Chronic valproate treatment increases expression of endoplasmic reticulum stress proteins in the rat cerebral cortex and hippocampus.
BACKGROUND
Sodium valproate is a highly effective treatment for bipolar disorder, but its mechanism of action remains poorly understood. We recently found with differential display polymerase chain reaction that valproate regulates the expression of the endoplasmic reticulum stress protein GRP78 in the rat cerebral cortex. In our study, we investigated the effect of this drug on the other members of the endoplasmic reticulum stress protein family, GRP94 and calreticulin, and we studied the brain regional distribution of GRP78, GRP94, and calreticulin.


METHODS
Immunohistochemistry was used to measure protein levels of GRP78, GRP94, and calreticulin after treatment with sodium valproate (300 mg/kg, intraperitoneal) in specific rat brain regions.


RESULTS
We report here that chronic treatment with valproate also increased expression of other members of the endoplasmic reticulum stress protein family, such as GRP94 and calreticulin. The brain regional distribution of these changes was similar for all three proteins, with marked increase detected in the frontal cortex, parietal cortex, and CA1 region of the hippocampus.


CONCLUSIONS
Because GRP78, GRP94, and calreticulin possess molecular chaperone activity and bind Ca(2+) in the endoplasmic reticulum, the pharmacologic action of valproate may involve one or more of these processes.
Chen
B
B
Department of Psychiatry and Behavioral Neuroscience, McMaster University, Hamilton, Canada.
Wang
J F
JF
Young
L T
LT
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000032:analysis; D037282:Calreticulin; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis; D006360:Heat-Shock Proteins / Q000032:analysis*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007124:Immunoenzyme Techniques; D007274:Injections, Intraperitoneal; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012261:Ribonucleoproteins / Q000032:analysis; D014635:Valproic Acid / Q000494:pharmacology*
D018692:Antimanic Agents; D002135:Calcium-Binding Proteins; D037282:Calreticulin; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D012261:Ribonucleoproteins; C018551:glucose-regulated proteins; D014635:Valproic Acid