In the previous study I posted on homocysteine and glutamate toxicity the researchers concluded that homocysteine compromises neuronal homeostasis by multiple, divergent routes. In addition to stimulating glutamate excitotoxicity, homocysteine also damages DNA. DNA damage activates a protein called poly ADP-ribose polymerase (PARP) that can trigger inflammation and cell death and is involved in oligodendrocyte loss and demyelination. Here is the study again.
J Neurosci Res. 2002 Dec 1;70(5):694-702.
Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage.
Ho PI, Ortiz D, Rogers E, Shea TB.
“Homocysteine (HC) is a neurotoxic amino acid that accumulates in several neurological disorders including Alzheimer's disease (AD)…Homocysteine-induced calcium influx through NMDA channel activation, which stimulated glutamate excitotoxicity…Apoptosis after HC treatment was reduced by co-treatment with 3-aminobenazmidine (3ab), an inhibitor of poly-ADP-ribosome polymerase (PARP), consistent with previous reports that ATP depletion by PARP-mediated repair of DNA strand breakage mediated HC-induced apoptosis.These findings indicate that HC compromises neuronal homeostasis by multiple, divergent routes.”
In the following study the researchers concluded their data demonstrated "PARP" activation within apoptotic oligodendrocytes and state in the title that inhibiting PARP may be a "potential therapy" against oligodendrocyte death.
Brain. 2010 Mar;133(Pt 3):822-34. doi: 10.1093/brain/awp337. Epub 2010 Feb 15.
Inhibiting poly(ADP-ribose) polymerase: a potential therapy against oligodendrocyte death.
Veto S, Acs P, Bauer J, Lassmann H, Berente Z, Setalo G Jr, Borgulya G, Sumegi B, Komoly S, Gallyas F Jr, Illes Z.
“Oligodendrocyte loss and demyelination are major pathological hallmarks of multiple sclerosis. In pattern III lesions, inflammation is minor in the early stages, and oligodendrocyte apoptosis prevails, which appears to be mediated at least in part through mitochondrial injury. Here, we demonstrate poly(ADP-ribose) polymerase activation and apoptosis inducing factor nuclear translocation within apoptotic oligodendrocytes in such multiple sclerosis lesions. The same morphological and molecular pathology was observed in an experimental model of primary demyelination, induced by the mitochondrial toxin cuprizone. Inhibition of poly(ADP-ribose) polymerase in this model attenuated oligodendrocyte depletion and decreased demyelination…Our data indicate that poly(ADP-ribose) polymerase activation plays a crucial role in the pathogenesis of pattern III multiple sclerosis lesions. Since poly(ADP-ribose) polymerase inhibition was also effective in the inflammatory model of multiple sclerosis, it may target all subtypes of multiple sclerosis, either by preventing oligodendrocyte death or attenuating inflammation.”
In the following study the researchers also discuss targeting PARP as a promising approach for treatment of MS.
Trends Mol Med. 2012 Feb;18(2):92-100. doi: 10.1016/j.molmed.2011.10.002. Epub 2011 Nov 9.
Targeting poly(ADP-ribose) polymerase-1 as a promising approach for immunomodulation in multiple sclerosis?
Cavone L, Chiarugi A.
“Despite significant advancement in developing therapies for multiple sclerosis (MS), drugs that cure this devastating disorder are an unmet need. Among the remedies showing efficacy in preclinical MS models, inhibitors of poly(ADP-ribose) polymerase (PARP)-1 have gained great momentum. Emerging evidence demonstrates that PARP-1 inhibitors epigenetically regulate gene expression and finely tune transcriptional activation in immune and neural cells. In this review, we present an appraisal of the effects of PARP-1 and its inhibitors on immune activation, with particular emphasis on the processes taking place during the autoimmune attack directed against the central nervous system. One explanation is that drugs inhibiting PARP-1 activity protect from neuroinflammation in MS models via immunomodulation and direct neuroprotection. PARP-1 inhibitors have already reached the clinical arena as cancer treatments, and observations made in treating these patients could help advance treatments for MS.”
The antibiotic "minocycline", one of the medications used in the treatment of MS inhibits PARP.
Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9685-90. Epub 2006 Jun 12.
Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations.
Alano CC, Kauppinen TM, Valls AV, Swanson RA.
“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…”
In the following study the researchers concluded that activation of PARP "occurs rapidly" after exposure to homocysteine.
Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity.http://www.jneurosci.org/content/20/18/6920.short
“Elevated plasma levels of the sulfur-containing amino acid homocysteine increase the risk for atherosclerosis, stroke, and possibly Alzheimer's disease, but the underlying mechanisms are unknown. We now report that homocysteine induces apoptosis in rat hippocampal neurons. DNA strand breaks and associated activation of poly-ADP-ribose polymerase (PARP) and NAD depletion occur rapidly after exposure to homocysteine and precede mitochondrial dysfunction, oxidative stress, and caspase activation…Homocysteine markedly increases the vulnerability of hippocampal neurons to excitotoxic and oxidative injury in cell culture and in vivo, suggesting a mechanism by which homocysteine may contribute to the pathogenesis of neurodegenerative disorders.”