title: A Pharmacogenetic Discovery: Cystamine Protects Against Haloperidol-Induced Toxicity and Ischemic Brain Injury.
abstract: Haloperidol is an effective antipsychotic agent, but it causes Parkinsonian-like extrapyramidal symptoms in the majority of treated subjects. To address this treatment-limiting toxicity, we analyzed a murine genetic model of haloperidol-induced toxicity (HIT). Analysis of a panel of consomic strains indicated that a genetic factor on chromosome 10 had a significant effect on susceptibility to HIT. We analyzed a whole-genome SNP database to identify allelic variants that were uniquely present on chromosome 10 in the strain that was previously shown to exhibit the highest level of susceptibility to HIT. This analysis implicated allelic variation within pantetheinase genes (Vnn1 and Vnn3), which we propose impaired the biosynthesis of cysteamine, could affect susceptibility to HIT. We demonstrate that administration of cystamine, which is rapidly metabolized to cysteamine, could completely prevent HIT in the murine model. Many of the haloperidol-induced gene expression changes in the striatum of the susceptible strain were reversed by cystamine coadministration. Since cystamine administration has previously been shown to have other neuroprotective actions, we investigated whether cystamine administration could have a broader neuroprotective effect. Cystamine administration caused a 23% reduction in infarct volume after experimentally induced cerebral ischemia. Characterization of this novel pharmacogenetic factor for HIT has identified a new approach for preventing the treatment-limiting toxicity of an antipsychotic agent, which could also be used to reduce the extent of brain damage after stroke.
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California.
authors.forename: Haili
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California.
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California.
authors.forename: Manhong
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California.
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California Center for the Advancement of Health and Bioscience, Sunnyvale, California 94089 Central Institute for Experimental Animals, Kawasaki, Japan, Stanford University School of Medicine, Stanford, California.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California.
authors.forename: Rona
authors.initials: R
authors.lastname: Giffard
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California.
authors.forename: Li Jun
authors.initials: LJ
authors.lastname: Xu
authors.affiliation: Department of Computer Science, Stanford University, Stanford, California.
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, California.
authors.forename: Peyman
authors.initials: P
authors.lastname: Sahbaie
authors.affiliation: Department of Computer Science, Stanford University, Stanford, California.
authors.forename: David L
authors.initials: DL
authors.lastname: Dill
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California gpeltz@stanford.edu.
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
mesh_terms: D000581:Amidohydrolases / Q000235:genetics; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000633:toxicity; D002545:Brain Ischemia / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control; D015815:Cell Adhesion Molecules / Q000235:genetics; D003538:Cystamine / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D058851:GPI-Linked Proteins / Q000235:genetics; D006220:Haloperidol / Q000009:adverse effects* / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide
chemical_list: D014150:Antipsychotic Agents; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D018696:Neuroprotective Agents; D000581:Amidohydrolases; C022314:pantetheinase; C511525:Vnn3 protein, mouse; D006220:Haloperidol; D003538:Cystamine
keywords: haloperidol toxicity; pharmacogenetics