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Decrease of the inflammatory response and induction of the Akt/protein kinase B pathway by poly-(ADP-ribose)
Balazs Veres1, Ferenc Gallyas, Gabor Varbiro
1Department of Biochemistry and Medical Chemistry, Faculty of Medicine, Pecs University, Hungary.
Abstract:
The lack of efficacy of anti-inflammatory drugs, anti-coagulants, anti-oxidants, etc. in critically ill patients has shifted interest towards developing alternative treatments. Since inhibitors of the nuclear enzyme 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 inhibitors are candidates for such a role. In this study, the mechanism of the protective effect of a potent PARP-1 inhibitor, PJ34 was studied in LPS-induced (20mg/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. We have 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-alpha levels in the serum and nuclear factor kappa B activation in liver of LPS-treated mice. Pre-treating the animals with PJ34 (10mg/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.
Insights
PARP inhibitors, like PJ34, show promise for treating septic shock by reducing inflammation and organ damage. This study reveals a potential protective mechanism involving the phosphatidylinositol 3-kinase-Akt pathway.
Area of Science:
- Biomedical Science
- Pharmacology
- Immunology
Background:
- Limited efficacy of conventional treatments for critically ill patients necessitates novel therapeutic strategies.
- Poly-(ADP-ribose) polymerase (PARP) inhibitors are emerging as potential treatments for conditions involving oxidative stress.
- PARP-1 knockout mice exhibit resistance to lipopolysaccharide (LPS)-induced septic shock, highlighting PARP-1's role in sepsis.
Purpose of the Study:
- To investigate the protective mechanism of the PARP-1 inhibitor PJ34 in a mouse model of LPS-induced septic shock.
- To elucidate how PJ34 mitigates the inflammatory and pathological consequences of sepsis.
Main Methods:
- Septic shock was induced in mice using lipopolysaccharide (LPS).
- The potent PARP-1 inhibitor PJ34 was administered prior to LPS challenge.
- Inflammatory responses were assessed using magnetic resonance imaging (MRI).
- Histological analysis examined tissue damage (necrosis, apoptosis, vascular obstruction) in the liver and small intestine.
- Serum tumor necrosis factor-alpha (TNF-α) levels and nuclear factor kappa B (NF-κB) activation in the liver were measured.
Main Results:
- LPS challenge induced significant inflammation, tissue damage (necrosis, apoptosis), and vascular obstruction in multiple organs.
- Elevated serum TNF-α levels and hepatic NF-κB activation were observed in LPS-treated mice.
- Pre-treatment with PJ34 significantly reduced mortality and attenuated LPS-induced inflammatory and pathological changes.
- PJ34's protective effects are presumably mediated by the activation of the phosphatidylinositol 3-kinase-Akt/protein kinase B cytoprotective pathway.
Conclusions:
- The PARP-1 inhibitor PJ34 demonstrates significant protective effects against LPS-induced septic shock in mice.
- PJ34 mitigates sepsis-related inflammation, organ damage, and mortality.
- Activation of the PI3K-Akt pathway is likely the mechanism underlying PJ34's cytoprotective action in sepsis.
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