Biomedical subjects
S S Parmar
Publications and source records attributed to S S Parmar.
Inhibition of rat brain monoamine oxidase and succinic dehydrogenase by anticonvulsant pyrazolines.
Substituted 1,5-diaryl-3(4-chlorophenyl)-delta 2-pyrazolines were synthesized and evaluated for anticonvulsant activity. Most pyrazolines (100 mg/kg) provided 20-80% protection against pentylenetetrazol-induced convulsions in mice. All compounds inhibited rat brain mitochondrial monoamine oxidase (MAO) and succinic dehydrogenase (SDH) and exhibited low toxicity as reflected by approximate LD50 values (500 to greater than 1000 mg/kg) in mice.
Monoamine oxidase inhibitory and anticonvulsant properties of some newer indolylimidazolones.
Newly synthesized indolylimidazolones were tested for their in vitro monoamine oxidase (MAO) inhibitory activity. These compounds were found to possess analgesic activity and anticonvulsant activity against maximal electroshock-induced convulsions in mice. The low toxicity of these compounds was reflected by their high approximate LD50 values.
Effects of abnormal metabolites of maple syrup urine disease on neurotransmitter receptor binding.
The deficiency of keto acid decarboxylase in maple syrup urine disease results in the accumulation of branched chain amino acids and their corresponding keto acids in tissues and body fluids. The effects of abnormal metabolites were investigated on neurotransmitter receptor binding in rat brain. alpha-Keto acids caused selective in vitro decrease in alpha-adrenergic, beta-adrenergic receptor binding in synaptosomal preparations from rat brain. No significant changes were observed in binding of cholinergic, GABA, and dopamine receptors binding in appropriate rat brain preparations. These results indicate that selective inhibition of adrenergic receptor binding by branched chain keto acids may presumably account for neural abnormality in maple syrup urine disease.
Effects of intracerebroventricular administration of bradykinin on rat brain serotonin and prostaglandins.
Intracerebroventricular (ICV) administration of bradykinin (5, 10 and 20 micrograms) produced a dose-related increase in the concentration of serotonin in rat brain. The maximum increase was observed after 15 min of bradykinin administration. Thereafter, the augmented levels of serotonin declined and tended to come to normal value after 60 min. Bradykinin (20 micrograms) significantly increased the concentrations of serotonin specifically in cortex, hypothalamus, midbrain and pons-medulla but not in cerebellum and spinal cord. The time course of increase and subsequent decline of regional concentrations of serotonin in brain were similar to that noted with bradykinin-induced changes in serotonin levels in whole brain. Bradykinin (5, 10 and 20 mg, ICV) increased the concentration of prostaglandin E2 (PGE2) but not of PGF2 alpha of rat brain. The time course of bradykinin-induced changes in PGE2 concentrations were similar to the effects of bradykinin on the levels of serotonin in rat brain. The inhibitors of PG synthesis, hydrocortisone, diclofenac and paracetamol, antagonized the bradykinin-induced increase of serotonin in rat brain. These results have provided support for the contention that PGs may presumably mediate some of the central actions of bradykinin and that bradykinin-induced augmentation of central serotonergic activity could possibly account for PGE2-induced modulation of rat brain serotonin.
Stress by restraining potentiates morphine catalepsy in rats.
Restraint-induced stress potentiated morphine catalepsy in rats. This potentiation was partially antagonized by pharmacologic treatments decreasing central serotonin, acetylcholine, prostaglandins and by naloxone. Selective increase in central dopamine also inhibited the potentiation.
Identification and characterization of hepatic carboxylesterases hydrolyzing hydrocortisone esters.
