Adrenergic and V_1-ergic Agonists/Antagonists Affecting Recovery from Brain Trauma in the Lund Project Act on Astrocytes

摘要

The Lund project (1992) recommended treatment with clonidine (alpha_2-adrenergic agonist) and metoprolol (beta_1adrenergic antagonist) to improve recovery after brain trauma, and discouraged use of the V_1 agonist vasopressin (ADH). Brain effects of these drugs and the ability of a post-traumatic elevation of extracellular K~+ concentrations ([K~+]_o) to activate mechanism(s) leading to secondary cytotoxic (cellular) edema were then virtually unknown. Now, it is established that interactions occur between effects on astrocytes by high [K~+]_o and vasopressin or alpha_2 and beta_1-adrenergic agonists and antagonists, and that the effects modify edema and thus intracranial pressure. In mouse astrocytes in primary cultures, reliably expressing characteristics of their in vivo counterparts, high [K~+]_oand each of the transmitters agonists activate a signal mechanism, transactivation, in which Ca~(2+) entry through depolarization-mediated channel opening or stimulation of G_q- or G_(i/o) protein-coupled receptors via PKC-, Ca~(2+)- and metalloproteinase-mediated signaling leads to release of an epidermal growth factor (EGF) receptor agonist. Minor, but important, differences exist between individual pathways. The agonist released by dexmedetomidine decreases neuronal vulnerability to oxidative damage by a paracrine effect, and in all cases the released EGF receptor agonist has autocrine effects. These include mitogen-activated protein (MAP) kinase-mediated phosphorylation of astrocytic extracellular-regulated kinase (ERK), and with high [K~+]_o also the cotransporter NKCC1, accumulating Na~+ and K~+ together with 2 Cl~- and water, causing edema. This effect, exerted specifically on astrocytes, is enhanced by beta_1-adrenergic or vasopressinergic V_1 signaling, explaining the beneficial effect of beta_1-adrenergic antagonists and why vasopressin should be omitted in edema treatment after brain trauma.