title: Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations.
abstract: Poly(ADP-ribose) polymerase-1 (PARP-1), when activated by DNA damage, promotes both cell death and inflammation. Here we report that PARP-1 enzymatic activity is directly inhibited by minocycline and other tetracycline derivatives that have previously been shown to have neuroprotective and anti-inflammatory actions. These agents were evaluated by using cortical neuron cultures in which PARP-1 activation was induced by the genotoxic agents N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or 3-morpholinosydnonimine (SIN-1). In both conditions, neuronal death was reduced by >80% either by 10 muM 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, an established PARP inhibitor, or by 100 nM minocycline. Neuronal NAD(+) depletion and poly(ADP-ribose) formation, which are biochemical markers of PARP-1 activation, were also blocked by 100 nM minocycline. A direct, competitive inhibition of PARP-1 by minocycline (K(i) = 13.8 +/- 1.5 nM) was confirmed by using recombinant PARP-1 in a cell-free assay. Comparison of several tetracycline derivatives showed a strong correlation (r(2) = 0.87) between potency as a PARP-1 inhibitor and potency as a neuroprotective agent during MNNG incubations, with the rank order of potency being minocycline > doxycycline > demeclocycline > chlortetracycline. These compounds are known to have other actions that could contribute their neuroprotective effects, but at far higher concentrations than shown here to inhibit PARP-1. The neuroprotective and antiinflammatory effects of minocycline and other tetracycline derivatives may be attributable to PARP-1 inhibition in some settings.
authors.affiliation: Department of Neurology, University of California-San Francisco and Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA.
authors.forename: Conrad C
authors.initials: CC
authors.lastname: Alano
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Kauppinen
authors.forename: Andreu Viader
authors.initials: AV
authors.lastname: Valls
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Swanson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008911:Minocycline / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013752:Tetracycline / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011994:Recombinant Proteins; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D013752:Tetracycline; D008911:Minocycline