PubMed Health⌕ Search

Biomedical subjects

P K Arora

Publications and source records attributed to P K Arora.

At least 55 records · Page 3Linked to original sources
PubMed1988

Chemical oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its in vivo metabolism in rat brain and liver.

We investigated in vivo the metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the brain and liver of rats 45 min after the systemic administration of 50 mg/kg of the neurotoxin. The metabolites present in brain and liver extracts were identified through multiple analytical methods by comparison to authentic compounds obtained from a number of chemical oxidations of MPTP. Our results indicate the presence of approximately 15% unreacted MPTP and relatively large amounts of both 1-methyl-4-phenylpyridinium (MPP+) and a mixture of three nonpolar lactams: 1-methyl-4-phenyl-5,6-dihydro-2(1H)-pyridinone, 1-methyl-4-phenyl-2(1H)-pyridinone, and a previously unreported metabolite 1-methyl-4-phenyl-2-piperidinone. Whereas MPP+ was more prevalent in the brain than in the liver, the lactam metabolites were more predominant in the liver. The amounts of the N-oxide and N-demethylated metabolites of MPTP were minimal.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Proteolytic degradation of protein kinase C in the phorbol ester-induced interleukin-2 secreting thymoma cells.

Effects of phorbol 12-myristate 13-acetate (PMA) on the fate of protein kinase C in two mouse thymoma cell lines, which are either responsive (EL4) or unresponsive (IEL4) to PMA-induced interleukin-2 (IL-2) production, were investigated with polyclonal antibodies raised against rat brain enzyme. These antibodies immunoprecipitated completely the protein kinase C from both cell lines and detected mainly an 82-kDa protein by immunoblot analysis of the crude homogenates as well as the partially purified kinase preparations. PMA elicited a time- and dose-dependent redistribution of protein kinase C from cytosol to the particulate fraction and proteolytic degradation of the kinase from both cell lines. The dose of PMA required for half-maximum protein kinase C translocation and degradation was at least five times lower for EL4 than for IEL4. In the presence of 16 nM PMA the rates of protein kinase C translocation and degradation were faster in EL4 than in IEL4, and the half-lives of protein kinase C in EL4 and IEL4 were less than 5 min and greater than 2 h, respectively. Analysis of the tryptic fragments of the immunoprecipitated enzyme, previously phosphorylated in the presence of [gamma-32P]ATP, revealed minor structural differences between the protein kinase C from these two cell lines. In neither cell line did the PMA-induced degradation of protein kinase C result in an accumulation of the Ca2+/phospholipid-independent kinase (catalytic unit) as analyzed by immunoblotting and gel filtration chromatography. Thus, activation of protein kinase C through the proteolytic conversion to the effector-independent catalytic unit plays little role in IL-2 production. The role of protein kinase C translocation and degradation in the PMA-induced responses in EL4 cells is unknown. However, IL-2 production in EL4 cells was reduced when PMA-induced degradation of protein kinase C was retarded by exogenously added protease inhibitors.

Animals↗
PubMed1988

Potent neurotoxic fluorinated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine analogs as potential probes in models of Parkinson disease.

We synthesized a number of fluorinated analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and tested their suitability as substrates for monoamine oxidase B in vitro and their dopaminergic neurotoxicity in vivo. Two of the compounds tested, 2'-F-MPTP and 2'-CF3-MPTP, were better enzyme substrates and possessed more potent neurotoxicity for nigrostriatal dopamine neurons than MPTP, especially 2'-F-MPTP. The results of the in vivo neurotoxicity experiments correlated well with the suitability of the compounds as substrates for monoamine oxidase. These findings could serve as a basis for the use of 18F-labeled analogs of MPTP for positron emission tomography studies of nonhuman primates for better understanding of the factors underlying MPTP toxicity. Furthermore, the discovery of two MPTP analogs with enhanced selective neurotoxicity to dopaminergic neurons may be an important clue in the continuing efforts to define the chemical structure-activity factors governing MPTP neurotoxic activation mechanisms.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Mechanism of neurotoxic action of beta,beta'-iminodipropionitrile (IDPN): N-hydroxylation enhances neurotoxic potency.

The molecular mechanism(s) whereby beta, beta'-iminodipropionitrile (IDPN) induces an excitatory behavioral syndrome and a distinct alteration of the axonal cytoskeleton in experimental animals is not known. We demonstrate here that upon intraperitoneal administration to rats, the N-hydroxy analog of IDPN (HOIDPN) induces a parallel spectrum of both neurotoxic effects of IDPN and is approximately 8 times more potent than IDPN in this regard. This is consistent with the involvement of a flavin monooxygenase-mediated N-oxygenation pathway in the toxic activation of IDPN.

