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Biomedical subjects

K Kisara

Publications and source records attributed to K Kisara.

At least 91 records · Page 5Linked to original sources
PubMed1992

[Pharmacological studies of nutritive and tonic crude drugs on fatigue in mice].

The aim of the present study was to clarify acute anti-fatiguing effects of three crude liquid drug preparations (S1-S3), containing almost the same amounts of Ginseng Radix, Epimedii Herba and Agkistrodon Japonicae, with each differentially containing an additional 11, 13 or 15 crude drugs. After preloading forced swimming or tetrabenazine (TBZ: 50, 100 mg/kg, i.p.), each of the S1-S3 preparations applied orally (0.1 ml/10 g) significantly increased the duration times of swimming together with decreased total duration times of immobility during swimming. These effects peaked 60 min postinjection with the following decreasing order of effectiveness: S3 > S2 > S1. The same order of efficacy was also found for increased locomotor activity and decreased durations of swimming immobility after TBZ. After pretreatment with 200 mg/kg TBZ preparations S1-S3 also increased the numbers of jumping on a hot plate with greatly reduced latency. Without preloading the forced swimming, S1-S3 did not have any effect on jumping and its latency, but both S2 and S3 significantly, but more weakly, as compared to those after its preloading, decreased the immobility times. These results indicate that these crude preparations may cause tonic effects and so far tested, these effects seem to be more effective on subjects fatigued with physical and/or mental works than an normal subjects.

Administration, Oral↗
PubMed1992

Antinociceptive mechanisms of [D-Arg2]-dermorphin tripeptide analogs.

These studies examined the antinociceptive effects and mechanisms of opioid activity of synthetic dermorphin tripeptide analogs containing D-Arg as the second amino acid, H-Tyr-D-Arg-Phe-NHCH3 and H-Tyr-D-Arg-Phe-N(CH3)2. Both tripeptides, administered i.c.v., i.t. and s.c. in mice, produced a potent and long-lasting antinociceptive activity as compared with morphine. In the guinea pig isolated ileum (GPI) assay, the IC50 value of both peptides was lower than that of morphine on the electrically induced contractions of the GPI. In radioligand binding studies with rat brain membrane synaptosomes, both tripeptides bound with high affinity to [3H]DAMGO-labeled mu-type sites, whereas they bound with no or negligible affinity to [3H]DPDPE-labeled delta sites and [3H]U-69593-labeled kappa sites. In the enzymatic degradation using high-performance liquid chromatography, both tripeptides showed good enzymatic stability after 25 hr of incubation with solubilized enzymes of mouse brain or spinal cord, in contrast to a rapid degradation of Met-enkephalin. The in vitro and in vivo pharmacological profile of [D-Arg2]-dermorphin tripeptide analogs demonstrates that they are potent and selective agonists at the mu opioid receptor. A high resistance of the tripeptides to enkephalin-degrading enzymes may largely contribute to their prolonged opioid activity.

Amino Acid Sequence↗
PubMed1992

A comparison of peripheral and central effects of clonidine on rat intestinal transit.

This study was designed to examine the effects of centrally or peripherally administered clonidine on small intestinal transit (SIT) in rats with diarrhea. Adult, male rats weighing 200 to 250 grams were surgically implanted with a silicone catheter in the proximal small intestine. Some animals were additionally implanted with a cannula in the right lateral cerebroventricle. SIT was determined by measuring the progression of an intraduodenally administered radioactive marker (Na2CrO4, 0.5uCi) along the small intestine. In most experiments, the effects of clonidine or saline were determined in animals challenged with sodium ricinoleate (100 mg) intraduodenally, the active ingredient in castor oil except treatment with reserpine. Given subcutaneously (s.c.) clonidine significantly inhibited SIT at doses between 25 and 200 micrograms/kg. The effects of s.c. clonidine were antagonized by yohimbine, but not by reserpine or subdiaphragmatic truncal vagotomy. In contrast, given intracerebroventricularly (i.c.v.) clonidine produced a more long lasting effect at total doses greater than 20 micrograms. Intestinal antipropulsive effects of i.c.v. clonidine were blocked by yohimbine, but not by prazosin. Reserpine (s.c.) or 6-hydroxydopamine (i.c.v.) did not affect the actions of central clonidine. However, effects of i.c.v. clonidine were abolished after vagotomy. The results indicate that clonidine inhibits rat intestinal transit in similar total doses when given s.c. or i.c.v. Inhibition of SIT by clonidine results from alpha-2 adrenergic receptor activation. In the case of i.c.v. clonidine, the receptors appear to be located postsynaptically and the response is dependent upon intact vagal innervation.

