Involvement of extracellular signal-regulated protein kinase in gliosis induced during recovery from metabolic inhibition

Brain reperfusion may be of particular importance in the etiology of perive ntricular leukomalacia, of which the common findings are gliosis and ventri cular dilatation. To investigate the mechanism of this pathogenesis, we use d a metabolic inhibition (MI) model using cyanide plus deoxyglucose treatme nt of cultured glia isolated from fetal rat brain and examined the activity of extracellular signal-regulated protein kinase (ERI) during MI and also during the recovery from MI of 30 min. ERK activation was stimulated during MI and the recovery from MI. The time course and extent of activation of E RK during Ra and the recovery from MI, however, were distinctly different. Activation of ERK was stimulated within 5 min of MI and declined thereafter . Activation of ERK was sustained during the recovery phase from MI and the extent of the activation was much greater than that during MI. Pretreatmen t with EGTA to eliminate extracellular Ca2+, or with APV, an NMDA receptor ant agonist, to inhibit Ca2+ influx through the NMDA receptor, attenuated t he activation of ERR Moreover, pretreatment with PMA to downregulate PKC ab olished the activation of ERR. PD98059, an inhibitor of ERK kinase, attenua ted the cell proliferation induced by MI followed by recovery from MI. Thes e results suggest that ERK is involved in gliosis during the recovery phase from MI and may play a role in the etiology of periventricular leukomalaci a. (C) 2000 Academic Press.