title: Delayed translocation of NGFI-B/RXR in glutamate stimulated neurons allows late protection by 9-cis retinoic acid.
abstract: Nuclear receptor and apoptosis inducer NGFI-B translocates out of the nucleus as a heterodimer with RXR in response to different apoptosis stimuli, and therefore represents a potential pharmacological target. We found that the cytosolic levels of NGFI-B and RXRα were increased in cultures of cerebellar granule neurons 2h after treatment with glutamate (excitatory neurotransmitter in the brain, involved in stroke). To find a time-window for potential intervention the neurons were transfected with gfp-tagged expressor plasmids for NGFI-B and RXR. The default localization of NGFI-Bgfp and RXRgfp was nuclear, however, translocation out of the nucleus was observed 2-3h after glutamate treatment. We therefore hypothesized that the time-window between treatment and translocation would allow late protection against neuronal death. The RXR ligand 9-cis retinoic acid was used to arrest NGFI-B and RXR in the nucleus. Addition of 9-cis retinoic acid 1h after treatment with glutamate reduced the cytosolic translocation of NGFI-B and RXRα, the cytosolic translocation of NGFI-Bgfp observed in live neurons, as well as the neuronal death. However, the reduced translocation and the reduced cell death were not observed when 9-cis retinoic acid was added after 3h. Thus, late protection from glutamate induced death by addition of 9-cis retinoic acid is possible in a time-window after apoptosis induction.
authors.affiliation: Department of Pharmaceutical Biosciences, University of Oslo, PO Box 1068, Blindern, N-0316 Oslo, Norway.
authors.forename: Gro H
authors.initials: GH
authors.lastname: Mathisen
authors.forename: Åsa B
authors.initials: ÅB
authors.lastname: Fallgren
authors.forename: Bjørn O
authors.initials: BO
authors.lastname: Strøm
authors.forename: Karen A
authors.initials: KA
authors.lastname: Boldingh Debernard
authors.forename: Beata U
authors.initials: BU
authors.lastname: Mohebi
authors.forename: Ragnhild E
authors.initials: RE
authors.lastname: Paulsen
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D019610:Cytoprotection; D018698:Glutamic Acid / Q000633:toxicity; D008024:Ligands; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D051381:Rats; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D008024:Ligands; D018696:Neuroprotective Agents; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D047490:Retinoid X Receptor alpha; D000077556:Alitretinoin; D018698:Glutamic Acid; D014212:Tretinoin