Adrenergic alpha-Antagonists↗
PubMed1991

Inhibition of monoamine oxidase by two substrate-analogues, with different preferences for 5-hydroxytryptamine neurons.

Various intraperitoneal doses of 5-fluoro-alpha-methyltryptamine (5-FMT), given to mice, dose-dependently inhibited only MAOA activity, with similar degrees of inhibition in the striatum, hypothalamus and the rest of the forebrain. The activity inhibited in these regions, completely recovered to control levels within 24 hr after the injection. In contrast, p-chloro-beta-methylphenethylamine (p-CMP), selectively inhibited MAOB activity, with complete recovery within 45 min after the injection. Regardless of the differences in time interval and degree of inhibition of MAOA by 5-FMT or MAOB by p-CMP, both kinds of inhibition were competitive, with respect to oxidation of the respective substrate. 5-Fluoro-alpha-methyltryptamine markedly protected only MAOA against inhibition by phenelzine, without protecting MAOB. Also, 5-FMT greatly increased one kind of animal behaviour, the head-twitch and this behaviour was greatly reduced by treatment with fluoxetine, but increased by reserpine. The results indicate that p-CMP is a short-acting, probably reversible, MAOB-selective inhibitor and 5-FMT has the same characteristics of selectivity for MAOA in central serotonergic neurons.

Animals↗
PubMed1991

Inhibition of rat brain monoamine oxidase activity by cerebral anti-ischemic agent, ifenprodil.

Ifenprodil, which is clinically used as a cerebral vasodilator, inhibited rat brain type A (MAO-A) and type B (MAO-B) monoamine oxidase activity. It did not, however, affect rat lung semicarbazide-sensitive amine oxidase. The degree of inhibition of either form of MAO was not changed by 30 min preincubation of the enzyme preparations at 37 degrees C with ifenprodil. Modes of inhibition of MAO-A and MAO-B by ifenprodil were competitive towards oxidation of their respective substrates, 5-hydroxytryptamine and benzylamine, with Ki values of 75 microM for inhibition of MAO-A and 110 microM for inhibition of MAO-B.

Amine Oxidase (Copper-Containing)↗
PubMed1991

Inhibition of brain MAO-A and animal behaviour induced by p-hydroxyamphetamine.

Intra- and extra-synaptosomal activity of monoamine oxidase-A (MAO-A) and -B (MAO-B), dopamine (DA) and its main metabolites were examined to clarify the mechanism of action(s) of p-hydroxyamphetamine (p-OHA) in animal behaviour mediated by central dopaminergic systems. Intrasynaptosomal DA was oxidized by MAO-A and MAO-B and this oxidation is inhibited by p-OHA. The inhibition is due to two effects: 1) uptake of DA is inhibited by p-OHA, and 2) p-OHA also inhibits intrasynaptosomal oxidation of DA by MAO-A and MAO-B. The inhibition of oxidation by MAO-A is predominant. Administration (ICV) of 80 and 160 micrograms p-OHA to mice, doses that cause various behavioural, significantly reduced striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels, but greatly increased 3-methoxytyramine, without significantly changing homovanillic acid (HVA). The release of DA and blockade of DA uptake into dopaminergic neurons by p-OHA, together with preferential inhibition of the DA metabolizing enzyme, MAO-A, may contribute to p-OHA-induced behaviour mediated by the central dopaminergic systems.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Changes in ingestive behavior induced by intracranial injection of spermine.

Effect of intracranial injection of spermine on feeding and drinking behavior was studied in rats. A significant and long-term suppression of feeding and drinking behavior appeared when 30 nmol/hemisphere of spermine was bilaterally injected into the lateral hypothalamic area, substantia nigra or ventral noradrenergic bundle. Micro-injected spermine into the medial amygdaloid nucleus produced a weak and short-time but significant suppression of ingestive behavior. On the other hand, a significant increase in feeding and drinking behavior was observed when spermine was injected into the ventromedial hypothalamic nucleus. These results suggest that spermine inhibits neuronal activity of all the brain regions studied here.

Animals↗
PubMed1991

Differential effects of substance P analogs on neurokinin 1 receptor agonists in the mouse spinal cord.

