Docosahexaenoic acid (DHA), the n-3 essential fatty acid that is highly enriched in the brain, increases neurite growth and synaptogenesis in cultured mouse fetal hippocampal neurons. These cellular effects may underlie the DHA-induced enhancement of hippocampus-dependent learning and memory functions. We found that N-docsahexaenoylethanolamide (DEA), an ethanolamide derivative of DHA, is a potent mediator for these actions. This is supported by the observation that DHA is converted to DEA by fetal mouse hippocampal neuron cultures and a hippocampal homogenate, and DEA is present endogenously in the mouse hippocampus. Furthermore, DEA stimulates neurite growth and synaptogenesis at substantially lower concentrations than DHA, and it enhances glutamatergic synaptic activities with concomitant increases in synapsin and glutamate receptor subunit expression in the hippocampal neurons. These findings suggest that DEA, an ethanolamide derivative of DHA, is a synaptogenic factor, and therefore we suggest utilizing the term ‘synaptamide’. This brief review summarizes the neuronal production and actions of synaptamide and describes other N-docosahexaenoyl amides that are present in the brain.

Background

Omega-3 fatty acid (O3FA) levels and dimensional personality measures have been associated with major depression and the course of depressive illness. We sought to study the utility of O3FA levels and dimensional personality measures as predictors of early improvement with escitalopram.

Methods

Twenty-four participants were enrolled in an open-label trial of escitalopram 10 mg/d for 4 weeks. Baseline erythrocyte O3 levels and dimensional personal assessments were obtained.

Results

Using a conservative, intention-to-treat analysis, baseline neuroticism (r = −0.57; P = .007), as measured by the Revised NEO Personality Inventory (NEO-PI-R) but not erythrocyte O3 levels, was correlated with improvements on escitalopram. A facet analysis of the neuroticism domain showed the relationship with antidepressant response to be focused on trait anxiety (r = −0.65; P = .002).

Conclusions

Anxiety may have important prognostic implications on subsequent response to selective serotonin reuptake inhibitors, such as escitalopram.

Soluble epoxide hydrolase (sEH) is the major enzyme responsible for the metabolism and inactivation of epoxyeicosatrienoic acids (EETs). EETs are produced by the cytochrome P450 (CYP) epoxygenase pathway of arachidonic acid (AA) metabolism and tend to be anti-hypertensive, anti-inflammatory and protective against ischemic injury. Since the metabolism of EETs by sEH reduces or eliminates their bioactivity, inhibition of sEH has become a therapeutic strategy for hypertension and inflammation. sEH is found in nearly all tissues so the systemic application of inhibitors is likely to affect more than blood pressure and inflammation. In the central nervous system, EETs are thought to play a role in the regulation of local blood flow, protection from ischemic injury, inhibition of inflammation, the release of peptide hormones and modulation of fever. However, little is known about region- and cell-specific expression of sEH in the brain. In the mouse brain, expression of sEH was found widely in cortical and hippocampal astrocytes and also in a few specific neuron-types in the cortex, cerebellum, and medulla. To assess the functional significance of neuronal sEH, we generated a transgenic mouse model, which over-expresses sEH specifically in neurons. Transgenic mice showed increased neuron labeling in cortex and hippocampus with little change in labeling of other brain regions. Despite a 3-fold increase in sEH activity in the brain, there was no change in arterial pressure. This data provides new information required for studying the central roles of the cytochrome P450 epoxygenase pathway.