The present study has provided evidence for the existence of three distinct carboxylesterases involved in the hydrolysis of steroid esters, where two enzymes are possibly responsible for the metabolism of hydrocortisone hemisuccinate (HCHS) at pH 5.5 and 8.0, and a third enzyme for the metabolism of hydrocortisone acetate (HCAC) at pH 8.0, in isolated rat liver microsomes. The activity of all three enzymes in rat liver was induced significantly by the administration of phenobarbital while no such function in enzyme activity was observed in animals receiving 3-methylcholanthrene or benzo[a] pyrene under similar experimental conditions. The increase in the activity of HCHS esterase I (HCHS-E1) active at pH 5.5, HCHS esterase II (HCHS-E2) active at pH 8.0, and HCAC esterase (HCAC-E) was approximately 7 to 8, 3- and 3-fold respectively. On the other hand, the degree of induction of nonspecific microsomal carboxylesterase acting on p-nitrophenylacetate (PNPA) was significantly less. The Km values for the hydrolysis of HCHS at pH 5.5 and 8.0 and HCAC by rat liver microsomes obtained from control rats were 2.45, 2.02 and 1.6 mM, respectively, and these Km values were not changed significantly in preparations obtained from rats treated with phenobarbital. The distinct in vitro responses displayed by hepatic microsomal steroid esterases to various inhibitors were able to distinguish three different enzymes which also differed from nonspecific carboxylesterases. The activity of HCAC-E was inhibited by NaAsO2 and AgNO3 while that of HCHS-E1 and HCHS-E2 remained unaffected. Selective inhibition of HCHS-E1 by NaF, HgCl2 and p-chloromercuribenzoate and that of HCHS-E2 by NiSO4 indicated the possible existence of different enzymes or isozymes of a carboxylesterase catalyzing HCHS hydrolysis. The effects elicited by the inhibitors on the activity of PNPA esterase were different from those observed with steroid esterases. Furthermore, the present study has also indicated species variations in the distribution of steroid esterases in the livers of rat, mouse, dog and cat.
Prostaglandin D2-induced potentiation of hexobarbitone hypnosis in rats: role of 5-hydroxytryptamine.
Prostaglandin D2 (PGD2) produced a dose-related increase in the duration and incidence of induction of sleep induced by hexobarbitone, in rats. Pretreatment with pharmacological agents known to reduce selectively brain 5-hydroxytryptaminergic activity, significantly inhibited PGD2-induced potentiation of hexobarbitone, indicating that this potentiation is mediated by 5-hydroxytryptamine.
Computer programming for the evaluation of dose-response activity of anticonvulsant compounds.
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Prostaglandin D2 mediated specific increase in rat brain serotonin.
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Bancroftian filariasis and malaria in island and hinterland populations in Sabah, Malaysia.
An epidemiological survey of filariasis and malaria in Banggi Island and Upper Kinabatangan, Sabah, revealed microfilarial rates of 7.2% and 8.6% respectively and malaria prevalence of 9.7% and 16.9% respectively. Wuchereria bancrofti was a rural nocturnally periodic type with a periodicity index of 137.2 and average peak hour at 01.32 hrs; 9.2% of microfilaremic carriers as compared to 2.4% amicrofilaremic subjects had clinical filariasis. The Plasmodium falciparum: P. vivax: P. malariae ratios were 1:1:0.17 and 1.4:1:0.12 for Banggi and Upper Kinabatangan respectively. Anopheles flavirostris was incriminated as a new malaria vector in Banggi where the well-known primary malaria vector is An. balabacensis. The latter was also found for the first time to be a vector of rural W. bancrofti in Upper Kinabatangan. Experimental feeding also showed that L3 larvae of W. bancrofti were recovered at low rates from An. balabacensis. Aedes togoi appeared to be a suitable laboratory vector for W. bancrofti.
Antinociceptive effect of intracerebroventricularly administered histamine in rats.
Intracerebroventricularly (icv) administered histamine produced a dose-related antinociceptive effect in rats, using the rat tail-hot wire technique as the experimental parameter. The H1-receptor agonist, 2-methyl-histamine, given icv, also induced marked antinociception, whereas the H2-receptor agonist, 4-methylhistamine, produced relatively weaker and transient antinociception. Histamine-induced antinociception was significantly inhibited by mepyramine, a H1-receptor antagonist, but not by cimetidine, a H2-receptor antagonist. 5,6-Dihydroxytryptamine, a specific serotonin neuronolytic agent, and p-chlorophenylalanine, which selectively inhibits serotonin synthesis, markedly inhibited the antinociceptive effect of histamine, which was also attenuated by naloxone, an antagonist for endogenous opioid receptors, and by dexamethasone, which is known to reduce central endorphin concentrations. On the contrary, the effect of histamine was potentiated by adrenalectomy and by metyrapone, an inhibitor of endogenous corticoid synthesis, which are known to enhance central endorphins.
