Inhibitory effects of omega-3 fatty acids on protein kinase C activity in vitro.

Preliminary clinical data indicate that omega-3 fatty acids may be effective mood stabilizers for patients with bipolar disorder. Both lithium and valproic acid are known to inhibit protein kinase C (PKC) activity after subchronic administration in cell culture and in vivo. The current study was undertaken to determine the effects of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on protein kinase C phosphotransferase activity in vitro. Various concentrations of DHA, EPA, and arachidonic acid (AA) were incubated with the catalytic domain of protein kinase C beta from rat brain. Protein kinase C activity was measured by quantifying incorporation of (32)P-PO(4) into a synthetic peptide substrate. Both DHA and EPA, as well as the combination of DHA and EPA, inhibited PKC activity at concentrations as low as 10 micromol l(-1). In contrast, arachidonic acid had no effect on PKC activity. Thus, PKC represents a potential site of action of omega-3 fatty acids in their effects on the treatment of bipolar disorder.

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 disorder; however, the mechanism of action of these compounds is unknown. Based on 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, Ca(2+)/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.

Functional impairment in COPD patients: the impact of anxiety and depression.

The authors examined the relationship between functional status and comorbid anxiety and depression and the relationship between utilization of health care resources and psychopathology in elderly patients with chronic obstructive pulmonary disease (COPD). Elderly male veterans (N = 43) with COPD completed anxiety, depression, and functional status measures. The authors constructed regression models to explore the contribution of COPD severity, medical burden, depression, and anxiety to the dependent variables of functional impairment and health care utilization. Anxiety and depression contributed significantly to the overall variance in functional status of COPD patients, over and above medical burden and COPD severity, as measured by the 8 scales of the Medical Outcomes Study (MOS) 36-item Short Form Health Survey. Surprisingly, medical burden and COPD severity did not contribute significantly to overall variance in functional status. Few patients were receiving any treatment for anxiety or depression.

Bilateral changes in striatal dopamine metabolism after unilateral intracarotid and intrastriatal administration of apomorphine.

Following cannulation of the common carotid artery of female Sprague-Dawley rats, 3 microCi (10 micrograms) of [3H]apomorphine were infused. At various time intervals, drug concentrations were determined in the right and left striata, anterior forebrains, posterior forebrains and cerebella. One minute following intracarotid infusion of apomorphine, approximately a 65-fold right/left difference in apomorphine concentrations was attained in all forebrain structures, and this difference steadily diminished with time as a result of declining drug levels in the infused hemisphere. The concentrations of dopamine and its metabolites (DOPAC, HVA and 3-MT) were quantified by gas chromatography-mass spectrometry in the right and left striata at 5 and 15 min after unilateral intracarotid infusion of 1 microgram apomorphine. At both time intervals and regardless of the side infused, the metabolites of dopamine increased ipsilateral to the side of infusion. Moreover, 3-MT levels were significantly decreased in the contralateral striatum. After direct intrastriatal injection of either 0.1 or 1.0 microgram apomorphine into the right striatum, the levels of dopamine metabolites were again increased in the ipsilateral striatum. 3-MT levels were also decreased significantly in the left striatum. In contrast to the effects observed after systemic administration of apomorphine, these results demonstrate that dopamine release in the striatum is increased by selectively delivering higher concentrations of apomorphine to the nerve terminals of the nigrostriatal neurons. The effects of unilateral apomorphine on dopamine metabolism in the contralateral striatum are most likely the effect of interhemispheric communication.