- Preferential Extracellular Generation of the Active Parkinsonian Toxin MPP+ by Transporter-Independent Export of the Intermediate MPDP+
-
Aims: 1-Methyl-4-phenyl-tetrahydropyridine (MPTP) is among the most widely used neurotoxins for inducing experimental parkinsonism. MPTP causes parkinsonian symptoms in mice, primates, and humans by killing a subpopulation of dopaminergic neurons. Extrapolations of data obtained using MPTP-based parkinsonism models to human disease are common; however, the precise mechanism by which MPTP is converted into its active neurotoxic metabolite, 1-methyl-4-phenyl-pyridinium (MPP+), has not been fully elucidated. In this study, we aimed to address two unanswered questions related to MPTP toxicology: (1) Why are MPTP-converting astrocytes largely spared from toxicity? (2) How does MPP+ reach the extracellular space? Results: In MPTP-treated astrocytes, we discovered that the membrane-impermeable MPP+, which is generally assumed to be formed inside astrocytes, is almost exclusively detected outside of these cells. Instead of a transporter-mediated export, we found that the intermediate, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+), and/or its uncharged conjugate base passively diffused across cell membranes and that MPP+ was formed predominately by the extracellular oxidation of MPDP+ into MPP+. This nonenzymatic extracellular conversion of MPDP+ was promoted by O2, a more alkaline pH, and dopamine autoxidation products. Innovation and Conclusion: Our data indicate that MPTP metabolism is compartmentalized between intracellular and extracellular environments, explain the absence of toxicity in MPTP-converting astrocytes, and provide a rationale for the preferential formation of MPP+ in the extracellular space. The mechanism of transporter-independent extracellular MPP+ formation described here indicates that extracellular genesis of MPP+ from MPDP is a necessary prerequisite for the selective uptake of this toxin by catecholaminergic neurons. Antioxid. Redox Signal. 23, 1001-1016.
- Schildknecht, Stefan,Pape, Regina,Meiser, Johannes,Karreman, Christiaan,Strittmatter, Tobias,Odermatt, Meike,Cirri, Erica,Friemel, Anke,Ringwald, Markus,Pasquarelli, Noemi,Ferger, Boris,Brunner, Thomas,Marx, Andreas,M?ller, Heiko M.,Hiller, Karsten,Leist, Marcel
-
-
Read Online
- (3R)-3-Amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide as a potent dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
-
Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides and 3-amino-N-(4-aryltetrahydropyran-4-yl)butanamides were synthesized and evaluated as dipeptidyl peptidase IV (DPP-IV) inhibitors. Derivatives incorporating the 6-substituted benzothiazole group showed highly potent DPP-IV inhibitory activity. Oral administration of (3R)-3-amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide (12u) reduced blood glucose excursion in an oral glucose tolerance test.
- Nitta, Aiko,Fujii, Hideaki,Sakami, Satoshi,Nishimura, Yutaka,Ohyama, Tomofumi,Satoh, Mikiya,Nakaki, Junko,Satoh, Shiho,Inada, Chifumi,Kozono, Hideki,Kumagai, Hiroki,Shimamura, Masahiro,Fukazawa, Tominaga,Kawai, Hideki
-
scheme or table
p. 5435 - 5438
(2009/05/30)
-
- Synthesis of the rigid analogues of an SSRI benzenepropanamine
-
Several 1-(substituted phenoxy)-3-{4-(4-trifluoromethyl) phenoxy] piperidin-1-yl} propan-2-ols (str.II) were prepared in a six-step reaction sequence starting from methylamine and ethyl acrylate and evaluated for antidepressant activity. The compounds were fully characterized by spectral and elemental analyses, and were tested for their effect on gross behavior, antireserpine and anorexigenic activity. No effect was observed on gross behavior and some of them showed fluoxetine like antireserpine and anorexigenic activity. Birkhaeuser Boston 2005.
- Kumar, S.T.V.S. Kiran,Sharma,Srivastava, Shipra,Bhandari, Kalpana,Shander, Girija,Singh
-
p. 518 - 527
(2007/10/03)
-
- Use of Zinc Borohydride in Reductive Amination: An Efficient and Mild Method for N-Methylation of Amines
-
An efficient method for the reductive methylation of amines using paraformaldehyde, zinc chloride and zinc borohydride is described.
- Bhattacharyya, Sukanta,Chatterjee, Arindam,Duttachowdhury, Shiti, Kantha
-
-
- Titanium(IV) Isopropoxide and Sodium Borohydride: A Reagent of Choice for Reductive Amination
-
The preliminary results on the novel use of titanium(IV) isopropoxide and sodium borohydride in reductive amination reactions are reported.A highly efficient and mild procedure for reductive aminations of formaldehyde with a variety of primary and secondary amines is described.
- Bhattacharyya, Sukanta
-
p. 2401 - 2404
(2007/10/02)
-
- Synthesis and toxicity toward nigrostriatal dopamine neurons of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) analogues
-
Six compounds having structural features in common with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were synthesized and tested in mice for the ability to produce a prolonged decrease in nigrostriatal dopamine (DA) and DA metabolites. The compounds that were prepared and tested include the ester elimination products of the analgetic drugs α-prodine and trimeperidine. None of the compounds in this study, except for MPTP, produced significant neurotoxic effects in the mouse model. The study shows that minor changes in the tetrahydropyridine ring of MPTP result in a marked decrease in neurotoxicity.
- Fries,De Vries,Hazelhoff,Horn
-
p. 424 - 427
(2007/10/02)
-
- [2]Benzopyrano[3,4-c]pyridines and process therefor
-
[2]Benzopyrano[3,4-c]pyridine derivatives characterized by having a 2,3,4,4a,6,10b-hexahydro-1H-[2]benzopyrano[3,4-c]pyridine nucleus bearing a substituent at position 6 are disclosed. The nucleus can be optionally further substituted at positions 2,3,4,6 and on the aromatic ring. The derivatives are useful diuretic, anorexic, antidepressant, anticonvulsant and antihypertensive agents. Methods for their preparation and use also are disclosed.
- -
-
-