geranylgeranylacetone and Necrosis

Geranylgeranylacetone (GGA), an anti-ulcer drug, has been reported to induce heat shock protein (HSP) 70 in several animal organs. The present study was performed to determine whether GGA protects mouse liver against acetaminophen (APAP)-induced injury and whether it has potential as a therapeutic agent for APAP overdose. Hepatic damage was induced by single oral administration of APAP (500 mg/kg). GGA at 400 mg/kg was given orally 4 or 8h before, or 0.5h after APAP administration. Treatment of mice with GGA 4h before or 0.5h after APAP administration suppressed increases in transaminase activities and ammonia content in blood as well as hepatic necrosis. Such GGA treatment significantly increased hepatic HSP70 accumulation after APAP administration. Furthermore, GGA inhibited increases in hepatic lipid peroxide content and hepatic myeloperoxidase activity after APAP administration. In contrast, GGA neither inhibited hepatic cytochrome P450 2E1 activity nor suppressed hepatic glutathione depletion after APAP administration. The protective effect of GGA treatment 4h before APAP on hepatotoxicity induced by APAP was completely inhibited with quercetin, known as an HSP inhibitor. In conclusion, GGA has been identified as a new antidote to APAP injury, acting by induction of HSP70. The potential of GGA as a therapeutic tool is strongly supported by its ability to inhibit hepatic injury even when administered after ingestion of APAP.

Topics: Acetaminophen; Alanine Transaminase; Ammonia; Analgesics, Non-Narcotic; Animals; Anti-Ulcer Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1; Diterpenes; Glutathione; HSP70 Heat-Shock Proteins; In Vitro Techniques; Lipid Peroxidation; Liver; Male; Mice; Microsomes, Liver; Necrosis; Peroxidase

This study evaluates the neuroprotective effects of geranylgeranylacetone (GGA), which is known as an antiulcer agent and more recently as a heat-shock and other neuroprotective protein inducer, on secondary degeneration after spinal cord injury in rats. Crush injuries were produced at the T8 level using an extradural approach. Optimal administration conditions of GGA were established in an initial experiment by evaluating the appearance of lesions 24 h after injury in sections stained with H-E. Then, in a second experiment, animals treated with the optimal condition (600 mg/kg, 24 h before injury and thereafter every 24 h) were allowed to survive for 6 and 24 h and 1, 3, and 8 weeks after injury, and spinal cords were prepared for histological evaluation by staining for H-E for general histopathology and by silver staining for axons. There was a significant reduction (46%) in lesion volume 24 h after injury in animals treated with optimal administration conditions. The increase in tumor necrosis factor-alpha (TNF-alpha) and the accumulation of neutrophils in the damaged segment of the spinal cord 4 h after injury were significantly inhibited in animals that received GGA. Lesion size and cavitation area remained smaller in treated animals throughout the post-injury survival interval. These results suggest that GGA administration significantly reduces the secondary degeneration that would otherwise occur. The mechanism by which GGA exerts its beneficial effect is unknown but may involve reduction of TNF-alpha activation at the injured cord and/or inhibition of inflammation.

Topics: Animals; Diagnostic Imaging; Diterpenes; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Granulocyte Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Interleukin-3; Locomotion; Male; Necrosis; Nerve Degeneration; Rats; Rats, Wistar; Recombinant Fusion Proteins; Recombinant Proteins; Silver Staining; Spinal Cord Injuries; Time Factors; Tumor Necrosis Factor-alpha

Gastric mucosal cell death due to various gastric stressors can cause several types of gastric diseases, such as gastric ulcers. In this study, we examined cell death following the short-term treatment of guinea pig gastric mucosal cells in primary culture with various gastric stressors. The short-term treatment of cells with ethanol, hydrogen peroxide or hydrochloric acid caused, in a dose-dependent manner, cell death in the absence of apoptotic DNA fragmentation and chromatin condensation. Cells lost membrane integrity following the treatment with each of these gastric stressors, suggesting that necrosis was induced in gastric mucosal cells by short-term treatment of the cells with gastric stressors. Geranylgeranylacetone, an anti-ulcer drug with heat-shock protein inducing properties, protected gastric mucosal cells from the necrotic cell death caused by each of these gastric stressors. Pretreatment of cells with low concentrations of ethanol (3%), which also induced heat-shock protein, made cells resistant to the necrotic cell death caused by the gastric stressors. These results suggest that heat-shock proteins is involved in the cytoprotective effect of geranylgeranylacetone against necrotic cell death.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Cell Death; Cell Membrane; Cell Nucleus; Cell Survival; Cells, Cultured; Chromatin; Diterpenes; DNA Fragmentation; Gastric Mucosa; Guinea Pigs; Heat-Shock Proteins; HSP72 Heat-Shock Proteins; Immunoblotting; Male; Necrosis