement of GABA response in single neurons of rat brain

Using unit recording and microelectrophoresis, influence of pipecolic acid (PA), a major metabolite of lysine in the brain, on GABA and glycine responses was studied in the cerebral cortical and hippocampal pyramidal neurons of rats. With small currents, PA had no effect on the single neuron activities but enhanced GABA response without affecting glycine response. The finding provides a new evidence that PA may have a connection with central GABA system.