title: Translocation of AIF in the human and rat striatum following protracted haloperidol, but not clozapine treatment.
abstract: Loss of mitochondrial membrane integrity and consequent release of apoptogenic factors may be involved in mediating striatal neurodegeneration after prolonged treatment with the typical antipsychotic drug haloperidol. Apoptosis-inducing factor (AIF), an intramitochondrial protein, may have a large influence on mediating haloperidol-induced striatal neuron destruction. Translocation of this protein from mitochondria to the nucleus promotes cell death independently of the caspase cascade. To examine how AIF may contribute to haloperidol-induced apoptosis, AIF translocation was observed in three haloperidol treatment paradigms. SH-SY5Y cells were treated with both haloperidol and clozapine and examined for AIF immunofluorescence. Immunohistochemistry was also performed on human striatal sections obtained from the Stanley Foundation Neuropathology Consortium and on rat brain sections following 28 days of antipsychotic drug treatment. In the cellular model haloperidol, but not clozapine treatment increased the nuclear AIF immunofluorescent signal and decreased cell viability. Corollary to these findings, striatal sections from patients who had taken haloperidol and rats who were administered haloperidol both had an elevated nuclear AIF signal. The results provide novel evidence implicating the involvement of AIF in haloperidol-associated apoptosis and its relevance to the development of typical antipsychotic drug-related adverse effects such as tardive dyskinesia.
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5.
authors.forename: K J
authors.initials: KJ
authors.lastname: Skoblenick
authors.forename: J M
authors.initials: JM
authors.lastname: Castellano
authors.forename: R M
authors.initials: RM
authors.lastname: Rogoza
authors.forename: B A
authors.initials: BA
authors.lastname: Dyck
authors.forename: N
authors.initials: N
authors.lastname: Thomas
authors.forename: J P
authors.initials: JP
authors.lastname: Gabriele
authors.forename: V Z
authors.initials: VZ
authors.lastname: Chong
authors.forename: R K
authors.initials: RK
authors.lastname: Mishra
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C494829:AIFM1 protein, human; C494831:Aifm1 protein, rat; D014150:Antipsychotic Agents; D051033:Apoptosis Inducing Factor; D003024:Clozapine; D006220:Haloperidol