title: Activation of the sigma-1 receptor by haloperidol metabolites facilitates brain-derived neurotrophic factor secretion from human astroglia.
abstract: Glial cells play a critical role in neuronal support which includes the production and release of the neurotrophin brain-derived neurotrophic factor (BDNF). Activation of the sigma-1 receptor (S1R) has been shown to attenuate inflammatory stress-mediated brain injuries, and there is emerging evidence that this may involve a BDNF-dependent mechanism. In this report we studied S1R-mediated BDNF release from human astrocytic glial cells. Astrocytes express the S1R, which mediates BDNF release when stimulated with the prototypical S1R agonists 4-PPBP and (+)-SKF10047. This effect could be antagonized by a selective concentration of the S1R antagonist BD1063. Haloperidol is known to have high affinity interactions with the S1R, yet it was unable to facilitate BDNF release. Remarkably, however, two metabolites of haloperidol, haloperidol I and haloperidol II (reduced haloperidol), were discovered to facilitate BDNF secretion and this effect was antagonized by BD1063. Neither 4-PPBP, nor either of the haloperidol metabolites affected the level of BDNF mRNA as assessed by qPCR. These results demonstrate for the first time that haloperidol metabolites I and II facilitate the secretion of BDNF from astrocytes by acting as functionally selective S1R agonists.
authors.affiliation: Department of Pharmacology & Neuroscience, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, Texas, 76107, United States.
authors.forename: Dhwanil A
authors.initials: DA
authors.lastname: Dalwadi
authors.affiliation: Department of Pharmacology & Neuroscience, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, Texas, 76107, United States.
authors.forename: Seongcheol
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pharmacology & Neuroscience, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, Texas, 76107, United States; Institute for Healthy Aging, Center for Neuroscience Discovery, United States. Electronic address: John.Schetz@unthsc.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Schetz
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017480:Receptors, sigma / Q000819:agonists / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D014150:Antipsychotic Agents; D019208:Brain-Derived Neurotrophic Factor; D006220:Haloperidol; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C579455:BDNF protein, human
keywords: (+)-SKF10047 (PubChem CID: 13286169); 4-PPBP (PubChem CID: 3035672); Astrocytes; BD1063 (PubChem CID: 574780); BDNF; Haloperidol (PubChem CID: 3559); Haloperidol metabolite I (PubChem CID: 38282); Haloperidol metabolite III (PubChem CID: 101359); In situ ELISA; NE-100 (PubChem CID: 9841596); Neurotrophin; PF-04418948 (PubChem CID: 25114442); PGE2 (PubChem CID: 5280360); Reduced haloperidol (PubChem CID: 119265); Sigma receptor