title: CD38 Knockout Mice Show Significant Protection Against Ischemic Brain Damage Despite High Level Poly-ADP-Ribosylation.
abstract: Several enzymes in cellular bioenergetics metabolism require NAD+as an essential cofactor for their activity. NAD+depletion following ischemic insult can result in cell death and has been associated with over-activation of poly-ADP-ribose polymerase PARP1 as well as an increase in NAD+consuming enzyme CD38. CD38 is an NAD+glycohydrolase that plays an important role in inflammatory responses. To determine the contribution of CD38 activity to the mechanisms of post-ischemic brain damage we subjected CD38 knockout (CD38KO) mice and wild-type (WT) mice to transient forebrain ischemia. The CD38KO mice showed a significant amelioration in both histological and neurologic outcome following ischemic insult. Decrease of hippocampal NAD+levels detected during reperfusion in WT mice was only transient in CD38KO animals, suggesting that CD38 contributes to post-ischemic NAD+catabolism. Surprisingly, pre-ischemic poly-ADP-ribose (PAR) levels were dramatically higher in CD38KO animals compared to WT animals and exhibited reduction post-ischemia in contrast to the increased levels in WT animals. The high PAR levels in CD38 mice were due to reduced expression levels of poly-ADP-ribose glycohydrolase (PARG). Thus, the absence of CD38 activity can not only directly affect inflammatory response, but also result in unpredicted alterations in the expression levels of enzymes participating in NAD+metabolism. Although the CD38KO mice showed significant protection against ischemic brain injury, the changes in enzyme activity related to NAD+metabolism makes the determination of the role of CD38 in mechanisms of ischemic brain damage more complex.
authors: Veterans Affairs Maryland Health Care System, 10 North Greene Street, Baltimore, MD, 21201, USA.
authors: Aaron
authors: A
authors: Long
authors: Veterans Affairs Maryland Health Care System, 10 North Greene Street, Baltimore, MD, 21201, USA.
authors: Ji H
authors: JH
authors: Park
authors: Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, School of Medicine, University of Maryland, 685 West Baltimore Street, MSTF 534, Baltimore, MD, 21201, USA.
authors: Nina
authors: N
authors: Klimova
authors: Veterans Affairs Maryland Health Care System, 10 North Greene Street, Baltimore, MD, 21201, USA.
authors: Carol
authors: C
authors: Fowler
authors: Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, School of Medicine, University of Maryland, 685 West Baltimore Street, MSTF 534, Baltimore, MD, 21201, USA.
authors: David J
authors: DJ
authors: Loane
authors: Veterans Affairs Maryland Health Care System, 10 North Greene Street, Baltimore, MD, 21201, USA. tkristian@anes.umm.edu.|Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, School of Medicine, University of Maryland, 685 West Baltimore Street, MSTF 534, Baltimore, MD, 21201, USA. tkristian@anes.umm.edu.
authors: Tibor
authors: T
authors: Kristian
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control*; D002478:Cells, Cultured; D006026:Glycoside Hydrolases / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011897:Random Allocation
chemical_list: D008562:Membrane Glycoproteins; D011064:Poly Adenosine Diphosphate Ribose; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1
keywords: Brain; Damage; Ischemia; Mouse; Nicotinamide dinucleotide; Poly-ADP-ribose