poly-(ADP-ribose) polymerase (PARP) were found to be beneficial in many pathophysiological conditions associated with oxidative stress and PARP-1 knock-out mice proved to be resistant to bacterial lipopolysaccharide (LPS)-induced septic shock, PARP. The mechanism of the protective effect of a potent PARP-1 inhibitor, PJ34 was studied in LPS-induced (20 mg/kg, i.p.) septic shock in mice. We demonstrated a significant inflammatory response by magnetic resonance imaging in the dorsal subcutaneous region, in the abdominal regions around the kidneys and in the inter-intestinal cavities. Wehave found necrotic and apoptotic histological changes as well as obstructed blood vessels in the liver and small intestine. Additionally, we have detected elevated tumor necrosis factor-a levels in the serum and nuclear factor kappa B activation in liver of LPS-treated mice. Pre-treating the animals with PJ34 (10 mg/kg, i.p.), before the LPS challenge, besides rescuing the animals from LPS-induced death, attenuated all these changes presumably by activating the phosphatidylinositol 3-kinase - Akt/protein kinase B cytoprotective pathway. PJ34, a novel, potent PARP-1 inhibitor was found to protect against LPS induced tissue damage. PARP inhibitors protected Langendorff-perfused hearts against ischemia-reperfusion induced damages by activating the PI3-kinase - Akt pathway. The importance of the PI3-kinase - Akt pathway in LPS induced inflammatory mechanisms has gained support, raising the question whether this pathway was involved in the effect of PJ34 on LPS-induced septic shock. Among all the observed LPS-induced inflammatory responses, we found the most characteristic and most pronounced increases in the gastro-intestinal tract, but no signal increase could be observed inside the kidneys and in skeletal muscle, in the paravertebral or in the femoral muscle. All increases in signal intensities were significantly attenuated in mice treated with PJ34.

## Effect of PJ34 on survival of LPS-treated mice

- • inhibitor significantly protected the animals against LPS-induced death, with 86 and 43% • inhibitor significantly protected the animals against LPS-induced death, with 86 and 43% surviving mice, respectively.
- • treatment itself did not induce death or any obvious damage. • treatment itself did not induce death or any obvious damage.

## Effect of PJ34 on LPS-induced NF-kB activation

- • treatment in the lung caused a significant increase in NF-kB activation that was slightly but • treatment in the lung caused a significant increase in NF-kB activation that was slightly but not statistically significantly attenuated by PJ34 pre-treatment.
- • contrast to the lung, NF-kB activation in the liver was prevented by PJ34 pre-treatment • contrast to the lung, NF-kB activation in the liver was prevented by PJ34 pre-treatment

The other tissue with observable LPS-induced pathological changes was the small intestine. Atrophy of villi may reflect the diarrhea observed in the LPS-treated animals and is in agreement with the results of Abreu et al. who found a Fas-mediated apoptosis in intestinal epithelial cells that was sensitised by inhibitors of PI3-kinase and opposed by expressing constitutively active Akt. Pre-treatment of the animals with a novel, potent PARP-1 inhibitor, PJ34, diminished the thoracic and abdominal inflammatory responses as revealed by T2 imaging, and abolished the above mentioned pathological changes.