α-Phenyl-n-tert-butyl-nitrone attenuates lipopolysaccharide-induced neuronal injury in the neonatal rat brain

Abstract

Although white matter damage is a fundamental neuropathological feature of periventricular leukomalacia (PVL), the motor and cognitive deficits observed later in infants with PVL indicate the possible involvement of cerebral neuronal dysfunction. Using a previously developed rat model of white matter injury induced by cerebral lipopolysaccharide (LPS) injection, we investigated whether LPS exposure also results in neuronal injury in the neonatal brain and whether α-phenyl-n-tert-butylnitrone (PBN), an antioxidant, offers protection against LPS-induced neuronal injury. A stereotactic intracerebral injection of LPS (1 mg/kg) was performed in Sprague-Dawley rats (postnatal day 5) and control rats were injected with sterile saline. LPS exposure resulted in axonal and neuronal injury in the cerebral cortex as indicated by elevated expression of β-amyloid precursor protein, altered axonal length and width, and increased size of cortical neuronal nuclei. LPS exposure also caused loss of tyrosine hydroxylase positive neurons in the substantia nigra and the ventral tegmental areas of the rat brain. Treatments with PBN (100 mg/kg) significantly reduced LPS-induced neuronal and axonal damage. The protection of PBN was associated with an attenuation of oxidative stress induced by LPS as indicated by the reduced number of 4-hydroxynonenal, malondialdehyde or nitrotyrosine positive cells in the cortical area following LPS exposure, and with the reduction in microglial activation stimulated by LPS. The finding that an inflammatory environment may cause both white matter and neuronal injury in the neonatal brain supports the possible anatomical correlate for the intellectual deficits and the other cortical and deep gray neuronal dysfunctions associated with PVL. The protection of PBN may indicate the potential usefulness of antioxidants for treatment of these neuronal dysfunctions.Keywords neuronal injury; tyrosine hydroxylase; microglial activation; oxidative stress; antioxidant Periventricular leukomalacia (PVL), the dominant form of brain injury in the preterm infant, is frequently associated with subsequent adverse neurological outcomes such as cerebral palsy and mental retardation (Rezaie and Dean, 2002;Volpe, 2003). Although white matter damage is a fundamental neuropathological feature of PVL, the motor and cognitive deficits observed later in these infants indicate possible cerebral cortical neuronal dysfunction. The precise nature Corresponding author: Dr. Zhengwei Cai Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS 39216-4504, USA Tel.: +1-601-984-2786 Fax: +1-601-815-3666 E-mail address: zcai@ped.umsmed.edu (Z. Cai). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Pleas...

Melatonin ameliorates brain injury induced by systemic lipopolysaccharide in neonatal rats

“…In the current study, systemic LPS exposure resulted in nitrosative and oxidative damage similar to that induced by i.c. LPS injection, as reported previously (Fan et al, 2008b, Fan et al, 2008c). Increased expression of NT (Figs.…”

“…Thus, systemic LPS exposure causes neural damage through induction of oxidative and nitrosative stress as well as by increasing i.c. LPS levels (Fan et al, 2008b) in neonatal rats.…”

“…Our previous studies have shown that neonatal exposure (postnatal day 5, P5) to lipopolysaccharide (LPS) through an intracerebral (i.c.) injection results in brain inflammation and white matter and neuronal injury in rats, which was closely associated with the increased nitrosative and oxidative stress following LPS exposure (Fan et al, 2008b, Fan et al, 2008c). The inflammatory response that ensues because of the initial occult exogenous oxidative/nitrosative stress becomes a secondary endogenous source of reactive oxygen species (ROS) and reactive nitrogen species (RNS).…”

Celecoxib attenuates systemic lipopolysaccharide-induced brain inflammation and white matter injury in the neonatal rats

“…resulted in similar brain injury induced by intracerebral (i.c.) LPS injection as we reported previously (Fan et al, 2008b, 2008c). No gender differences in LPS-induced brain injury were observed in the P6 rat brain.…”

“…LPS injection, systemic exposure to LPS through i.p. injection in the neonatal rats may cause brain inflammatory responses and brain injury, such as increments in the number of activated microglia and the elevated concentrations of IL-1β and TNFα, and apoptotic death of OLs (Cai et al, 2003; Fan et al, 2005a, 2005b, 2008a, 2008b, 2008c). LPS has been detected in the amniotic fluid (Romero et al, 1987).…”