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8-(3-Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism.
J Biol Chem. 2002 Sep 27; 277(39):36040-4.JB

Abstract

Caffeine and more specific antagonists of the adenosine A(2A) receptor recently have been found to be neuroprotective in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. Here we show that 8-(3-chlorostyryl)caffeine (CSC), a specific A(2A) antagonist closely related to caffeine, also attenuates MPTP-induced neurotoxicity. Because the neurotoxicity of MPTP relies on its oxidative metabolism to the mitochondrial toxin MPP(+), we investigated the actions of CSC on striatal MPTP metabolism in vivo. CSC elevated striatal levels of MPTP but lowered levels of the oxidative intermediate MPDP(+) and of MPP(+), suggesting that CSC blocks the conversion of MPTP to MPDP(+) in vivo. In assessing the direct effects of CSC and A(2A) receptors on monoamine oxidase (MAO) activity, we found that CSC potently and specifically inhibited mouse brain mitochondrial MAO-B activity in vitro with a K(i) value of 100 nm, whereas caffeine and another relatively specific A(2A) antagonist produced little or no inhibition. The A(2A) receptor independence of MAO-B inhibition by CSC was further supported by the similarity of brain MAO activities derived from A(2A) receptor knockout and wild-type mice and was confirmed by demonstrating potent inhibition of A(2A) receptor knockout-derived MAO-B by CSC. Together, these data indicate that CSC possesses dual actions of MAO-B inhibition and A(2A) receptor antagonism, a unique combination suggesting a new class of compounds with the potential for enhanced neuroprotective properties.

Authors+Show Affiliations

Department of Neurology, Molecular Neurobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA. chenjf@bu.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12130655

Citation

Chen, Jiang-Fan, et al. "8-(3-Chlorostyryl)caffeine May Attenuate MPTP Neurotoxicity Through Dual Actions of Monoamine Oxidase Inhibition and A2A Receptor Antagonism." The Journal of Biological Chemistry, vol. 277, no. 39, 2002, pp. 36040-4.
Chen JF, Steyn S, Staal R, et al. 8-(3-Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism. J Biol Chem. 2002;277(39):36040-4.
Chen, J. F., Steyn, S., Staal, R., Petzer, J. P., Xu, K., Van Der Schyf, C. J., Castagnoli, K., Sonsalla, P. K., Castagnoli, N., & Schwarzschild, M. A. (2002). 8-(3-Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism. The Journal of Biological Chemistry, 277(39), 36040-4.
Chen JF, et al. 8-(3-Chlorostyryl)caffeine May Attenuate MPTP Neurotoxicity Through Dual Actions of Monoamine Oxidase Inhibition and A2A Receptor Antagonism. J Biol Chem. 2002 Sep 27;277(39):36040-4. PubMed PMID: 12130655.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 8-(3-Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism. AU - Chen,Jiang-Fan, AU - Steyn,Salome, AU - Staal,Roland, AU - Petzer,Jacobus P, AU - Xu,Kui, AU - Van Der Schyf,Cornelis J, AU - Castagnoli,Kay, AU - Sonsalla,Patricia K, AU - Castagnoli,Neal,Jr AU - Schwarzschild,Michael A, Y1 - 2002/07/18/ PY - 2002/7/20/pubmed PY - 2002/11/26/medline PY - 2002/7/20/entrez SP - 36040 EP - 4 JF - The Journal of biological chemistry JO - J Biol Chem VL - 277 IS - 39 N2 - Caffeine and more specific antagonists of the adenosine A(2A) receptor recently have been found to be neuroprotective in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. Here we show that 8-(3-chlorostyryl)caffeine (CSC), a specific A(2A) antagonist closely related to caffeine, also attenuates MPTP-induced neurotoxicity. Because the neurotoxicity of MPTP relies on its oxidative metabolism to the mitochondrial toxin MPP(+), we investigated the actions of CSC on striatal MPTP metabolism in vivo. CSC elevated striatal levels of MPTP but lowered levels of the oxidative intermediate MPDP(+) and of MPP(+), suggesting that CSC blocks the conversion of MPTP to MPDP(+) in vivo. In assessing the direct effects of CSC and A(2A) receptors on monoamine oxidase (MAO) activity, we found that CSC potently and specifically inhibited mouse brain mitochondrial MAO-B activity in vitro with a K(i) value of 100 nm, whereas caffeine and another relatively specific A(2A) antagonist produced little or no inhibition. The A(2A) receptor independence of MAO-B inhibition by CSC was further supported by the similarity of brain MAO activities derived from A(2A) receptor knockout and wild-type mice and was confirmed by demonstrating potent inhibition of A(2A) receptor knockout-derived MAO-B by CSC. Together, these data indicate that CSC possesses dual actions of MAO-B inhibition and A(2A) receptor antagonism, a unique combination suggesting a new class of compounds with the potential for enhanced neuroprotective properties. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/12130655/8__3_Chlorostyryl_caffeine_may_attenuate_MPTP_neurotoxicity_through_dual_actions_of_monoamine_oxidase_inhibition_and_A2A_receptor_antagonism_ DB - PRIME DP - Unbound Medicine ER -