Mediators of injury in neurotrauma: intracellular signal transduction and gene expression.
Membrane lipid-derived second messengers are generated by phospholipase A2 (PLA2) during synaptic activity. Overstimulation of this enzyme during neurotrauma results in the accumulation of bioactive metabolites such as arachidonic acid, oxygenated derivatives of arachidonic acid, and platelet-activating factor (PAF). Several of these bioactive lipids participate in cell damage, cell death, or repair-regenerative neural plasticity. Neurotransmitters may activate PLA2 directly when linked to receptors coupled to G proteins and/or indirectly as calcium influx or mobilization from intracellular stores is stimulated. The release of arachidonic acid and its subsequent metabolism to prostaglandins are early responses linked to neuronal signal transduction. Free arachidonic acid may interact with membrane proteins, i.e., receptors, ion channels, and enzymes, modifying their activity. It can also be acted upon by prostaglandin synthase isoenzymes (the constitutive prostaglandin synthase PGS-1 or the inducible PGS-2) and by lipoxygenases, with the resulting formation of different prostaglandins and leukotrienes. Glutamatergic synaptic activity and activation of postsynaptic NMDA receptors are examples of neuronal activity, linked to memory and learning processes, which activate PLA2 with the consequent release of arachidonic acid and platelet-activating factor (PAF), another lipid mediator. Both mediators may exert presynaptic and postsynaptic effects contributing to long-lasting changes in glutamate synaptic efficacy or long-term potentiation (LTP), PAF, a potential retrograde messenger in LTP, stimulates glutamate release. The PAF antagonist BN 52021 competes for receptors in presynaptic membranes and blocks this effect. PAF may also be involved in plasticity responses because PAF leads to the expression of early response genes and subsequent gene cascades. The PAF antagonist BN 50730, selective for PAF intracellular binding, blocks PAF-mediated induction of gene expression. A consequence of neural injury induced by ischemia, trauma, or seizures is an increased release of neurotransmitters, that in turn generates an overproduction of second messengers. Glutamate, a key player in excitotoxic neuronal damage, triggers increased permeation of calcium mediated by NMDA receptors and activation of PLA2 in postsynaptic neurons. NMDA receptor antagonists reduce the accumulation of free fatty acids and elicit neuroprotection in ischemic damage. Increased production of free arachidonic acid and PAF converges to exacerbate glutamate-mediated neurotransmission. These neurotoxic actions may be brought about by arachidonic acid-induced potentiation of NMDA receptor activity and decreased glutamate reuptake. On the other hand, PAF stimulates the further release of glutamate at presynaptic endings. The neuroprotective effects of the PAF antagonist BN 52021 in ischemia-reperfusion are due, at least in part, to an inhibition of presynaptic glutamate release. PAF also induces expression of the inducible prostaglandin synthase gene, and PAF antagonists selective for the intracellular sites inhibit this effect. The PAF antagonist also inhibits the enhanced abundance, due to vasogenic cerebral edema and ischemia-reperfusion damage, of inducible prostaglandin synthase mRNA in vivo. Therefore, PAF, an injury-generated mediator, may favor the formation of other cell injury and inflammation mediators by turning on the expression of the gene that encodes prostaglandin synthase.
Bazan
N G
NG
LSU Neuroscience Center, Louisiana State University Medical Center, New Orleans 70112, USA.
Rodriguez de Turco
E B
EB
Allan
G
G
D000818:Animals; D001095:Arachidonic Acids / Q000502:physiology; D001921:Brain / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D009420:Nervous System / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000502:physiology; D015398:Signal Transduction; D020196:Trauma, Nervous System
D001095:Arachidonic Acids; D018377:Neurotransmitter Agents; D010972:Platelet Activating Factor; D010741:Phospholipases A; D054467:Phospholipases A2