Mikiko Kataoka

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.

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.

Potentiation of phenobarbital-induced anticonvulsant activity by pipecolic acid

Pipecolic acid (PA) is an intermediate of lysine metabolism in the mammalian brain. Recent findings suggest a functional connection of PA as neuromodulator in GABAergic transmission. Since many drugs are postulated to produce their effects by interaction with the central GABA system, the influence of PA on the anticonvulsant activity of phenobarbital was examined. Pretreatment of mice with 50 mg . kg-1 of PA potentiated the suppressing effects of the barbiturate on electrically and chemically induced convulsions. However, there was no potentiation of the behavioral effects and hypothermia induced by phenobarbital. PA itself had no or only little effect on the convulsions, motor function and rectal temperature when given in i.p. doses up to 500 mg . kg-1. Intraventricular administration of 500 microgram of PA also did not suppress either type of convulsion, although it produced ptosis, hypotonia, sedation and hypothermia. The results are discussed in relation to GABA system.

Significance of magnetic resonance image and blood manganese measurement for the assessment of brain manganese during total parenteral nutrition in rats

In this study, we report on the influence of trace elements (TE) on signal intensities of nuclear magnetic resonance images (MRI), both in vivo and in vitro. Optimal parameters for the assessment of Mn concentration in the brain of rats on total parenteral nutrition were established.For the in vitro study, Mn and trace element solutions, one containing Zn, Cu, Fe, and I (TE-4) and another containing the above elements plus Mn (TE-5), were diluted with physiological saline or with rat brain homogenate and used to measure signal intensities in MRI. Concentration-dependent signal hyperintensity was observed in both cases in the Mn and the TE-5 solutions, but no effect was observed with the TE-4 solution. The signal increase was greater for brain tissue homogenates.In the in vivo study, the experimental animals were maintained under total parenteral nutrition (TPN) with a standard clinical dose of TE-5 and/or with 10-fold the clinical dose of TE-4 and TE-5 for 1 wk. Only rats that were receiving the increased TE-5 dose showed signal hyperintensity on MRI. Positive correlations were observed among the signal hyperintensity, the blood Mn concentrations, and that of the rat brain.Our results suggest that Mn in TE preparations may be the cause of signal hyperintensity on MRI in a concentration-dependent fashion, and that MRI and measurement of blood Mn may be used to estimate Mn accumulation in brain tissue.

Anti-inflammatory effects of BX661A, a novel therapeutic drug for ulcerative colitis.

To clarify the mechanism of action of 5- [4- (2-carboxyethylcarbamoyl) -phenylazo] -salicylic acid disodium salt dehydrate (BX661A) as a therapeutic drug for ulcerative colitis, we investigated the effects on carrageenin edema, adjuvant arthritis, polymorphonuclear leukocyte (PMN) chemotaxis and degranulation of mesenteric mast cell, and following results were obtained.1. Although BX661A, salazosulfapyridine (SASP), 4-aminobenzoyl-β-alanine (4-ABA) and sulfapyridine (SP) did not inhibit the carrageenin edema at pretreatment for 30 min, BX661A and SASP showed the inhibitory effect on carrageenin edema at pretreatment for 8 hrs.2. SASP showed the slight therapeutic effect on adjuvant arthritis, but BX661A and 5-aminosalicylic acid (5-ASA) had no effect.3. BX661A, SASP and SP dose-dependently inhibited the PMN chemotaxis induced by zymosan-treated serum, N-formyl-methionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4) . 4-ABA only inhibited the FMLP-induced chemotaxis. On the other hand, 5-ASA at concentration up to 10 mM exhibited almost no effects on all PMN chemotaxis.4. BX661A, SASP and SP dose-dependently inhibited the mast cell degranulation induced by compound 48/80, substance P and IgE. 5-ASA showed the inhibitory effects on compound 48/80 and IgE-induced mast cell degranulation, but 4-ABA only inhibited the IgE-induced degranulation.From these results, it was suggested that inhibitory effect of BX661A on carrageenin-induced edema may be due to 5-ASA, further that inhibitory effects on PMN chemotaxis activity and degranulation of mesenteric mast cell partially may be concerned in therapeutic effects of BX661A on ulcerative colitis.

ANTITUSSIVE ACTIVITY AND OTHER RELATED PHARMA-COLOGICAL PROPERTIES OF 2-ALLYLOXY-4-CHLORO-N-(2-PIPERIDINOETHYL) BENZAMIDE AND ITS CONGENERS

In a study of structure-activity relationship in antitussive agents, a working hypothesis has been presented that the introduction of a piperidino group into a compound showing any actions on the central nervous system, can produce antitussive activity if the activity has been latent, or strengthen it if such activity is already manifest (1, 2). In the previous study, antitussive activity of 2-allyloxy-4-chloro-N-(2-diethylaminoethyl) benzamide (264-CE, Hexacol®) had been investigated and it was found that the activity of the drug was 1/4 to 1/3 as potent as that of codeine (3). Therefore, in order to strengthen the antitussive activity, 2-allyloxy-4-chloro-N-(2-piperidinoethyl) benzamide (abbreviated as 264CP) in which a piperidino group was introduced in stead of a diethylamino group in the structure of 264CE was synthesized. Other 6 compounds including amino groups such as pyrrolidino, morpholino, piperazino, dimethylamino and primary amino groups in stead of a diethylamino group, and a trifluoromethyl group in stead of chlor (2-allyloxy-4-trifluoromethyl-N-(2-diethylaminoethyl) benzamide, 305-CE) were also synthesized for testing their antitussive activities. In the present experiment, the antitussive actions and other pharmacological actions of these 7 compounds, especially those of 264CP, have been compared with those of 264-CE.