O. Goureau et al., Requirement for nitric oxide in retinal neuronal cell death induced by activated Muller glial cells, J NEUROCHEM, 72(6), 1999, pp. 2506-2515
Retinal Muller glial cells express the inducible isoform (-2) of nitric oxi
de (NO) synthase (NOS) in vitro after stimulation by lipopolysaccharide (LP
S) and interferon-gamma (lFN-gamma) or in vivo in some retinal pathologies.
Because NO may have beneficial or detrimental effects in the retina, we ha
ve Used cocultures of retinal neurons with retinal Muller glial (RMG) cells
from mice disrupted for the gene of NOS-2 [NOS-2 (-/-)] to clarify the rol
e of NO in retinal neurotoxicity. We first demonstrated that NO produced by
activated RMG cells was not toxic for RMG cells themselves. Second, the NO
released from LPS/IFN-gamma-stimulated RMG cells induced neuronal cell dea
th, because no neuronal cell death has been observed in cocultures with RMG
cells from NOS-2 (-/-) mice and because inhibition of NOS-2 induction by t
ransforming growth factor-beta or blockade of NO release by different NOS i
nhibitors prevented neuronal cell death. Addition of urate, a peroxynitrite
scavenger, or superoxide dismutase partially prevented neuronal cell death
induced by NO, whereas the presence of a poly(ADP-ribose) synthetase inhib
itor, caspase inhibitors, or a guanylate cyclase inhibitor had no significa
nt effect on cell death. These results demonstrated that a large release of
NO from RMG cells is responsible for retinal neuronal cell death in vitro,
suggesting a neurotoxic role for NO and peroxynitrite during retinal infla
mmatory or degenerative diseases, where RMG cells were activated.