gw-5074 and Neurodegenerative-Diseases

Increasing evidence implicates aberrant apoptosis as a fundamental cause of neurodegenerative diseases. Thus elucidating the underlying causes of neuronal programmed cell death may foster the development of therapeutic interventions. Research in the last 15 years provided a solid foundation for understanding molecular mechanisms of neuronal apoptosis. This review discusses the major molecules and signaling pathways leading to neuronal survival or apoptosis with emphasis on several small molecule inhibitors that target neuronal survival with the hope of impeding the detrimental effects of neurodegenerative diseases.

Topics: Animals; Apoptosis; Brain Neoplasms; Carbazoles; Enzyme Inhibitors; Humans; Indoles; MAP Kinase Kinase 4; Models, Biological; Neurodegenerative Diseases; Neurons; p38 Mitogen-Activated Protein Kinases; Phenols; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-bcl-2; Signal Transduction

Cerebellar granule neurons undergo apoptosis when switched from a medium containing high potassium (HK) to one that has low potassium (LK). LK-induced cell death is blocked by GW5074 [5-Iodo-3-[(3,5-dibromo-4-hydroxyphenyl) methylene]-2-indolinone], a synthetic drug that inhibits c-Raf activity in vitro. GW5074 has no direct effect on the activities of several apoptosis-associated kinases when assayed in vitro. In contrast to its effect in vitro, treatment of neurons with GW5074 causes c-Raf activation (when measured in vitro in the absence of the drug) and stimulates the Raf-MEK-ERK pathway. Treatment of neurons with GW5074 also leads to an increase in the activity of B-Raf, which is not inhibited by GW5074 in vitro at concentrations at which the drug exerts its neuroprotective effect. PD98059 and U0126, two distinct inhibitors of MEK, block the activation of ERK by GW5074 but have no effect on its ability to prevent cell death. Overexpression of a dominant-negative form of Akt does not reduce the efficacy of GW5074, demonstrating an Akt-independent mechanism of action. Neuroprotection is inhibited by SN-50, a specific inhibitor of nuclear factor-kappa B (NF-kappaB) and by the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS) implicating NF-kappaB and Ras in the neuroprotective signaling pathway activated by GW5074. In addition to preventing LK-induced apoptosis, treatment with GW5074 protects against the neurotoxic effects of MPP+ and methylmercury in cerebellar granule neurons, and glutathione depletion-induced oxidative stress in cortical neurons. Furthermore, GW5074 prevents neurodegeneration and improves behavioral outcome in an animal model of Huntington's disease. Given its neuroprotective effect on distinct types of cultured neurons, in response to different neurotoxic stimuli, and in an animal model of neurodegeneration, GW5074 could have therapeutic value against neurodegenerative pathologies in humans.

Topics: Animals; Cell Death; Cells, Cultured; Disease Models, Animal; Enzyme Inhibitors; Farnesol; Huntington Disease; Indoles; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Neurotoxins; Nitro Compounds; Phenols; Propionates; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-raf; Rats; Rats, Sprague-Dawley; Salicylates; Signal Transduction