phenanthrenes and Cerebral-Infarction

The objective of this study was to evaluate whether Tanshinone IIA (TSA) was neuroprotective in permanent focal cerebral ischemia and to determine the possible mechanisms of its neuroprotection. Mice were subjected to permanent middle cerebral artery occlusion. The neuroprotection of TSA was investigated with respect to neurological deficit scores and infarct volume. Biochemical analyses for malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in serum, and nitric oxide (NO) content and the inducible nitric oxide synthase (iNOS) activity in brain tissue were performed at 24 h after ischemia. Immunohistochemistry was used to measure the expression of iNOS. In vitro, the effects of TSA were tested in the cultured astrocytes exposed to hydrogen dioxide (H2O2). TSA (5, 10 and 20 mg/kg, i.p.) significantly reduced the infarct volume and improve neurological deficit. TSA also significantly increased the activity of SOD after 24 h of ischemia and decreased the MDA level, NO content, and iNOS expression. In vitro, the translocation of NF-kappaB was inhibited by TSA and the survival rate of astrocytes was markedly increased and the NO production was decreased. In conclusion, these results illustrated that TSA protected the brain from ischemic injury by suppressing the oxidative stress and the radical-mediated inflammatory insult.

Topics: Abietanes; Animals; Astrocytes; Brain; Brain Ischemia; Cells, Cultured; Cerebral Infarction; Drugs, Chinese Herbal; Hydrogen Peroxide; Infarction, Middle Cerebral Artery; Male; Malondialdehyde; Mice; Mice, Inbred ICR; Neuroprotective Agents; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Phenanthrenes; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Hemorrhagic transformation is an aggravating event that occurs in 15 to 43% of patients suffering from ischemic stroke. This phenomenon due to blood-brain barrier breakdown appears to be mediated in part by matrix metalloproteinases (MMPs) among which MMP-2 and MMP-9 could be particularly involved. Recent experimental studies demonstrated that post-ischemic MMP-9 overexpression is regulated by poly(ADP-ribose)polymerase (PARP). In this context, our study aimed to evaluate the effect of PJ34 (N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-2-(N,N-dimethylamino)acetamide), a potent PARP inhibitor, on MMP-2 and MMP-9 levels and on hemorrhagic transformations in a model of permanent focal cerebral ischemia in mice. PJ34 (6.25-12.5 mg/kg, i.p.) was given at the time of ischemia onset and 4 h later. Hemorrhagic transformations, divided into microscopic and macroscopic hemorrhages, were counted 48 h after ischemia on 12 coronal brain slices. Microscopic and macroscopic hemorrhages were respectively reduced by 38% and 69% with 6.25 mg/kg PJ34. The anti-hemorrhagic effect of PJ34 was associated with a 57% decrease in MMP-9 overexpression assessed by gelatin zymography. No increase in MMP-2 activity was observed after ischemia in our model. The vascular protection achieved by PJ34 was associated with a reduction in the motor deficit (P<0.05) and in infarct volume (-31%, P<0.01). In conclusion, our study demonstrates for the first time that PJ34 reduces hemorrhagic transformations after cerebral ischemia. Thus this PARP inhibitor exhibits both anti-hemorrhagic and neuroprotective effects that may be of valuable interest for the treatment of stroke.

Topics: Animals; Brain Ischemia; Cerebral Hemorrhage; Cerebral Infarction; Enzyme Inhibitors; Male; Metalloproteases; Mice; Motor Activity; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Psychomotor Performance

Activation of poly(ADP-ribose) polymerase (PARP) is deleterious during cerebral ischemia. We assessed the influence of PARP activation induced by cerebral ischemia on the synthesis of proinflammatory mediators including the cytokines, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) and the adhesion molecules, E-selectin and intercellular adhesion molecule-1 (ICAM-1).. Ischemia was induced by intravascular occlusion of the left middle cerebral artery for 1 h in male Swiss mice anaesthetized with ketamine and xylazine. The PARP inhibitor PJ34 (1.25-25 mg kg(-1)) was administered intraperitoneally 15 min before and 4 hours after, the onset of ischemia. Animals were killed 6 h or 24 h after ischemia and cerebral tissue removed for analysis.. Ischemia increased TNF-alpha protein in cerebral tissue at 6 and 24 h after ischemia. All doses of PJ34 blocked the increase in TNF-alpha at 6 h and 25 mg kg(-1) PJ34 had a sustained effect for up to 24 h. Quantitative real time polymerase chain reaction showed that PJ34 (25 mg kg(-1)) reduced the increase in TNF-alpha mRNA by 70% at 6 h. PJ34 also prevented the increase in mRNAs encoding IL-6 (-41%), E-selectin (-81%) and ICAM-1 (-54%). PJ34 (25 mg kg(-1)) reduced the infarct volume (-26%) and improved neurological deficit, 24 h after ischemia.. PJ34 inhibited the increase in the mRNAs of four inflammatory mediators, caused by cerebral ischemia. The contribution of this effect of PJ34 to neuroprotection remains to be clarified.

Topics: Animals; Anti-Inflammatory Agents; Brain; Cell Adhesion Molecules; Cerebral Infarction; Cytokines; Dose-Response Relationship, Drug; E-Selectin; Enzyme Inhibitors; Intercellular Adhesion Molecule-1; Interleukin-6; Ischemic Attack, Transient; Male; Mice; Nervous System Diseases; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; RNA, Messenger; Tumor Necrosis Factor-alpha