Protein kinase inhibition by omega-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 d isorder; however, the mechanism of action of these compounds is unknown. Ba sed oh earlier studies implicating omega -3 fatty acids as inhibitors of pr otein kinase C activity in intact cells, we hypothesized that omega -3 fatt y acids may act through direct inhibition of second messenger-regulated kin ases and sought to determine whether the omega -3 double bond might uniquel y confer pharmacologic efficacy and potency for fatty acids of this type. I n our studies we observed that omega -3 fatty acids inhibited the in vitro activities of cAMP-dependent protein kinase, protein kinase C, Ca2+/calmodu lin-dependent protein kinase II, and the mitogen-activated protein kinase ( MAPK), Our results with a series of long-chain fatty acid structural homolo gs suggest an important role for the omega -3 double bond in conferring inh ibitory efficacy. To assess whether omega -3 fatty acids were capable of in hibiting protein kinases in living neurons, we evaluated their effect on si gnal transduction pathways in the hippocampus. We found that omega -3 fatty acids could prevent serotonin receptor-induced MAPK activation in hippocam pal slice preparations, In addition, we evaluated the effect of omega -3 fa tty acids on hippocampal long-term potentiation, a form of synaptic plastic ity known to be dependent on protein kinase activation. We observed that om ega -3 fatty acids blocked long-term potentiation induction without inhibit ing basal synaptic transmission. Overall, our results from both in vitro an d live cell preparations suggest that inhibition of second messenger-regula ted protein kinases is one locus of action of omega -3 fatty acids.