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lowed by tyrosine phosphorylation of other peptide substrates, including insulin-receptor substrate-1 (IRS-1). Srchomology-2 domains on phosphorylated IRS-1 activate intracellular signaling cascades. Both pancreatic insulin secretion and the kinase activity of the insulin receptor are markedly downregulated by adrenergic signaling mediated through cyclic adenosine monophosphate and protein kinase A (PKA), and hypovolemia is clinically well known to be associated with insulin resistance. Thus, insulin-mediated growth factor signaling is inhibited by ischemia and reperfusion.
Sullivan and colleagues (1998) have recently used simultaneous autoradiography of pulse-labeled protein synthesis and immunohistochemical mapping of eIF2α(P) to confirm the colocalization of inhibited protein synthesis and eIF2α(P) during brain reperfusion. That same study found that 20 units of insulin per kilogram of body weight administered intravenously at reperfusion caused restoration of normal protein synthesis in and elimination of eIF2α(P) from vulnerable hippocampal neurons by 90 minutes of reperfusion after a 10-minute cardiac arrest.
There is precedent for insulin-mediated downregulation of eIF2α kinases; activation of Ras, an intermediate in insulin signaling, leads to activation of a 97-kDa inhibitor of PKR (Bandyopadhyhay and Sen, 1992), although as already indicated, this enzyme is not required for phosphorylation of eIF2α during brain reperfusion. The reversal of eIF2α phosphorylation in vulnerable neurons by insulin during early reperfusion also might be due to the activation of an eIF2α(P) phosphatase. PP1, which is activated in response to insulin signaling (Begum, 1995; Srinivasan and Begum, 1994), is the enzyme responsible for the dephosphorylation of eIF2α(P) in vivo (Ernst et al., 1982; Foulkes et al., 1983; Ingebritsen and Cohen, 1983; Redpath and Proud, 1990), and isoforms PP1α and PP1γ are present in the brain and are concentrated in the neocortex and hippocampus (Hubbard and Cohen, 1993; Ouimet et al, 1995; Takizawa et al., 1994).
There are several possible explanations for the high dose of insulin required for neuron sparing during postischemic reperfusion. Adrenergic downregulation of insulin secretion and of the insulin receptor itself has already been mentioned. Glucocorticoids also inhibit insulin transport into the central nervous system (Baura et al., 1996). Alternatively, other signaling mechanisms may also decrease the responsiveness of the insulin receptor. TNF-α levels are elevated in the reperfused brain (Lavine et al., 1998), and TNF-α induces insulin resistance by increasing serine and threonine phosphorylation of the insulin receptor and of the major insulin receptor substrates IRS-1 and IRS-2 (Paz et al., 1997). It is also possible that the neuroprotective effects of insulin occur by activation of the IGF-1 receptor (Gluckman et al., 1993). Although insulin and IGF-1 have significant sequence homology, the affinity of insulin for the IGF-1 receptor is about 100-fold lower than that of IGF-1 (Le Roith et al., 1993). Autoradiographic studies have shown large quantities of [125I]IGF-1 receptors in hippocampal neurons (Bohannon et al., 1988; Kar et al., 1993; Lesniak et al., 1988).