title: Neuroprotective effects of genistein in VSC4.1 motoneurons exposed to activated microglial cytokines.
abstract: Pro-inflammatory cytokines released from activated microglia may be responsible for neuronal damage and resulting motor deficits associated with CNS disorders such as spinal cord injury, Parkinson's disease, and multiple sclerosis. Estrogen (17β-estradiol) is capable of ameliorating motoneuron death following spinal cord injury, but has a number of deleterious side effects. Genistein (GEN), an estrogen receptor beta agonist and potent antioxidant, may represent an alternative to estrogen in treating neurodegenerative disorders. However, little is known about the neuroprotective effects of GEN. We therefore tested whether GEN would prevent apoptosis in cultured motoneurons following exposure to pro-inflammatory cytokines released from IFN-γ activated microglia. Exposure of ventral spinal cord 4.1 motoneurons to microglial cytokine supernatant in vitro caused significant apoptosis and reduced mitochondrial membrane potential. An increase in reactive oxygen species, intracellular Ca(2+), calpain, caspases, cytochrome c, and the bax:bcl-2 ratio were also noted. GEN treatment reversed apoptotic death and cellular changes following cytokine exposure and was associated with increased expression of estrogen receptor β suggesting that GEN may promote neuroprotection via receptor-mediated pathways. The addition of ICI 182, 780, an estrogen receptor antagonist following GEN treatment attenuated neuroprotection, suggesting that GEN may act mainly via estrogen receptor β to protect VSC4.1 motoneurons. We conclude that GEN protects cultured ventral spinal cord 4.1 cells from inflammatory insult and thus may represent a potential beneficial therapy in the treatment of neurodegenerative disorders.
authors.affiliation: Department of Neurosciences, Division of Neurology, Medical University of South Carolina, 96 Jonathan Lucas St., 309 Clinical Sciences Building, Charleston, SC 29425, USA. mcdowelm@musc.edu
authors.forename: Misty L
authors.initials: ML
authors.lastname: McDowell
authors.forename: Arabinda
authors.initials: A
authors.lastname: Das
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Smith
authors.forename: Abhay K
authors.initials: AK
authors.lastname: Varma
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Ray
authors.forename: Naren L
authors.initials: NL
authors.lastname: Banik
mesh_terms: D000818:Animals; D017209:Apoptosis; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D019833:Genistein / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016207:Cytokines; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D007371:Interferon-gamma; D045304:Cytochromes c; D019833:Genistein; D053453:Caspase 9