The Antibiotic Minocycline
Offers Neuron Protective Actions?
Protective effects of minocycline on 3,4-methylenedioxymethamphetamine-induced neurotoxicity in serotonergic and dopaminergic neurons of mouse brain.Zhang L, Shirayama Y, Shimizu E, Iyo M, Hashimoto K.
The repeated administration of 3,4-methylenedioxymethamphetamine
(MDMA) produces neurotoxicity in the 5-hydroxytryptamine (5-HT) and dopamine systems of the brain. In this study, we investigated the
effects of minocycline, a second-generation tetracycline derivative,
on MDMA-induced neurotoxicity in the 5-HT and dopaminergic systems of
the mouse brain. The repeated administration of MDMA (10 mg/kgx3, 3-h
intervals, s.c.) significantly decreased the contents of 5-HT and its
major metabolite 5-hydroxyindole acetic acid (5-HIAA) in the frontal
cortex and hippocampus, and the density of the 5-HT transporter
(5-HTT) in the frontal cortex, hippocampus and striatum. The repeated
administration of MDMA (10 mg/kgx3, 3-h intervals, s.c.) significantly
decreased the contents of the dopamine and the density of the dopamine
transporter (DAT) in the striatum, but not the frontal cortex.
Furthermore, pretreatment and the subsequent administration of
minocycline (40 mg/kg, i.p.) significantly attenuated the reduction of
5-HT and dopamine as well as the density of 5-HTT and DAT in the mouse
brain by the repeated administration of MDMA. Moreover, pretreatment
and the subsequent administration of minocycline (40 mg/kg)
significantly attenuated the increase of activated microglia in the
hippocampus and striatum after the repeated administration of MDMA.
Our findings suggest that minocycline protects the neurotoxicity of
the 5-HT and dopamine systems in the mouse brain after the
administration of MDMA.
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.
1: Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9685-90. Epub 2006
Jun 12. Links Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations.Alano CC, Kauppinen TM, Valls AV, Swanson RA.
Department of Neurology, University of California-San Francisco and
Veterans Affairs Medical Center, 4150 Clement Street, San Francisco,
CA 94121, USA.