-
-
N-acetylcysteine prevents endotoxin-induced degeneration of
oligodendrocyte progenitors and hypomyelination in developing rat
brain.
Department of Pediatrics, Medical University
of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425,
USA.
Periventricular leukomalacia (PVL), the
dominant form of brain injury in premature infants, is
characterized by diffuse white matter injury and is associated with
cerebral palsy (CP). Maternal and placental infections are major
causes of prematurity and identifiable etiology of PVL and CP. Here
we have evaluated the therapeutic efficacy of N-acetylcysteine
(NAC), a potent antioxidant and precursor of glutathione, to
attenuate lipopolysaccharide (LPS)-induced white matter injury and
hypomyelination in the developing rat brain, an animal model of
PVL. Intraperitoneal pretreatment of pregnant female rats with NAC
(50 mg/kg), 2 hr prior to administration of LPS at embryonic day 18
(E18), attenuated the LPS-induced expression of inflammatory
cytokines such as tumor necrosis factor-alpha, interleukin-1beta,
and inducible nitric oxide synthase in fetal rat brains. There were
significantly reduced numbers of TUNEL(+) nuclei coimmunostained
for platelet-derived growth factor-alphaR(+) [a surface marker for
oligodendrocyte progenitor cells (OPCs)] at E20 in the
subventricular zone of fetal rat brain in the NAC + LPS group
compared with the untreated LPS group. Interestingly,
immunostaining for O4 and O1 as markers for late OPCs and immature
oligodendrocytes demonstrated fewer O4(+) and O1(+) cells in the
LPS group compared with the NAC + LPS and control groups.
Consistent with O4(+)/O1(+) cell counts, the expression of myelin
proteins such as myelin basic protein, proteolipid protein, and
2'3'-cyclic nucleotide phosphodiesterase, including transcription
factors such as MyT1 and Gtx, was less in the LPS group at late
postnatal days, indicating severe hypomyelination in the developing
rat brain when compared with NAC + LPS and control groups.
Collectively, these data support the hypothesis that NAC may
provide neuroprotection and attenuate the degeneration of OPCs
against LPS evoked inflammatory response and white matter injury in
developing rat brain. Moreover, these data suggest the possible use
of NAC as a treatment for pregnant women with maternal or placental
infection as a means of minimizing the risk of PVL and CP.
Copyright 2004 Wiley-Liss, Inc.