Prostaglandin-induced neurodegeneration is associated with increased levels of oxidative markers and reduced by a mixture of antioxidants.
Prostaglandin E2 (PGE2), one product of inflammatory reactions, and PGA1, which is formed during PGE2 extraction, induce degeneration in adenosine 3',5'-cyclic monophosphate (cAMP)-induced differentiated neuroblastoma (NB) cells in culture. The mechanisms of action of PGE2 on neurodegeneration are not well understood. To investigate this, we have utilized PGA(1), which mimics the effect of PGE2 and is very stable in solution. We have assayed selected markers of oxidative stress such as heme oxygenase-1 (HO-1), catalase, glutathione peroxidase (GPx1), mitochondrial superoxide dismutase (Mn-SOD-2) and cytosolic superoxide dismutase (Cu/Zn-SOD-1). The results showed that the treatment of differentiated NB cells with PGA1 for a period of 48 hr increased the expression of HO-1 and catalase, decreased the expression of GPx1 and Mn-SOD-2, and did not change the expression of Cu/Zn-SOD-1 as measured by gene array and confirmed by real-time PCR. The protein levels of HO-1 and GPx1 increased; however, the protein level of Mn-SOD-2 decreased and the levels of catalase and Cu/Zn-SOD-1 did not change as determined by Western blot. The increases in the levels of HO-1 and GPx1 reflected an adaptive response to increased oxidative stress, whereas decrease in the level of Mn-SOD-2 may make cells more sensitive to oxidative damage. These data suggest that one of the mechanisms of action of PGA1 on neurodegeneration may involve increased oxidative stress. This was supported further by the fact that a mixture of antioxidants (alpha-tocopherol, vitamin C, selenomethionine, and reduced glutathione), but not the individual antioxidants, reduced the level of PGA1-induced degeneration in differentiated NB cells. The addition of a single antioxidant at two or four times the concentration used in the mixture was toxic.
Yan
Xiang-Dong
XD
Center for Vitamins and Cancer Research, Department of Radiology, School of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Kumar
Bipin
B
Nahreini
Piruz
P
Hanson
Amy J
AJ
Prasad
Judith E
JE
Prasad
Kedar N
KN
D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D005979:Glutathione Peroxidase / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D051379:Mice; D009410:Nerve Degeneration / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011454:Prostaglandins A / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism
D000975:Antioxidants; D008565:Membrane Proteins; D011454:Prostaglandins A; D002374:Catalase; D005979:Glutathione Peroxidase; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D013482:Superoxide Dismutase; C100573:prostaglandin A1