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I Unique among the phospholipids, phosphatidylserine depresses brain energy metabolism when injected intravenously into mice in the form of sonicated liposomes. The possibility that this effect results from a metabolic transformation of phosphatidylserine is examined in this paper. 2 A strong enhancement of the phosphatidylserine effect is induced by the incubation of liposomes with rat serum. Similar phosphatidylserine activation is observed after the incubation of the phospholipid with purified phospholipase A2 from pancreas. In both cases phosphatidylserine is split into the deacylated derivative, lysophosphatidylserine. 3 Lysophosphatidylserine reproduces with greater efficacy the effect of phosphatidylserine on brain energy metabolism. Other lysophospholipids are not effective. 4 It is concluded that the pharmacological effects of phosphatidylserine liposomes is due to the generation of lysophosphatidylserine. IntroductionMethods

The pharmacological action of the l‐ and d‐enantiomers of lysophosphatidylserine has been studied in vivo by following the increase in blood and brain glucose content caused by this phospholipid in mice. Preliminary experiments have confirmed that these effects are the consequence of lysophosphatidylserine‐induced mast cell activation since they are not observed in mast cell‐deficient mice bearing the W/Wv genotype. Maximal hyperglycaemic response and brain glucose accumulation occur at 10 mg kg−1 lysophosphatidyl‐l‐serine (i.v.). Half‐maximal effect is at 3.5 mg kg−1. Lysophosphatidyl‐d‐serine at doses of up to 25 mg kg−1 i.v. elicits 40% (blood glucose) and 60% (brain glucose) of the maximal effect. The difference in activity between the two enantiomers is also observed in the desensitization to lysophosphatidylserine occurring when this phospholipid is administered by the oral route. Lysophosphatidyl‐l‐serine is more active than the d‐enantiomer in mouse isolated peritoneal mast cells. Activity ratios of 10 are observed between 20 and 50% histamine release. Similar results are obtained with rat isolated peritoneal mast cells. It is concluded that the configuration of the alpha carbon atom of serine influences the activity of lysophosphatidylserine in vivo and in vitro. Thus, the appropriate position of the serine amino group is required for optimal interaction of the phospholipid head group and a receptor in the mast cell membrane.

Lysophosphatidylserine is a specific inducer of histamine release in isolated mast cells. To determine whether a similar effect is manifest in vivo, the phospholipid was injected (1-5 mg/kg i.v.) into mice and rats. A dose-dependent rise in blood histamine was observed in both animals. The several-fold increase in blood histamine occurred in the first minutes and was followed by a slower decline toward normal values. A second dose of lysophosphatidylserine was without effect. Systemic manifestations (depression, hypothermia, hypotension) were associated with the increased blood histamine level. When the tissue histamine stores accessible to lysophosphatidylserine were previously decreased by repeated phospholipid injections, no systemic symptoms occurred. Mobilization of carbohydrate reserves was also manifest during the action of lysophosphatidylserine. Prior treatment with compound 48/80 induced sustained refractoriness to lysophosphatidylserine. Structure-activity relationship demonstrated that the property to induce histamine release was linked to the structure of serine head group. Thus, other natural phospholipids or lysophospholipids were inactive. It is concluded that in analogy with the effect seen in vitro lysophosphatidylserine produces in vivo release of mast cell histamine.