One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats

258

151

Decreased docosahexaenoic acid (DHA) and brain-derived neurotrophic factor (BDNF) have been implicated in bipolar disorder. It also has been reported that dietary deprivation of n-3 polyunsaturated fatty acids (PUFAs) for 15 weeks in rats, increased their depression and aggression scores. Here, we show that n-3 PUFA deprivation for 15 weeks decreased the frontal cortex DHA level and reduced frontal cortex BDNF expression, cAMP response element binding protein (CREB) transcription factor activity and p38 mitogen-activated protein kinase (MAPK) activity. Activities of other CREB activating protein kinases were not significantly changed. The addition of DHA to rat primary cortical astrocytes in vitro, induced BDNF protein expression and this was blocked by a p38 MAPK inhibitor. DHA's ability to regulate BDNF via a p38 MAPK-dependent mechanism may contribute to its therapeutic efficacy in brain diseases having disordered cell survival and neuroplasticity.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

n-3 Polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism

et al. 2006

258

151

“…If reliable rodent models of bipolar disorder are developed, it would be useful to test if they are associated with increased AA turnover and AA incorporation into brain phospholipids using quantitative autoradiography and/or chemical analysis. In this regard, 15 weeks of nÀ3 polyunsaturated fatty acid deprivation in rats increased their depression and aggression scores 143 and these altered behavioral scores were associated with increased cPLA 2 activity, protein and mRNA as well as increased COX-2 protein and mRNA expression in the frontal cortex. 144 Approaches to developing novel therapeutics for bipolar disorder by targeting the AA cascade Chronic, therapeutically relevant doses of lithium, carbamazepine and valproate decrease the brain concentration of PGE 2 and the turnover of AA but not of DHA in brain phospholipids of the unanesthetized rat, albeit via different mechanisms ( Figure 3 and Table 2).…”

Section: Observations Related To Aa In Bipolar Disorder Patientsmentioning

confidence: 99%

Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

et al. 2008

108

Bipolar disorder is a major medical, social and economic burden worldwide. However, the mechanisms of action of effective antibipolar disorder drugs remain elusive. In this paper, we review studies using a neuropharmacological approach in unanesthetized rats, combined with kinetic, biochemical and molecular biology techniques, showing that chronic administration of three Food and Drug Administration-approved mood stabilizers (lithium, valproate and carbamazepine) at therapeutically relevant doses, selectively target the brain arachidonic acid (AA) cascade. Whereas chronic lithium and carbamazepine decrease the binding activity of activator protein-2 and in turn the transcription, translation and activity of its AA-selective calcium-dependent phospholipase A 2 gene product, valproate appears to be a non-competitive inhibitor of long-chain acyl-CoA synthetase. The net overlapping effects of the three drugs are decreased turnover of AA but not of docosahexaenoic acid in rat brain phospholipids, and decreased brain cyclooxygenase-2 and prostaglandin E 2 . Although these observations support the hypothesis proposed by Rapoport and colleagues that the AA cascade is a common target of mood stabilizers, this hypothesis is not necessarily exclusive of other targets. Targeting the AA cascade with drugs or diet may be a useful therapeutic approach in bipolar disorder, and examining the AA cascade in patients might help in better understanding the disease.

“…Fifteen weeks of n-3 PUFA deprivation in rats also increased test scores of depression and aggression, behaviors that are found in bipolar disorder in humans. 23 The frontal cortex has been implicated in the pathogenesis of bipolar disorder. [24][25][26] In light of this and to better compare our results with previous findings, [27][28][29][30] we examined the expression and activities of enzymes that regulate AA and DHA metabolic cascades in frontal cortex of n-3 PUFA deprived and adequate rats.…”

Section: Introductionmentioning

confidence: 99%

Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex

et al. 2006

177

150

The enzymes that regulate the brain arachidonic acid (AA) cascade have been implicated in bipolar disorder and neuroinflammation. Fifteen weeks of dietary n-3 polyunsaturated fatty acid (PUFA) deprivation in rats decreases the concentration of docosahexaenoic acid (DHA) and increases its half-life within the brain. Based on this, we hypothesized that such dietary deprivation would decrease expression of enzymes responsible for the metabolic loss of DHA while increasing expression of those responsible for the metabolism of AA. Fifteen weeks of n-3 PUFA deprivation significantly decreased the activity, protein and mRNA expression of the DHA regulatory phospholipase A 2 (PLA 2 ), calcium-independent iPLA 2 , in rat frontal cortex. In contrast the activities, protein and mRNA levels of the AA selective calcium-dependent cytosolic phospholipase (cPLA 2 ) and secretory sPLA 2 were increased. Cyclooxygenase (COX)-1 protein but not mRNA was decreased in the n-3 PUFA-deprived rats whereas COX-2 protein and mRNA were increased. This study suggests that n-3 PUFA deprivation increases the halflive of brain DHA by downregulating iPLA 2 . The finding that n-3 PUFA deprivation increases cPLA 2 , sPLA 2 and COX-2 is opposite to what has been reported after chronic administration of anti-manic agents to rats and suggests that n-3 PUFA deprivation may increase susceptibility to bipolar disorder. Molecular Psychiatry (2007) 12, 151-157.