Prostanoids and their role in cell-cell interactions in the central nervous system.
Although the presence of prostaglandin PGF(2?) has been demonstrated in the central nervous system in the mid sixties, it has taken a rather long time to pinpoint a role of certain metabolites of arachidonic acid in the regulation of neural activity. The modern family of bioactive compounds known as "prostanoids" or "eicosanoids" includes the classical end-products of the cyclooxygenase pathway (prostaglandins, prostacyclin and thromboxane), as well as the molecules formed after the activation of 5- and/or 15-lipoxygenases (leucotrienes and lipoxines), 12-lipoxygenase (hepoxilins) or of epoxygenase (epoxides). Although the brain levels of arachidonic acid-the precursor generating prostaglandins from the series 2-are very low, a plethora of stimuli appears to trigger its release from membrane phospholipids mainly by activation of phospholipase A(2) or subordinately phospholipase C; furthermore, its reesterification can also be subtly regulated by endogenous metabolic processes. Numerous prostanoids have now been detected in the nervous system, namely in neurons, astrocytes, cerebrospinal fluid and cerebral vascular endothelium. Efforts have been oriented at the elucidation of the roles of prostanoids in some physiological conditions (for example sleep regulation) or pathological situations (fever, migraine, epilepsy, schizophrenia). Moreover, several investigators have examined the localization of neuronal membrane receptors for prostanoids and searched for the mechanisms of signal transduction or the identity of second messengers. Those embody cyclic nucleotides (cAMP and cGMP) and calcium. There is also compelling evidence for a modulation by prostanoids of the release of noradrenaline, serotonin and vasoactive intestinal peptide (VIP) as well as of several hormones of the hypothalamic-hypophyseal tract. In addition, neurotransmitters can influence prostanoid synthesis; this has been demonstrated in particular for noradrenaline and more recently for acetylcholine. Prostanoids can also amplify neurotransmitter-mediated signals. Thus, ?(1)-adrenergic agonists, H(1)-histaminergic agonists as well as adenosine potentiate cAMP formation elicited by the VIP, through a concomitant generation of prostaglandins mediated by a direct coupling with phospholipase A(2). Baclofen (a GABA(B)-receptor agonist) exerts a similar potentiation mediated in part by the increased activity of 5-lipoxygenase. Furthermore, eicosanoids generated by 12-lipoxygenase are involved in the histamine- or FMRFamide-induced hyperpolarization (opening of K(+) channels) that has been demonstrated in identified sensory neurons of Aplysia. Finally, the stimulation of N- methyl - d - aspartate receptors (a subclass of glutamate receptors) leads to a release of arachidonic acid as well as of 11- and 12-hydroxyeicosatetraenoic acids in cultured striatal neurons. Arachidonic acid and a large number of its classical or recently discovered metabolites therefore display various effects in the central nervous system, both at the level of integrated processes and of the fine synaptic circuitry, where they can act as intracellular or extracellular local messengers triggering new cascades of short term or long term cellular events.
Schaad
N C
NC
Département de Pharmacologie, CMU, 1 rue M. Servet, CH 1211 Genève 4, Switzerland.
Magistretti
P J
PJ
Schorderet
M
M