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The Journal of Neuroscience, January 7, 2009, 29(1):14-22; doi:10.1523/JNEUROSCI.3569-08.2009

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Neurobiology of Disease
Increased Phospholipase A2 Activity and Inflammatory Response But Decreased Nerve Growth Factor Expression in the Olfactory Bulbectomized Rat Model of Depression: Effects of Chronic Ethyl-Eicosapentaenoate Treatment

Cai Song,^1,2 Xiang Yang Zhang,³ and Mehar Manku⁴

¹Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada C1A 4P3, ²National Research Council Institute for Nutrisciences and Health, Charlottetown, Prince Edward Island, Canada C1A 4P3, ³Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas 77030, and ⁴Amarin Neuroscience, Oxford OX4 4GA, United Kingdom

Correspondence should be addressed to Dr. Cai Song, Department of Biomedical Sciences, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward Island, Canada C1A 4P3. Email: cai.song{at}nrc.gc.ca

An increased inflammatory response and deficient synthesis of neurotrophic factors (NTFs) may contribute to the etiology of depression. However, the interrelationship between inflammation and NTFs is unknown. Recently, ethyl-eicosapentaenoate (EPA) has been used to treat depression. The mechanism by which EPA benefits depression is also unclear. Using the olfactory bulbectomized (OB) rat model of depression, this study evaluated two pathways from bulbectomy to the induction of depression-like changes (the inflammation–hypothalamic–pituitary–adrenal axis–stress response pathway and inflammation–nerve growth factor–memory pathway) and the effect of EPA on these pathways. When compared with sham-operated rats fed a control diet, significantly increased locomotor and rearing activities in an "open field," impaired memory in the Morris water maze, increased expression of corticotrophin-releasing factor (CRF), and increased secretion of corticosterone were found in OB rats. mRNA expression of nerve growth factor (NGF) was significantly lower in the hippocampus, and phospholipase A2 (PLA2) was higher in the hypothalamus; this change was associated with increased interleukin-1β (IL-1β) and prostaglandin E2 (PGE2) in the serum and brain. EPA treatments normalized these behavioral impairments and reduced CRF expression and corticosterone secretion. EPA also reduced serum concentrations of IL-1β and PGE2, but reversed NGF reduction. Similar to the effects of EPA, the anti-inflammatory drug celecoxib significantly reduced blood PGE2, IL-1β, and corticosterone concentrations and increased NGF expression in OB rats. Furthermore, anti-NGF treatment blocked EPA effects on behavior. These results suggest that an interaction exists between inflammation and NGF in the depression model. EPA may improve depression via its anti-inflammation properties and the upregulation of NGF.

Key words: depression model; behavior; inflammation; EPA; NGF; celecoxib

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Received July 29, 2008; revised Oct. 9, 2008; accepted Nov. 13, 2008.

Correspondence should be addressed to Dr. Cai Song, Department of Biomedical Sciences, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward Island, Canada C1A 4P3. Email: cai.song{at}nrc.gc.ca

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