PARP inhibition improves the effectiveness of neural stem cell transplantation in experimental brain trauma.
Neural stem cell transplantation is a promising new treatment of ischemic or traumatic brain injury. We have now investigated the involvement of the peroxynitrite - poly(ADP-ribose) polymerase (ONOO- - PARP) activation cascade in brain trauma and neural stem cell transplantation. The forelimb motor cortex of adult male rats was exposed to cold lesion (-60 degrees C) and motor function was monitored. Neural stem cells isolated from E14 rat embryos were labeled with brome deoxyuridine (BrDU) and injected into the injured cortex 6 days after the lesion. After another 6 days, the survival and differentiation of the grafted cells were investigated with immunohistochemistry. Increased production of ONOO- revealed by tyrosine nitration was seen in the lesion 2 days after transplantation. Animals treated with the ONOO- decomposition catalyst FP15 or the PARP inhibitor PJ34 had a significantly improved motor score, when compared to vehicle-treated controls. The neurological score further improved following stem cell grafting in the PJ34 treated, but not in the control animals. Six days after transplantation, differentiated BrDU positive cells were found in the cortical penumbra. The majority of these differentiated cells expressed an astrocyte marker and some of the cells expressed oligodendrocyte or neuronal markers. The number of surviving transplanted cells was significantly higher in the PJ34 treated group. Inhibition of the ONOO- - PARP activation cascade significantly improves the effectiveness of neural stem cell transplantation and promotes rapid functional recovery.
Lacza
Zsombor
Z
Department of Physioloty/Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. zlacza@mac.com
Horváth
Eszter M
EM
Komjáti
Katalin
K
Hortobágyi
Tibor
T
Szabó
Csaba
C
Busija
David W
DW
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D009044:Motor Cortex; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D030421:Peroxynitrous Acid / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology; D014443:Tyrosine / Q000032:analysis / Q000378:metabolism
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D030421:Peroxynitrous Acid; D014443:Tyrosine; D011065:Poly(ADP-ribose) Polymerases