The effects of
prostaglandin (PG) E(1) on NO neurotoxicity were examined using rat cultured spinal neurons. Rat cultured spinal neurons exposed to the NO donor, 2,2'-(hydroxynitrosohydrazono) bis-ethanamine (NOC18), showed neurotoxic effects that were accompanied by apoptotic nuclear change,
free radical generation, a reduction in
glutathione, and
mitochondrial dysfunction.
PGE(1), at concentrations of 1-100 nM, protected cultured spinal neurons from NO toxicity by reversing the oxidative and pro-apoptotic properties elicited by NOC18 exposure. The administration of
PGE(1) increased the intracellular
cyclic AMP (cAMP) levels in cultured spinal neurons. In addition,
reverse transcriptase-polymerase chain reaction (RT-PCR) analysis confirmed the existence of EP4, a cAMP-elevating
PGE receptor, in cultured spinal neurons. The protective effects of
PGE(1) against NO neurotoxicity was partially blocked by an inhibitor of
MEK [the
mitogen-activated protein kinase (MAPK)/
extracellular-signal-regulated kinase (ERK)
kinase], suggesting that the MAPK/ERK pathway may play a significant role in the activity of
PGE(1).
PGE(1) up-regulated the expression of the
anti-apoptotic protein, Bcl-2, as determined by Western blot analysis.
PGE(1) also induced the expression of
thioredoxin in cultured spinal neurons. Our data indicate that
PGE(1) exerts a protective action against NO neurotoxicity in cultured spinal neurons, and suggests a therapeutic potential of
PGE(1) against
spinal cord disease, such as
amyotrophic lateral sclerosis.