Effect of piracetam on polyphosphoinositide metabolism, cytosolic calcium release, and oxidative burst in human polymorphonuclear cells: Interaction with fMLP-induced stimulation

We investigated the action of piracetam on human polymorphonuclear leukocyt e (PMN) responsiveness in vitro. We first studied phosphoinositide metaboli sm and calcium release with and without fMLP (formyl-methionyl-leucyl-pheny lalanine) stimulation. Piracetam at concentrations from 10(-4) to 10(-2) M induced a slight increase in inositol 1,4,5-trisphosphate (IP3) release and phosphatidylinositol 4,5-bisphosphate (PIP2) breakdown. At concentrations above 10(-3) M, piracetam sensitized PMNs to subsequent stimulation by rMLP used at subliminal concentrations (10(-9) and 10(-8) M), inducing a signif icant increase in IF3 release and PIP2 breakdown similar to that obtained w ith cells stimulated by the highest effective concentrations of fMLP (10(-7 ) and 10(-6) M). In the same way, piracetam greatly enhanced calcium releas e induced by weak concentrations of fMLP. However, piracetam had no effect on oxidative metabolism. We then studied the binding of (H-3)fMLP to the PM N membrane in the presence of various concentrations of piracetam. We were not able to demonstrate an obvious action of piracetam either on receptor r ecruitment or on receptor affinity to fMLP. The difference between the acti ons of piracetam on phosphoinositide metabolism and calcium release on the one hand and oxidative burst on the other could be explained by an uncoupli ng of the triggering and activating effects of piracetam on PMNs. The enhan cement by piracetam of intracellular cyclic AMP revels rapidly induced term ination of the PMN response and accounted for the lack of effect on superox ide production. Thus, piracetam was able to modulate human PMN reactivity a nd in particular to exert a "priming effect" (rather due to structural modi fications of the membrane), which might be of importance in infectious epis odes given the absence of deleterious actions such as oxygen free radical p roduction leading to tissue injury. BIOCHEM PHARMACOL 57;2:163-170, 1999. ( C) 1998 Elsevier Science Inc.