Effects of five substance P (SP) analogs on the licking, biting and scratching response induced by neurokinin (NK) 1 receptor agonists such as SP, physalaemin and (p-Glu6,Pro9)-SP (6-11) (septide) were studied after intrathecal injections in mice. Septide brought about a SP-like behavioral response, and was approximately 25 times more potent than the D-Pro9 analog, D-septide. When administered simultaneously with NK-1 receptor agonists, a putative SP antagonist, spantide inhibited SP-, physalaemin- and septide-induced behavioral response in a dose-dependent manner with ED50 values of 1.0, 0.65 and 1.3 nmol/mouse, respectively. Septide-induced response was significantly reduced by lower doses of (D-Arg1, D-Pro2,4, D-Phe7, D-His9, Leu11)-SP than (D-Phe7, D-His9, Leu11)-SP (6-11). In contrast, (D-Arg1, D-Pro2,4, D-Phe7, D-His9)-SP (0.5-1.0 nmol) and (D-Phe7, D-His9)-SP (6-11) (0.5-2.0 nmol) inhibited only SP-induced behavioral response, but not physalaemin- or septide-induced response. The results of this study indicate that NK-1 receptor agonists are not necessarily affected to a same degree by SP analogs containing D-His. These findings may be interpreted as indicative of the existence of different NK-1 receptor subtypes.

Analgesics↗
PubMed1990

N-terminal substance P fragments inhibit the spinally induced, NK 1 receptor mediated behavioural responses in mice.

N-terminal fragments of substance P (SP) were tested for antagonism against the aversive responses induced in mice by various tachykinin receptor agonists, somatostatin and bombesin. When co-administered with SP intrathecally, low doses (1.0-4.0 pmol) of SP (1-7) or SP (1-8) reduced the SP-induced behavioural responses of scratching, biting and licking. Aversive responses induced by two other neurokinin (NK) 1 receptor agonists, Septide and physalaemin, were also dose-dependently decreased by the simultaneous injection of small doses of SP (1-7) or SP (1-8). Aversive responses induced by 400 pmol of NK A were also significantly reduced by co-administration of SP (1-7) or SP (1-8). No significant effects of the N-terminal fragments were observed against the aversive responses elicited by NK A (300 pmol), eledoisin, NK B, somatostatin or bombesin. These results suggest that the behavioural antagonism produced by SP (1-7) and SP (1-8) may be limited to the NK 1 receptor at the spinal level in mice.

Animals↗
PubMed1990

N-terminal tetrapeptide of dermorphin and D-Arg-substituted tetrapeptides: inactivation process of the antinociceptive activity by peptidase.

Degradation products of the N-terminal tetrapeptide of dermorphin, H-Tyr-D-Ala-Phe-Gly-OH (ALPG) and D-Arg2-substituted tetrapeptide analogs of dermorphin, H-Tyr-D-Arg-Phe-Gly-OH (ARPG), H-Tyr-D-Arg-Phe-Gly-NH2 (TDAPG-NH2) and H-Tyr-D-Arg-Phe-beta-Ala-OH (TDAPA) by enkephalin degrading enzymes were studied by using reversed-phase high-performance liquid chromatography. After 5 and 25 hr incubations of the peptides with solubilized enzymes of mouse brain or spinal cord, liberation of the appreciable Tyr1 residue was observed in ALPG but not in ARPG, TDAPG-NH2 and TDAPA. When ARPG and TDAPG-NH2 were incubated with enzymes for 25 hr, a main degradation product was the N-terminal tripeptide produced from the hydrolysis of Phe3-Gly4 bond. Conversely, TDAPA did not produce the N-terminal tripeptide after 25 hr incubation with enzymes. In the enzyme assay, Tyr1-D-Arg2 bond of ARPG, TDAPG-NH2 and TDAPA was more stable than that of ALPG to the cleavage by aminopeptidase M (AP-M). Phe3-Gly4 bond of ALPG, ARPG and TDAPG-NH2 were easily hydrolyzed by carboxypeptidase Y (CP-Y) within 3 hr incubation, whereas the hydrolysis of Phe3-beta-Ala4 bond of TDAPA by CP-Y was not observed after 3 hr incubation. The present results and previous behavioural data suggest that a potent and prolonged antinociceptive activity of the D-Arg-substituted tetrapeptides is mainly attributed to the stability of Tyr1-D-Arg2 bond against aminopeptidase of peptidases.

Amino Acid Sequence↗
PubMed1990

Spinal antinociception: comparison of a dermorphin tetrapeptide analogue, [D-arginine2, sarcosine4]-dermorphin (1-4) and morphine in rats.

