02 May 2003
Role of poly(ADP-ribose) polymerase (PARP) activation in the mitochondrial to nuclear translocation of apoptosis inducing factor (AIF) in strokeK. Komjati, C. Szabo
Med Sci Monit 2003; 9(1): 32- :: ID: 15091
Focal cerebral ischemia activates the nuclear protein poly(ADP-ribose) polymerase (PARP) by single DNA strand breaks which leads to energy depletion and cell death and significantly contributes to the pathogenesis of stroke. Apoptosis Inducing Factor (AIF) is a flavoprotein that is normally confined to the mithochondrial intermembrane space, yet translocates to the nucleus, as shown in several in vitro models of neuronal injury. Here we examined the AIF tranclocation changes in a rat model of focal cerebral ischemia and using INO-1001, a novel potent inhibitor of PARP, we determined the role of PARP activation in the process of AIF translocation in vivo. We used a standard rat middle cerebral artery occlusion model with 2h ischemia and 22h reperfusion. INO-1001 (3 mg/kg/24h) provided a 85% reduction in total hemispheric infarct size, when its administration began 2 hours after the MCA occlusion. INO-1001 attenuated the accumulation of poly(ADP-ribose) in the ischemic/reperfused hemisphere and reduced the accumulation of APP in the white matter of the affected hemisphere, consistently with protection against neuronal necrosis and axonal damage, respectively. Immunocytochemical analysis showed the appearance of AIF labeling in neuronal nuclei of the border zone ischemic area in the striatum after stroke. Cytoplasmatic (axonal) AIF staining was significantly diminished in the necrotic core of the striatum, while it was somewhat enhanced at the borderline ischemic territories of the white matter (ie. in the inner layer of the external capsule). Inhibition of PARP with INO-1001 reshifted the location of the apoptotic marker to the axons in the ipsilateral striatum. Thus, PARP inhibition provides marked protection in the rat model of MCA occlusion induced stroke, both in terms of histological damage (perykarial and axonal) and in terms of functional parameters. Moreover, PARP appears to be involved in the ischemic nuclear translocation of AIF. References: 1.Yu SW, Wang H, Poitras MF, Coombs C et al: Mediation of PARP-1-dependent cell death by apoptosis-inducing factor. Science, 2002; 297: 259-63 2.Virág L, Szabó C: The therapeutic potential of PARP inhibition. Pharmacological Reviews, 2002; 54: 375-429
Keywords: Ligation, gingivitis, periodontitis, oral flora, Bacteria, peroxynitrite, Nitric Oxide
01 October 2023 : EditorialEditorial: Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 Guidelines for COPD, Including COVID-19, Climate Change, and Air Pollution
Med Sci Monit 2023; 29:e942672
02 Oct 2023 : Clinical ResearchComparison of Nanocrystalline Hydroxyapatite Bone Graft with Empty Defects in Long Bone Fractures: A Retros...
Med Sci Monit In Press; DOI: 10.12659/MSM.941112
02 Oct 2023 : Review articleCircadian Rhythms in Cardiovascular Function: Implications for Cardiac Diseases and Therapeutic Opportunities
Med Sci Monit In Press; DOI: 10.12659/MSM.942215
30 Sep 2023 : Clinical ResearchInfluence of Age, Gender, Frailty, and Body Mass Index on Serum IL-17A Levels in Mature Type 2 Diabetic Pat...
Med Sci Monit In Press; DOI: 10.12659/MSM.940128
Most Viewed Current Articles
13 Nov 2021 : Clinical ResearchAcceptance of COVID-19 Vaccination and Its Associated Factors Among Cancer Patients Attending the Oncology ...
Med Sci Monit 2021; 27:e932788
30 Dec 2021 : Clinical ResearchRetrospective Study of Outcomes and Hospitalization Rates of Patients in Italy with a Confirmed Diagnosis o...
Med Sci Monit 2021; 27:e935379
14 Dec 2022 : Clinical ResearchPrevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase Levels
Med Sci Monit 2022; 28:e937990
08 Mar 2022 : Review articleA Review of the Potential Roles of Antioxidant and Anti-Inflammatory Pharmacological Approaches for the Man...
Med Sci Monit 2022; 28:e936292