Upregulation of iNOS expression and phosphorylation of eIF-2 alpha are paralleled by suppression of protein synthesis in rat hypothalamus in a closedhead trauma model
T. Petrov et al., Upregulation of iNOS expression and phosphorylation of eIF-2 alpha are paralleled by suppression of protein synthesis in rat hypothalamus in a closedhead trauma model, J NEUROTRAU, 18(8), 2001, pp. 799-812
When the inducible form of nitric oxide synthase (iNOS) is expressed after
challenge to the nervous system, it results in abnormally high concentratio
ns of nitric oxide (NO). Under such conditions, NO could phosphorylate the
eukaryotic translation initiation factor (eIF)-2(alpha), thus suppressing p
rotein synthesis in neurons that play a role in endocrine and autonomic fun
ctions. Using the Marmarou model of traumatic brain injury (TBI), we observ
ed a rapid increase (at 4 h after TBI) of iNOS mRNA in magno- and parvocell
ular supraoptic and paraventricular neurons, declining gradually by similar
to 30% at 24 h and by similar to 80% at 48 h. Western analysis indicated a
trend towards increased iNOS protein synthesis at 4 h, which peaked at 8 h
, and tended to decrease at the later time points. At the same time points,
we detected immunocytochemically the phosphorylated form of eIF-2 alpha (e
IF-2 alpha [P]) as cytoplasmic and more often as nuclear labeling. The inci
dence of double-labeled [iNOS and eIF-2 alpha (P)] neuronal profiles, parti
cularly at 24 h and 48 h after TBI, was high. De novo protein synthesis ass
essed quantitatively after infusion of S-35 methionine/cysteine was reduced
by similar to 20% at 4 h, remained depressed at 24 h, and did not return t
o control levels up to 48 h following the trauma. The results suggest that
MOS may trigger phosphorylation of eIF-2 alpha, which in turn interferes wi
th protein synthesis at the translational (ribosomal complex) and transcrip
tional (chromatin) levels. The depression in protein synthesis may include
downregulation of iNOS itself, which could be an autoregulatory inhibitory
feedback mechanism for NO synthesis. Excessive amounts of NO may also parti
cipate in dysfunction of hypothalamic circuits that underlie endocrine and
autonomic alterations following TBI.