TY - JOUR
T1 - Role of poly(ADP-ribose) synthetase in inflammation
AU - Szabó, Csaba
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (R29GM54773 and R01HL59266).
PY - 1998/5/29
Y1 - 1998/5/29
N2 - Peroxynitrite and hydroxyl radicals are potent initiators of DNA single strand breakage, which is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose)synthetase (PARS). Rapid activation of PARS depletes the intracellular concentration of its substrate, NAD+, slowing the rate of glycolysis, electron transport and ATP formation. This process can result in acute cell dysfunction and cell necrosis. Accordingly, inhibitors of PARS protect against cell death under these conditions. In addition to the direct cytotoxic pathway regulated by DNA injury and PARS activation, PARS also appears to modulate the course of inflammation by regulating the expression of a number of genes, including the gene for intercellular adhesion molecule 1, collagenase and the inducible nitric oxide synthase. The research into the role of PARS in inflammatory conditions is now supported by novel tools, such as novel, potent inhibitors of PARS, and genetically engineered animals lacking the gene for PARS. In vivo data demonstrate that inhibition of PARS protects against various forms of inflammation, including zymosan or endotoxin induced multiple organ failure, arthritis, allergic encephalomyelitis, and diabetic islet cell destruction. Pharmacological inhibition of PARS may be a promising novel approach for the experimental therapy of various forms of inflammation.
AB - Peroxynitrite and hydroxyl radicals are potent initiators of DNA single strand breakage, which is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose)synthetase (PARS). Rapid activation of PARS depletes the intracellular concentration of its substrate, NAD+, slowing the rate of glycolysis, electron transport and ATP formation. This process can result in acute cell dysfunction and cell necrosis. Accordingly, inhibitors of PARS protect against cell death under these conditions. In addition to the direct cytotoxic pathway regulated by DNA injury and PARS activation, PARS also appears to modulate the course of inflammation by regulating the expression of a number of genes, including the gene for intercellular adhesion molecule 1, collagenase and the inducible nitric oxide synthase. The research into the role of PARS in inflammatory conditions is now supported by novel tools, such as novel, potent inhibitors of PARS, and genetically engineered animals lacking the gene for PARS. In vivo data demonstrate that inhibition of PARS protects against various forms of inflammation, including zymosan or endotoxin induced multiple organ failure, arthritis, allergic encephalomyelitis, and diabetic islet cell destruction. Pharmacological inhibition of PARS may be a promising novel approach for the experimental therapy of various forms of inflammation.
KW - 3-Aminobenzamide
KW - Diabetes
KW - Endotoxin
KW - Free radical
KW - Inflammation
KW - Mitochondrial respiration
KW - Nicotinamide
KW - Nitric oxide, (NO)
KW - Peroxynitrite
KW - Poly(ADP-ribose)synthetase
KW - Septic shock
KW - Stroke
KW - Superoxide
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U2 - 10.1016/S0014-2999(98)00249-0
DO - 10.1016/S0014-2999(98)00249-0
M3 - Review article
C2 - 9683009
AN - SCOPUS:0032577469
SN - 0014-2999
VL - 350
SP - 1
EP - 19
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1
ER -