Intracerebroventricular injections of [D-arginine2, sarcosine4]-dermorphin (1-4) (DAS-DER 1-4) and morphine produced a dose-dependent inhibition of the tail-flick response to thermal stimulation. The ED50 value for each drug was 3.23 (1.35-7.73) nmol/rat and 32.0 (13.3-76.6) nmol/rat, respectively. When injected into the spinal subarachnoid space, the ED50 value was 0.035 (0.015-0.086) nmol/rat for the tetrapeptide and 11.9 (5.7-25.2) nmol/rat for morphine, respectively. Antinociception induced by DAS-DER 1-4 and morphine, through the intracerebroventricular and intrathecal routes, was clearly reduced by pretreatment with a small dose of naloxone. After spinal transection, the antinociceptive potency of systemically-administered morphine was significantly reduced while that of DAS-DER 1-4 was unaltered. The activity of DAS-DER 1-4 and morphine was also reversed by naloxone in spinal animals. It is concluded that DAS-DER 1-4, a dermorphin analogue, has a minor supraspinal action but acts mainly at the level of the spinal cord, in contrast to the action of morphine.

Analgesics↗
PubMed1990

Phosphoramidon potentiates mammalian tachykinin-induced biting, licking and scratching behaviour in mice.

The effects of peptidase inhibitors were examined upon behavioural responses including scratch, bite and lick produced by intrathecal (IT) injection of substance P (SP) and neurokinin A (NK A) in mice. Phosphoramidon (0.002-2.0 nmol), an endopeptidase-24.11 inhibitor, simultaneously injected with SP or NK A, remarkably enhanced and prolonged SP- or NK A-induced behavioural response in a dose-dependent manner. The behavioural response to SP was significantly increased by 2.0 nmol of bestatin, an aminopeptidase inhibitor, but not by 1.0 nmol. Captopril, an angiotensin-converting enzyme inhibitor, was without effect on both tachykinin-induced responses. When phosphoramidon was injected together with bestatin and captopril which have no significant effect alone, SP- or NK A-induced behavioral response was significantly increased. These data suggest that endopeptidase-24.11 may be an important enzyme responsible for terminating of SP- or NK A-induced behavioral response at the spinal cord level.

Aggression↗
PubMed1990

Monosodium urate test: a new analgesic test by crystal-induced monoarthritis in rats.

The analgesic effects of various agents were evaluated in knee joint monoarthritic rats where arthritis was induced by monosodium urate (MSU) crystals injected into the knee joint cavities. The weight supported by each hind limb was measured quantitatively using pressure transducers, which revealed dose-dependent recovery produced by various analgesics including morphine but no changes in value by sedatives such as chlorpromazine. Relative potency obtained from the value of ED50 of each analgesic agent was congruent with that in clinical use. The MSU test may be quite suitable for quantitative and objective evaluation of the analgesic effects of various agents, particularly for spontaneous and tonic pain.

Analgesia↗
PubMed1990

Inhibition of brain type A monoamine oxidase and 5-hydroxytryptamine uptake by two amphetamine metabolites, p-hydroxyamphetamine and p-hydroxynorephedrine.

Two amphetamine metabolites, p-hydroxyamphetamine (p-OHA) and p-hydroxynorephedrine (p-OHN), selectively inhibited the A form of monoamine oxidase (MAO) in rat and mouse forebrain homogenates. Of these two metabolites, p-OHA inhibited MAO-A more strongly than p-OHN. This MAO-A-selective inhibition by p-OHA or p-OHN was found to be competitive with respect to deamination of its substrate, 5-hydroxytryptamine (5-HT). The degree of MAO-A inhibition was not changed by 90 min of preincubation of the enzyme preparations with either metabolite, and the activity inhibited by p-OHA after the preincubation recovered completely to the control level after repeated washing. Uptake of 5-HT or dopamine into mouse forebrain synaptosomes was highly reduced by both p-OHA and p-OHN. Both metabolites were more potent in reducing dopamine uptake than in reducing 5-HT uptake. In reduction of 5-HT and of dopamine uptake, p-OHA was more potent than p-OHN. These results indicate that p-OHA is a more selective inhibitor of brain MAO-A activity and 5-HT uptake than its subsequent metabolite, p-OHN. These two actions of p-OHA might, together with possible 5-HT efflux into the synaptic cleft, greatly contribute to head twitch, a brain 5-HT-mediated animal behavior induced by p-OHA.

Amphetamines↗
PubMed1990

The effects of substance P analogues on the scratching, biting and licking response induced by intrathecal injection of N-methyl-D-aspartate in mice.

