Inhibiting poly(ADP-ribose) polymerase: a potential therapy against oligodendrocyte death

Abstract

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. Poly(ADP-ribose) polymerase inhibition suppressed c-Jun N-terminal kinase and p38 mitogen-activated protein kinase phosphorylation, increased the activation of the cytoprotective phosphatidylinositol-3 kinase-Akt pathway and prevented caspase-independent apoptosis inducing factor-mediated apoptosis. 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.

Catalpol Protects Pre-Myelinating Oligodendrocytes against Ischemia-induced Oxidative Injury through ERK1/2 Signaling Pathway

“…These observations suggest that PARP-1 activation occurs downstream of ERK1/2 activation and that the ERK/PARP pathway is involved in catalpol-mediated cytoprotection. PARP-1 activation is associated with the degeneration of OL processes and mediates OL loss and demyelination in experimental models of multiple sclerosis 48, 49. These morphological degeneration were also observed in PreOLs in our ischemic model, as shown by reduced process complexity and decreased myelination, further confirming the role of PARP-1 activation in PreOL injury.…”

“…PARP-1 has been implicated in caspase-independent cell death due to its role in cellular NAD depletion, which further induces energy failure, mitochondrial depolarization, MPT pore opening, and apoptosis-inducing factor translocation in response to stress 46, 47. A recent study indicated that PARP-1 plays important roles in OL death 48. In an in vitro model of ischemia, ERK1/2-mediated PARP-1 activation was involved in OL death in a caspase-independent manner 20.…”

Role of inflammation and apoptosis in multiple sclerosis: Comparative analysis between the periphery and the central nervous system

“…Interestingly, massive alterations in respiratory chain proteins and mitochondrial DNA were reported in a case of acute MS lesions (Mahad et al, 2008). Observation of MS preactive lesions ex vivo or in a model of demyelination induced by cuprizone indicated that apoptosis in oligodendrocytes occurred through the mitochondrial pathway by means of PARP activation and caspase-independent translocation of the apoptosis inducing factor (AIF) from mitochondria to nucleus (Veto et al, 2010). Inhibition of poly(ADP-ribose) polymerase-impaired oligodendrocyte depletion further supported a role of PARP in the pathogenesis of MS lesions.…”

A research update on the potential roles of aquaporin 4 in neuroinflammation

“…Mitochondrial injury, which is most likely induced by reactive oxygen and nitrogen species [27,28], has been suggested as one possible mechanism of neurodegeneration in AD, Parkinson's disease, and MS [29]. Free radicals are produced through different pathways, including oxidative burst in activated microglia [30], and liberation of toxic iron from intracellular stores [31] as well as from mitochondrial injury themselves [32]. In MS, this pathway of tissue injury apparently is dominantly driven by the inflammatory process; however, amyloid toxicity may induce oxidative damage directly through mitochondrial injury as well as indirectly through microglia activation in AD.…”