Effect of bax deletion on ethanol sensitivity in the neonatal rat cerebellum.
The developing cerebellum is highly sensitive to ethanol during discrete neonatal periods. This sensitivity has been linked to ethanol-induced alterations in molecules of the Bcl-2 survival-regulatory gene family. Ethanol exposure during peak periods of cerebellar sensitivity, for example, results in increased expression of proapoptotic proteins of this family, while overexpression of the antiapoptotic Bcl-2 protein in the nervous system protects against ethanol neurotoxicity. For the present study, neonatal mice with a targeted deletion of the proapoptotic bax gene were used to determine whether elimination of this protein would mitigate ethanol toxicity. bax knock-out and wild-type mice pups were exposed to ethanol via vapor inhalation during the maximal period of neonatal cerebellar ethanol sensitivity and cerebellar tissue was subsequently assessed for Purkinje and granule cell number and ethanol-mediated generation of reactive oxygen species (ROS). The results revealed that: (1) ethanol exposure during the peak period of cerebellar vulnerability resulted in substantial loss of Purkinje cells in wild-type animals, but not in bax knock-outs; (2) granule cells in the bax gene-deleted animals were not similarly protected from ethanol effects; and (3) levels of ROS following acute ethanol exposure were appreciably enhanced in the wild-type animals but not in the bax knock-outs. These results imply that Bax is important to ethanol-induced Purkinje cell death during critical neonatal periods, but that ethanol effects on granule cells may function at least partially independent of this apoptosis agonist. Amelioration of ethanol-mediated increases in ROS production in the knock-outs may contribute to the observed effects.
Heaton
Marieta Barrow
MB
Department of Neuroscience, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, 32610-0244, USA. heaton@ufbi.ufl.edu
Paiva
Michael
M
Madorsky
Irina
I
Siler-Marsiglio
Kendra
K
Shaw
Gerry
G
D000280:Administration, Inhalation; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D001522:Behavior, Animal; D002452:Cell Count / Q000379:methods; D002492:Central Nervous System Depressants / Q000008:administration & dosage* / Q000097:blood; D002531:Cerebellum / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D000431:Ethanol / Q000008:administration & dosage* / Q000097:blood; D021621:Imaging, Three-Dimensional / Q000379:methods; D051379:Mice; D009474:Neurons / Q000145:classification / Q000187:drug effects* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000172:deficiency*
C494828:Bax protein, rat; D002492:Central Nervous System Depressants; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D000431:Ethanol