Ethanol withdrawal acts as an age-specific stressor to activate cerebellar p38 kinase.
We investigated whether protein kinase p38 plays a role in the brain-aging changes associated with repeated ethanol withdrawal (EW). Ovariectomized young, middle-age and older rats, with or without 17β-estradiol (E2) implantation, received a 90-day ethanol with repeated withdrawal. They were tested for active pP38 expression in cerebellar Purkinje neurons and whole-cerebellar lysates using immunohistochemistry and enzyme-linked immunosorbent assay, respectively. They were also tested for the Rotarod task to determine the behavioral manifestation of cerebellar neuronal stress and for reactive oxygen species (ROS) and mitochondrial protein carbonyls to determine oxidative mechanisms. Middle-age EW rats showed higher levels of pP38-positive Purkinje neurons/cerebellar lysates, which coincided with increased mitochondrial protein oxidation than other diet/age groups. Exacerbated motor deficit due to age-EW combination also began at the middle-age. In comparison, ROS contents peaked in older EW rats. E2 treatment mitigated each of the EW effects to a different extent. Collectively, pP38 may mediate the brain-aging changes associated with pro-oxidant EW at vulnerable ages and in vulnerable neurons in a manner protected by estrogen.
Jung
Marianna E
ME
Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's disease, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Blvd., Fort Worth, TX 76107-2699, USA. mjung@hsc.unt.edu
Ju
Xiaohua
X
Simpkins
James W
JW
Metzger
Daniel B
DB
Yan
Liang-Jun
LJ
Wen
Yi
Y
D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000201:enzymology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000431:Ethanol; D048051:p38 Mitogen-Activated Protein Kinases