Involvement of extracellular signal regulated kinases in traumatic brain injury-induced depression in rodents.
Traumatic brain injury (TBI) is the most common cause of death and acquired disability among children and young adults in the developed countries. In clinical studies, the incidence of depression is high after TBI, and the mechanisms behind TBI-induced depression remain unclear. In the present study, we subjected rats to a moderate fluid percussion into the closed cranial cavity to induce TBI. After 3 days of recovery, injured rats were given a forced swim test (FST) and novelty-suppressed feeding tests. We found that TBI rats exhibited increased duration of immobility and longer latency to begin chewing food in a new environment compared with sham-operated rats. Western blot analysis showed that TBI led to a decrease in the phosphorylated levels of extracellular signal regulated kinases (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK). Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), significantly reduced the duration of immobility when administered once per day for 14 days. Consistent with behavioral tests, fluoxetine treatment reversed TBI-induced decrease in p-ERK1/2 and p-p38 MAPK levels. Pre-treatment with a selective tryptophan hydroxylase inhibitor para-chlorophenylalanine (PCPA) blocked the antidepressant effect of fluoxetine. PCPA also prevented the effect of fluoxetine on ERK1/2 phosphorylation without affecting p38 MAPK phosphorylation. Pre-treatment with ERK inhibitor SL327 but not p38 MAPK inhibitor SB203580 prevented the antidepressant effect of fluoxetine. These results suggest that ERK1/2 plays a critical role in TBI-induced depression.
Department of Neurosurgery, Chi Mei Medical Center, Taiwan University of Science and Technology, Tainan, Taiwan.
Jinn-Rung
JR
Kuo
Yi-Hsuan
YH
Cheng
Yi-Shion
YS
Chen
Chung-Ching
CC
Chio
Po-Wu
PW
Gean
D000818:Animals; D001007:Anxiety / Q000523:psychology; D015153:Blotting, Western; D001930:Brain Injuries / Q000150:complications* / Q000201:enzymology*; D004396:Coloring Agents; D003863:Depression / Q000201:enzymology* / Q000209:etiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005247:Feeding Behavior / Q000502:physiology; D010134:Fenclonine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D005518:Food Preferences / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007398:Interpersonal Relations; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D009043:Motor Activity / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018490:Serotonin Agents / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013550:Swimming / Q000523:psychology; D013778:Tetrazolium Salts
D004396:Coloring Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D010134:Fenclonine; D005473:Fluoxetine; D007093:Imidazoles; D011725:Pyridines; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; C093642:SB 203580