Soluble epoxide hydrolase (sEH) plays a major role in regulating vascular epoxyeicosatrienoic acid metabolism and function, and substituted urea derivatives that inhibit sEH activity reduce blood pressure in hypertensive rats. We found that substituted urea derivatives containing a dodecanoic acid group, besides effectively inhibiting sEH, increased peroxisome proliferator-activated receptor (PPAR) α activity. In PPARα transfected COS-7 cells, treatment with 10 μM N-cyclohexyl-N′-dodecanoic acid urea (CUDA) or N-adamantanyl-N′-dodecanoic acid urea (AUDA) produced 6- and 3-fold increases, respectively, in PPARα activation. Neither CUDA nor AUDA activated PPARδ or PPARγ directly, indicating selectivity for PPARα. CUDA did not alter PPARα protein expression, and it competitively inhibited the binding of Wy-14643 (pirinixic acid) to the ligand binding domain of PPARα, suggesting that it functions as a PPARα ligand. CUDA and AUDA were metabolized to chain-shortened β-oxidation products, a process that reduced their potency as sEH inhibitors and their ability to bind and activate PPARα. N,N′-Dicylclohexylurea and N-cyclohexyl-N′-dodecylurea, sEH inhibitors that do not contain a carboxylic acid group, did not activate PPARα. In HepG2 cells, CUDA increased the expression of the PPARα-responsive gene carnitine palmitoyltransferase 1A. We conclude that CUDA and AUDA, by virtue of their carboxylic acid substitution, activate PPARα in addition to potently inhibiting sEH. Further development of these compounds could lead to a class of agents with hypotensive and lipid-lowering properties that may be valuable for the prevention and treatment of cardiovascular disease.

The 24 hr sterol excretion from the entire skin surface was determined in six normal and five hypercholesterolemic (Type II) patients fed a controlled, eucaloric diet containing 400 mg of plant sterols. All subjects received radiolabeled cholesterol intravenously in order to measure cholesterol turnover and exchange. The 24 hr skin surface lipids were collected subsequently at intervals of 7-10 days. Sterols were quantified and identified by a combination of thin-layer and gas-liquid chromatographic methods. The mean 24 hr excretion of cholesterol in milligrams was 82.6 in the normal subjects and 82.7 in the hypercholesterolemic patients. Cholesterol constituted 89% of the total sterol excretion through the skin surface in both groups.

The specific radioactivity of cholesterol in the skin surface lipids increased gradually after the intravenous administration of the isotope. Within 4-5 wk the specific activity equaled and then remained higher than that of the plasma up to 10 wk. These specific activity curves suggested that, for at least some of skin surface cholesterol, there was a precursor-product relationship between the plasma cholesterol and the skin cholesterol.

The presence of plant sterols, β-sitosterol, campesterol, and stigmasterol in the skin surface lipids of man has not been reported previously. We identified these sterols in the skin surface lipids of all of our subjects. They constituted about 7% of the total skin surface sterols. The occurrence of plant sterols in the skin surface lipids suggested that plasma sterols were transferred from the plasma into the skin. 1-2% of the skin surface sterols were tentatively identified as lathosterol and lanosterol.

The present study documented that a significant amount of cholesterol was excreted from the skin surface and that probably there was a net transfer of plasma cholesterol into the skin surface lipids. Both normal subjects and hypercholesterolemic patients excreted similar amounts of cholesterol per day into the skin surface lipids. We suggest that this daily loss of cholesterol from the skin surface may need to be considered in sterol balance studies.

There was a rapid net uptake of free fatty acid (FFA) by human platelets when long-chain FFA, bound to human serum albumin, were incubated with platelet suspensions. Results from experiments in which both palmitate and albumin were labeled indicated that the fatty acid dissociated from the protein during uptake. Much of the FFA taken up by the platelet in short-term incubations remained in unesterified form, i.e., it was recovered as platelet FFA. As the incubation continued, increasing amounts of FFA were oxidized to CO2 and incorporated into platelet lipid esters, particularly lecithin. Essentially all of the fatty acid that was incorporated into the platelet FFA fraction was released rapidly from the cells when they were exposed to a medium containing FFA-free albumin. The magnitude of uptake into the platelet FFA fraction was similiar at 0° and 37°C. Likewise, the rate and magnitude of FFA release from the platelet were similar at 0° and 37°C. Therefore, it is likely that both FFA uptake and FFA release occur by energy-independent mechanisms. The major effect of increasing the FFA concentration of the incubation medium was increased fatty acid uptake into the platelet FFA fraction. Similar results occurred when platelets were incubated in human plasma containing increasing amounts of added palmitate. At a given extracellular FFA concentration, considerably more of the saturated fatty acids, palmitate and stearate, were taken up as platelet FFA than either oleate or linoleate.