1. Intrathecal (i.t.) administration of N-methyl-D-aspartate (NMDA) elicited a dose-dependent behavioural response consisting of licking, biting and scratching in mice. 2. Repeated i.t. injections of 0.4 nmol NMDA, at 5 min intervals, resulted in the rapid development of desensitization to this NMDA-induced behavioural phenomenon. 3. The NMDA-induced response was dose-dependently inhibited by the simultaneous injection of a selective NMDA-receptor antagonist, D-2-amino-5-phosphonovaleric acid. 4. The substance P (SP) analogues [D-Pro2, D-Trp7,9] SP and [D-Arg1, D-Trp7,9, Leu11] SP (spantide) inhibited NMDA-induced behavioural responses in a dose-dependent manner. However, [D-Phe7, D-His9] SP (6-11), a SP analogue selective for neurokinin1 (NK1) receptors, failed to inhibit NMDA-induced responses even at a dose of 4.0 nmol. 5. These results indicate that NMDA-induced behavioural responses are mainly mediated through NMDA receptors without affecting NK1 receptors in the spinal cord.

2-Amino-5-phosphonovalerate↗
PubMed1989

Substance P analogues containing D-histidine antagonize the behavioural effects of intrathecally co-administered substance P in mice.

The antagonistic effect of newly synthesized substance P (SP) analogues containing D-histidine was examined on behavioural responses induced in mice by SP, neurokinin (NK) A, physalaemin, eledoisin, somatostatin and bombesin. [D-Pro2,D-Trp7,9]SP (DPDT-SP) and [D-Arg1,D-Trp7,9,Leu11]SP (spantide) were used as references for comparison. When co-administered with SP intrathecally, all the SP analogues used decreased the SP-induced response which consists of scratching, biting and licking. DPDT-SP and spantide attenuated non-specifically the SP-like behavioural responses induced by physalaemin, eledoisin, NK A and somatostatin. In general, the introduction of D-histidine in position 9 of the SP molecule resulted in potent antagonistic activity of the SP derivative on the behavioural responses to SP. Of these SP analogues, [D-Arg1,D-Pro2,4,D-Phe7,D-His9]SP attenuated selectively the behavioural responses produced by NK-1 receptor agonists such as SP and physalaemin. Simultaneous injection of [D-Phe7,D-His9]SP-(6-11) selectively inhibited the SP-induced behavioural response without affecting the other peptide-induced behavioral response. The results suggest that the behavioural antagonism induced by [D-Arg1,D-Pro2,4,D-Phe7,D-His9]SP and [D-Phe7,D-His9]SP-(6-11) is probably due to the specific blockade of spinal NK-1 receptors.

Amino Acid Sequence↗
PubMed1989

Potentiation of para-hydroxyamphetamine-induced head-twitch response by inhibition of monoamine oxidase type A in the brain.

After pretreatment with either clorgyline, a monoamine oxidase (MAO)-A-selective inhibitor, or pargyline, an MAO-B-selective inhibitor with less selectivity than l-deprenyl, i.c.v. administration of para-hydroxyamphetamine (p-OHA) significantly increased both the frequency and total number of head-twitches in mice. A typical MAO-B-selective inhibitor, l-deprenyl, however, did not change the total count of the p-OHA-induced head-twitch response (HTR). These effects were also found with fixed doses of the selective MAO inhibitors when p-OHA was varied. Administration of clorgyline (1 mg/kg) or pargyline (5 mg/kg) almost inhibited completely MAO-A in the mouse forebrain, and pargyline also almost inhibited completely MAO-B. l-Deprenyl, in contrast, almost inhibited completely MAO-B without affecting MAO-A activity. Systemic administration of l-5-hydroxytryptophan also induced HTR and the total number of twitches was enhanced by clorgyline, but not by pargyline or l-deprenyl. Chlorimipramine or cocaine significantly reduced p-OHA-induced HTR, suggesting an intraneuronal site of action. Together with the presence of considerable MAO-A in 5-hydroxytryptamine (5-HT) neurons of various animal species, and possible accumulation and subsequent monoamine-releasing properties of p-OHA, the present results indicate that p-OHA might induce the HTR by interaction with intraneuronally increased 5-HT. This mechanism probably results in 5-HT release onto the postsynaptic 5-HT2 receptors. Taken together, different roles of MAO-B in "the hyperactivity syndrome" and the HTR are discussed.

Amphetamines↗