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.

PARP1-mediated PARylation activity is essential for oligodendroglial differentiation and CNS myelination

“…Our study suggests that PARP1 promotes remyelination in the CPZ model, which mimics pattern III MS lesions of primary oligodendrogliopathy. Our results also indicate that PARP1 plays a minor role in OL death, a conclusion which seems contradictory with previous data reporting that PARP1 inhibition protects OLs from CPZ-induced death (Veto et al, 2010). However, the timecourse analysis showed that PARP1 was activated primarily in CD68 + activated microglia (Figure 7D) and minimally in Sox10 + oligodendroglia (Figure 7C) during CPZ-induced demyelination stages.…”

PARP1-mediated PARylation activity is essential for oligodendroglial differentiation and CNS myelination

“…Our study suggests that PARP1 promotes remyelination in the CPZ model, which mimics pattern III MS lesions of primary oligodendrogliopathy. Our results also indicate that PARP1 plays a minor role in OL death, a conclusion which seems contradictory with previous data reporting that PARP1 inhibition protects OLs from CPZ-induced death (Veto et al, 2010). However, the timecourse analysis showed that PARP1 was activated primarily in CD68 + activated microglia (Figure 7D) and minimally in Sox10 + oligodendroglia (Figure 7C) during CPZ-induced demyelination stages.…”

PARP Inhibition Attenuates Acute Kidney Allograft Rejection by Suppressing Cell Death Pathways and Activating PI-3K-Akt Cascade

“…2C, D ). This is in accordance to our previous studies in various oxidative stress model systems [18] , [32] , [27] , [55] . PARP inhibition also increased the expression of Bcl-2 and decreased the Bax expression in transplanted kidneys ( Fig.…”

Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis

“…The observed large lysosomes could result from lysosome membrane permeabilisation, which contributes to thymocyte apoptosis by releasing lysosomal proteases, thereby causing the degradation of vital cytosolic proteins and the activation of additional hydrolases, including caspases [ 34 ]. This scenario is consistent with the finding that, unlike in the case of oligodendrocytes [ 6 ], both AIF- and caspase-mediated apoptosis was observed in the thymi of cuprizone-treated mice ( Fig 7A ). On the other hand, cytoplasmic translocation of mitochondrial cytochrome C ( Fig 7A ) may entirely account for the observed caspase-3 activation.…”

PARP1-mediated PARylation activity is essential for oligodendroglial differentiation and CNS myelination

“…Our study suggests that PARP1 promotes remyelination in the CPZ model, which mimics pattern III MS lesions of primary oligodendrogliopathy. Our results also indicate that PARP1 plays a minor role in OL death, a conclusion which seems contradictory with previous data reporting that PARP1 inhibition protects OLs from CPZ-induced death (Veto et al, 2010). However, the timecourse analysis showed that PARP1 was activated primarily in CD68 + activated microglia (Figure 7D) and minimally in Sox10 + oligodendroglia (Figure 7C) during CPZ-induced demyelination stages.…”

PARP Inhibition Attenuates Acute Kidney Allograft Rejection by Suppressing Cell Death Pathways and Activating PI-3K-Akt Cascade

“…2C, D ). This is in accordance to our previous studies in various oxidative stress model systems [18] , [32] , [27] , [55] . PARP inhibition also increased the expression of Bcl-2 and decreased the Bax expression in transplanted kidneys ( Fig.…”

Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis

“…The observed large lysosomes could result from lysosome membrane permeabilisation, which contributes to thymocyte apoptosis by releasing lysosomal proteases, thereby causing the degradation of vital cytosolic proteins and the activation of additional hydrolases, including caspases [ 34 ]. This scenario is consistent with the finding that, unlike in the case of oligodendrocytes [ 6 ], both AIF- and caspase-mediated apoptosis was observed in the thymi of cuprizone-treated mice ( Fig 7A ). On the other hand, cytoplasmic translocation of mitochondrial cytochrome C ( Fig 7A ) may entirely account for the observed caspase-3 activation.…”

PARP1-mediated PARylation activity is essential for oligodendroglial differentiation and CNS myelination

“…Our study suggests that PARP1 promotes remyelination in the CPZ model, which mimics pattern III MS lesions of primary oligodendrogliopathy. Our results also indicate that PARP1 plays a minor role in OL death, a conclusion which seems contradictory with previous data reporting that PARP1 inhibition protects OLs from CPZ-induced death (Veto et al, 2010). However, the timecourse analysis showed that PARP1 was activated primarily in CD68 + activated microglia (Figure 7D) and minimally in Sox10 + oligodendroglia (Figure 7C) during CPZ-induced demyelination stages.…”

PARP Inhibition Attenuates Acute Kidney Allograft Rejection by Suppressing Cell Death Pathways and Activating PI-3K-Akt Cascade

“…2C, D ). This is in accordance to our previous studies in various oxidative stress model systems [18] , [32] , [27] , [55] . PARP inhibition also increased the expression of Bcl-2 and decreased the Bax expression in transplanted kidneys ( Fig.…”

Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis

“…The observed large lysosomes could result from lysosome membrane permeabilisation, which contributes to thymocyte apoptosis by releasing lysosomal proteases, thereby causing the degradation of vital cytosolic proteins and the activation of additional hydrolases, including caspases [ 34 ]. This scenario is consistent with the finding that, unlike in the case of oligodendrocytes [ 6 ], both AIF- and caspase-mediated apoptosis was observed in the thymi of cuprizone-treated mice ( Fig 7A ). On the other hand, cytoplasmic translocation of mitochondrial cytochrome C ( Fig 7A ) may entirely account for the observed caspase-3 activation.…”