Protein kinase inhibition by ω-3 fatty acids

Recent data suggest that omega -3 fatty acids may be effective in epilepsy, cardiovascular disorders, arthritis, and as mood stabilizers for bipolar disorder; however, the mechanism of action of these compounds is unknown. Based oh earlier studies implicating omega -3 fatty acids as inhibitors of protein kinase C activity in intact cells, we hypothesized that omega -3 fatty acids may act through direct inhibition of second messenger-regulated kinases and sought to determine whether the omega -3 double bond might uniquely confer pharmacologic efficacy and potency for fatty acids of this type. In our studies we observed that omega -3 fatty acids inhibited the in vitro activities of cAMP-dependent protein kinase, protein kinase C, Ca2+/calmodulin-dependent protein kinase II, and the mitogen-activated protein kinase (MAPK), Our results with a series of long-chain fatty acid structural homologs suggest an important role for the omega -3 double bond in conferring inhibitory efficacy. To assess whether omega -3 fatty acids were capable of inhibiting protein kinases in living neurons, we evaluated their effect on signal transduction pathways in the hippocampus. We found that omega -3 fatty acids could prevent serotonin receptor-induced MAPK activation in hippocampal slice preparations, In addition, we evaluated the effect of omega -3 fatty acids on hippocampal long-term potentiation, a form of synaptic plasticity known to be dependent on protein kinase activation. We observed that omega -3 fatty acids blocked long-term potentiation induction without inhibiting basal synaptic transmission. Overall, our results from both in vitro and live cell preparations suggest that inhibition of second messenger-regulated protein kinases is one locus of action of omega -3 fatty acids.