02 May 2003
Role of poly(ADP-ribose) polymerase (PARP) activation in the mitochondrial to nuclear translocation of apoptosis inducing factor (AIF) in stroke
K. Komjati, C. SzaboMed Sci Monit 2003; 9(1): 32-0 :: ID: 15091
Abstract
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
Editorial
01 March 2024 : Editorial
Editorial: First Regulatory Approvals for CRISPR-Cas9 Therapeutic Gene Editing for Sickle Cell Disease and Transfusion-Dependent β-ThalassemiaDOI: 10.12659/MSM.944204
Med Sci Monit 2024; 30:e944204
In Press
18 Mar 2024 : Clinical Research
Sexual Dysfunction in Women After Tibial Fracture: A Retrospective Comparative StudyMed Sci Monit In Press; DOI: 10.12659/MSM.944136
21 Feb 2024 : Clinical Research
Potential Value of HSP90α in Prognosis of Triple-Negative Breast CancerMed Sci Monit In Press; DOI: 10.12659/MSM.943049
22 Feb 2024 : Review article
Differentiation of Native Vertebral Osteomyelitis: A Comprehensive Review of Imaging Techniques and Future ...Med Sci Monit In Press; DOI: 10.12659/MSM.943168
23 Feb 2024 : Clinical Research
A Study of 60 Patients with Low Back Pain to Compare Outcomes Following Magnetotherapy, Ultrasound, Laser, ...Med Sci Monit In Press; DOI: 10.12659/MSM.943732
Most Viewed Current Articles
16 May 2023 : Clinical Research
Electrophysiological Testing for an Auditory Processing Disorder and Reading Performance in 54 School Stude...DOI :10.12659/MSM.940387
Med Sci Monit 2023; 29:e940387
17 Jan 2024 : Review article
Vaccination Guidelines for Pregnant Women: Addressing COVID-19 and the Omicron VariantDOI :10.12659/MSM.942799
Med Sci Monit 2024; 30:e942799
14 Dec 2022 : Clinical Research
Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase LevelsDOI :10.12659/MSM.937990
Med Sci Monit 2022; 28:e937990
01 Jan 2022 : Editorial
Editorial: Current Status of Oral Antiviral Drug Treatments for SARS-CoV-2 Infection in Non-Hospitalized Pa...DOI :10.12659/MSM.935952
Med Sci Monit 2022; 28:e935952