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NeuroRX : Volume 11, Issue 2, April 2014

NeuroRX : Volume 11, Issue 1, January 2014

PARP Inhibition Delays Progression of Mitochondrial Encephalopathy in Mice

Content Provider	Springer Nature Link
Author	Felici, Roberta Cavone, Leonardo Lapucci, Andrea Guasti, Daniele Bani, Daniele Chiarugi, Alberto
Copyright Year	2014
Abstract	Mitochondrial disorders are deadly childhood diseases for which therapeutic remedies are an unmet need. Given that genetic suppression of the nuclear enzyme poly (adenine diphosphate-ribose) polymerase(PARP)-1 improves mitochondrial functioning, we investigated whether pharmacological inhibition of the enzyme affords protection in a mouse model of a mitochondrial disorder. We used mice lacking the Ndufs4 subunit of the respiratory complex I (Ndufs4 knockout [ KO] mice); these mice undergo progressive encephalopathy and die around postnatal day 50. Mice were treated daily with the potent PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride (PJ34); neurological parameters, PARP activity, and mitochondrial homeostasis were evaluated. We found that mice receiving N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride from postnatal day 30 to postnatal day 50 show reduced neurological impairment, and increased exploratory activity and motor skills compared with vehicle-treated animals. However, drug treatment did not delay or reduce death. We found no evidence of increased PARP activity within the brain of KO mice compared with heterozygous, healthy controls. Conversely, a 10-day treatment with the PARP inhibitor significantly reduced basal poly(ADP-ribosyl)ation in different organs of the KO mice, including brain, skeletal muscle, liver, pancreas, and spleen. In keeping with the epigenetic role of PARP-1, its inhibition correlated with increased expression of mitochondrial respiratory complex subunits and organelle number. Remarkably, pharmacological targeting of PARP reduced astrogliosis in olfactory bulb and motor cortex, but did not affect neuronal loss of KO mice. In light of the advanced clinical development of PARP inhibitors, these data emphasize their relevance to treatment of mitochondrial respiratory defects.
Starting Page	651
Ending Page	664
Page Count	14
File Format	PDF
ISSN	19337213
Journal	NeuroRX
Volume Number	11
Issue Number	3
e-ISSN	18787479
Language	English
Publisher	Springer US
Publisher Date	2014-06-17
Publisher Institution	American Society for Experimental NeuroTherapeutics
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Mitochondrial diseases complex I deficiency Ndufs4 knockout poly (ADP-ribose) polymerase PARP inhibitor mitochondrial biogenesis. Neurosciences Neurology Neurosurgery Neurobiology
Content Type	Text
Resource Type	Article
Subject	Neurology (clinical) Pharmacology Pharmacology (medical)

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