Animals↗
PubMed1987

Inhibition of mitochondrial respiration by analogs of 4-phenylpyridine and 1-methyl-4-phenylpyridinium cation (MPP+), the neurotoxic metabolite of MPTP.

In order to clarify the structural requirements associated with the inhibition of mitochondrial respiration by MPP+, the neurotoxic metabolites of the Parkinsonian agent MPTP, ten sets of pyridine/N-methylpyridinium pairs and a few miscellaneous compounds were evaluated on rat liver intact mitochondria (Mw) and on submitochondrial particles (SMP). The pyridinium partners were much more potent inhibitors on Mw than on SMP, indicating that they are concentrated inside mitochondria by the energy-dependent process previously reported for MPP+, probably as a consequence of non-specific passive transport across the mitochondrial inner membrane in response to the transmembrane potential. In the SMP assay, the neutral pyridines were stronger inhibitors than were the pyridinium cations, and the inhibitory potency varied little with structural changes. The N-methylated forms of beta-carbolines may act as endogenous MPP+-like agents.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Model study on the bioreduction of paraquat, MPP+, and analogs. Evidence against a "redox cycling" mechanism in MPTP neurotoxicity.

The ability of paraquat, MPP+, and analogs to be reduced by chemical reductants and by NADPH, as catalyzed by liver microsomes or purified NADPH cytochrome P-450 reductase, is reported. The analogs span a range of electrochemical potential, including values in-between that of paraquat and MPP+. Analogs with an Eo below -.55 V (vs. NHE) are not reduced by either the NADPH-microsomes or NADPH-reductase systems. The inability of MPP+ to be bio-reduced or to stimulate the production of superoxide during aerobic reduction is evidence against a redox-cycling (oxidant stress) role of MPP+ in MPTP neurotoxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Suppression of the cytotoxic T-lymphocyte response in mice by pertussis toxin.

Pertussis toxin (PT), the major toxin produced by Bordetella pertussis, has been reported both to enhance and to suppress immune responsiveness. These findings suggested that PT contributes to the virulence of B. pertussis through mechanisms involving immune regulation. We report that PT suppressed both the primary and the secondary cytotoxic T-lymphocyte (CTL) responses of mouse spleen cells cultured against two different allogeneic stimulator spleen cells in vitro. This suppression was dependent on the dose of PT used. PT must be present during the initial stages (within the first 24 hr) of CTL generation. Soluble factor(s) obtained from spleen cells preexposed to PT did not suppress the CTL response. Suppression of the CTL response observed was not due to depletion of the antigen by PT. The cytotoxic activity of CTL clones could not be suppressed by PT. The analysis of responder spleen cells, fractionated by anti-immunoglobulin panning techniques, provided evidence that L3T4-, Lyt 2+ cells mediate the PT-induced immunosuppression. We propose that suppression of the CTL response by PT is generated through the activation of L3T4-, Lyt 2+ suppressor T lymphocytes.

Animals↗
PubMed1987

Suppression of the immune response by benzodiazepine receptor inverse agonists.

24 h after administration of a single dose of the benzodiazepine receptor inverse agonists N'-methyl-beta-carboline-3-carboxamide (FG 7142) and 3-carbomethoxy-4-ethyl-6,7-dimethoxy-beta-carboline (DMCM), a profound suppression of the immune response was observed in rodents. This immunosuppression was manifest as a decrease in phytohemagglutinin (PHA) and concanavalin-A (Con-A) stimulated T cell proliferation in rats and mice administered FG 7142 and a decrease in allogeneic cytotoxic T lymphocyte activity in mice administered either FG 7142 or DMCM. The effects of FG 7142 were antagonized by the prior administration of Ro 15-1788, a benzodiazepine receptor antagonist. These findings demonstrate that the neural pathways subserved by benzodiazepine receptors can modulate immune function, and suggest that these receptors may be involved in the stress-induced modulation of immune function.

Animals↗
PubMed1987

On the mechanisms underlying 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity: the effect of perinigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, its metabolite and their analogs in the rat.

The discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and other primates by selective destruction of substantia nigra dopaminergic neurons has spurred research to define the mechanisms underlying its toxicity. To avoid variables such as tissue distribution, extracerebral metabolism and blood-brain barrier permeability, the authors studied the neurochemical and morphologic effects of direct perinigral infusions of various concentrations of MPTP, its metabolites and analogs in the rat. MPTP, in the highest dose used, 1000 nmol, decreased dopamine and its metabolites in ipsilateral striatum by approximately 75%, whereas 3,3-dimethyl-MPTP (which is oxidized to 1,3,3-trimethyl-4-phenyl-2,3-dihydropyridinium cation but not to a pyridinium species) had no effect. The 2,2 and 3,3-dimethyl analogs of 1-methyl-4-phenyl-2,3-dihydropyridinium cation which also cannot be oxidized to pyridinium species, reduced striatal dopamine, suggesting that these compounds are toxic in their own right. 1-Methyl-4-phenylpyridinium cation (MPP+) and its 4-(4-fluorophenyl) and 4-(2-pyridyl) analogs that have less negative reduction potentials than MPP+, were most potent in decreasing striatal dopamine and metabolites, with MPP+ being 5 to 10 times more effective than its two analogs and approximately 100 times more potent than MPTP and the two dimethyl 1-methyl-4-phenyl-2,3-dihydropyridinium cation analogs. These findings suggest that MPP+ is ultimately responsible for MPTP toxicity but does not act via oxidant stress mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Comparative toxicity of MPTP, MPP+ and 3,3-dimethyl-MPDP+ to dopaminergic neurons of the rat substantia nigra.

The depletion of dopamine and its metabolites in the striatum of rats was assessed 3 weeks after the unilateral intranigral infusion of different doses of MPTP, its ultimate metabolite MPP+, and 3,3-DM-MPDP+, a non-oxidizable analog of the initial MPTP metabolite 2,3-MPDP+. MPP+ was found to be 2-3 orders of magnitude more toxic than the other two agents, consistent with the view that it is primarily responsible for MPTP neurotoxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1982

Preferential response patterns of cytotoxic T lymphocytes specific for fluorescein isothiocyanate-[FITC] modified autologous cells.

Murine cytotoxic responses to TNP-modified syngeneic cells (TNP-self) have been shown to exhibit preferential recognition of K or D end self products encoded by the H-2 complex. In the present study, a number of B10 congenic and recombinant mouse strains were investigated to determine the H-2K and H-2D-restricted FTC-self CTL response patterns, and these were compared with the CTL response patterns obtained for TNP-self. The results indicate that for strains possessing the H-2k,d,h2,h4 haplotypes, respectively, preferential CTL responses were observed against FTC recognized in association with Kk over Dk, Dd over Kd, and Kk over Db. These patterns of preferential CTL responses were the same as those reported for TNP-self as well as several anti-viral CTL responses. In contrast to the results obtained in the B10.A strain, in which Kk preference was observed over Dd for TNP-self CTL, no preferential CTL response was observed when FTC was recognized in association with Kk and with Dd. In this context, it was observed that the CTL response to FTC recognized in association with Dd was particularly strong. This strong D end-associated response was shown to involve D locus products, and no evidence was obtained indicating that L locus self products were involved. These studies are discussed with respect to the possibility that different haptens can be recognized by CTL in association with different self determinants encoded by the same H-2 gene products.

Animals↗
PubMed1982

Non-H-2-linked genetic control of murine cell-mediated lympholysis to autologous cells modified with fluorescein isothiocyanate (FTC-self).

Spleen cells from mouse strains expressing the H-2b haplotype (C57BL/6J, C57BL/6N, C57BL/10J, and C3H.SW) were compared for their ability to generate primary in vitro cytotoxic responses to autologous cells modified with either fluorescein isothiocyanate (FITC) (FTC-self) or trinitrobenzene sulfonate (TNBS) (TNP-self). The resulting hapten-specific cytotoxic T lymphocyte (CTL) responses were assayed on hapten-self Con A blast target cells. Among the four H-2b strains tested, C57BL/6J and C57BL/6N were high responders, whereas C57BL/10J and C3H.SW were low responders for CTL generated against FTC-self. Studies using (C57BL/6J x C3H.SW)F1 responding cells and F1 or parenteral-modified stimulating cells indicated that the F1 cells generated cytotoxic activity equivalent to that of the high-responder strain C57BL/6J. Further comparisons of the C57BL/6J and C2H.SW strains indicated that C57BL/6J is a high responder to both FTC-self and TNP-self, whereas C3H.SW is a high responder to TNP-self but a low responder to FTC-self. The results of this study indicate that non-H-2-linked genetic control of CTL response to hapten-self depends not only on the self determinant but also on the foreign antigens.

Animals↗