title: Mechanisms underlying the protective potential of alpha-tocopherol (vitamin E) against haloperidol-associated neurotoxicity.
abstract: The undesired side-effects of haloperidol treatment include a number of extrapyramidal side-effects which have been proposed to result from drug-induced damage to the basal ganglia. The drug also causes irregular movements and locomotor patterns in experimental animals. Here we show that haloperidol treatment in rats is associated with increases in the expression of p53 and the ratio of pro-apoptotic (Bax) to anti-apoptotic (Bcl-2/Bcl-x(L)) proteins in the hippocampus and caudate putamen (CPu). In addition, haloperidol induces the DNA binding activity of the redox-sensitive nuclear factor-kappa B (NF-kappaB) and concomitantly upregulates the levels of the phosphorylated form of IkappaBalpha protein in vivo. Similar responses are observed when a mouse hippocampal cell line (HT-22) is treated with haloperidol and/or vitamin E. Interestingly, all of these biochemical effects of haloperidol are significantly attenuated when animals or cultured cells are pretreated with alpha-tocopherol (vitamin E). Consistent with this, vitamin E is demonstrated to substantially reduce the haloperidol-induced impairment of locomotor activity in rats. Collectively, the data indicate the usefulness of vitamin E as an adjunct to haloperidol treatment and provide initial clues about the underlying molecular mechanisms involved in these effects.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany. post@mpipsykl.mpg.de
authors.forename: Anke
authors.initials: A
authors.lastname: Post
authors.forename: Monika
authors.initials: M
authors.lastname: Rücker
authors.forename: Frauke
authors.initials: F
authors.lastname: Ohl
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Osborne F X
authors.initials: OF
authors.lastname: Almeida
authors.forename: Theologos M
authors.initials: TM
authors.lastname: Michaelidis
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D006220:Haloperidol / Q000494:pharmacology* / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000096:biosynthesis; D009498:Neurotoxins / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D024502:alpha-Tocopherol / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D014150:Antipsychotic Agents; D016328:NF-kappa B; D009498:Neurotoxins; D020011:Protective Agents; D024502:alpha-Tocopherol; D006220:Haloperidol