Receptor-binding changes in copper-deficient rats.
Male weanling Sprague-Dawley rats were fed a copper-deficient diet for 40 days. Copper-deficient rats weighed significantly (p less than 0.001) less (175 +/- 7 g) than copper-supplemented rats (230 +/- 6 g). Hematocrits were also significantly (p less than 0.001) decreased in deficient as compared to control animals from 43 +/- 0.6 to 30 +/- 2.7%. The binding of 3H-QNB to striatal and cerebellar membrane muscarinic receptors from control and deficient rats increased from 594 +/- 25 to 704 +/- 31 (p less than 0.02) and from 19 +/- 2 to 28 +/- 3 (p less than 0.01) pmol/g protein, respectively. Similarly, 3H-muscimol binding to GABA receptors (cerebellum) also increased from 39 +/- 5 to 58 +/- 3 (p less than 0.02) pmol/g protein. 3H-diazepam binding to benzodiazepine receptors in deficient versus control animal frontal cortex membranes decreased from 92 +/- 8 to 75 +/- 5 (p less than 0.02) pmol/g protein, respectively. These results may help explain CNS manifestations of copper deficiency.
Synthesis of some substituted benzodiazepines as possible CNS depressant drugs.
A new series of 2,3-cyclopentano-3,4-dihydro-4-spirocyclopentano-1,5-benzodi azepine which are substituted in 5-position with beta-N-heterocycloethyl or gamma-N-heterocyclo-n-propyl groups have been synthesized and evaluated for their CNS depressant activity including anticonvulsant, analgesic and pentobarbital induced hypnosis. These compounds were also investigated for their ability to inhibit in vitro succinate dehydrogenase (SDH). In most of the compounds an appreciable CNS depressant activity has been found to be associated with the compounds possessing good SDH inhibitory activity. Low toxicity of these compounds was reflected by their high approximate LD50 values.
Substituted triazoles as anti-inflammatory agents.
Newly synthesized triazoles were evaluated for their anti-inflammatory and antiproteolytic activities. These derivatives possessed potent anti-inflammatory and antiproteolytic activities. In addition, these compounds were relatively less toxic.
Evidence for distinct carboxylesterases/amidases for hydrolytic metabolism of procaine, acetanilide and 2-acetylaminofluorene.
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Central nervous system depressant, analgesic and monoamine oxidase inhibitory properties of substituted piperidines.
Eight 1-(arylaminothiocarbonyl)-4-hydroxy-4-phenyl piperidines were evaluated for their central nervous system depressant, analgesic, and monoamine oxidase inhibitory properties. The central nervous system depressant property of these substituted piperidines was reflected by their ability to potentiate pentobarbital-induced sleep in mice ranging from 18.3 to 58.5 minutes. The analgesic activity possessed by these substituted piperidines, with the exception of one compound, was shown by their ability to provide 16.7 to 50 percent protection against tail pinch response in mice. All substituted piperidines (1 mM) inhibited in vitro activity of rat brain monoamine oxidase with the degree of inhibition ranging from 17.2 to 18.3 percent.
Inhibition of brain monoamine oxidase by 1,2,4-trisubstituted 5-imidazolones.
Nine 1-(3,4-dimethoxyphenethyl)-2-methyl-4-(substituted benzylidene)-5- imidazolones were evaluated for their ability to inhibit the activity of rat brain monoamine oxidase during oxidative deamination of tyramine, 5-hydroxytryptamine (serotonin), and kynuramine. All substituted imidazolones inhibited monoamine oxidase activity. A concentration-dependent inhibition of monoamine oxidase was observed using kynuramine as the substrate and the degree of enzyme inhibition was also evaluated on the basis of their I50 values. Preincubation of imidazolones with the enzyme preparations for varying lengths of time prior to the addition of substrate in no way altered their degree of inhibition and thus exhibited a reversible nature of inhibition. A kinetic study carried out with 1-(3,4-dimethoxy-phenethyl)-2-methyl-4-(4- nitrobenzylidene )-5- i midazolone revealed a competitive nature of inhibition of rat brain monoamine oxidase.