Free radical spin trap α-phenyl-N- tert -butyl-nitron inhibits caspase-3 activation and reduces brain damage following a severe forebrain ischemic injury

Li, Ping An; He, Qing; Nakamura, Leah; Csiszár, Katalin

doi:10.1016/s0891-5849(01)00700-6

Cited by 41 publications

(23 citation statements)

References 41 publications

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“…PBN has been shown to be neuroprotective in many neurodegenerative diseases, such as Alzheimer's disease (Floyd et al, 2002;, LPS-mediated septic shock (Sang et al, 1999), hypoxia-ischemia (Lin et al, 2004(Lin et al, , 2006, and stroke (Green et al, 2003). The neuroprotective action of PBN has been attributed to many factors, including formation of a spin adduct with the free radical (Green et al, 2003, Lee andPark, 2005), suppression of ROS production from mitochondria , inhibition of the induction of pro-inflammatory cytokines and iNOS (Kotake et al, 1998;Lin et al, 2006;Sang et al, 1999), inhibition of nuclear factor-kappa B (NF-κB, a transcription factor for a wide variety of pro-inflammatory cytokine genes) (Kotake et al, 1998;Sang et al, 1999), and its anti-apoptosis properties (Lee and Park, 2005;Li et al, 2001). We have shown in our previous study that developing OLs were under oxidative and nitrosative stress following LPS injection and the death of O4 OLs was a result of such a stress (Fan et al, 2005a).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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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...

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Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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“…The neuroprotective action of PBN has been attributed to many factors, including formation of a spin adduct with the free radical (Green et al, 2003;Lee and Park, 2005), suppression of ROS production from mitochondria , inhibition of the induction of proinflammatory cytokines and iNOS (Kotake et al, 1998;Sang et al, 1999;Lin et al, 2006), inhibition of nuclear factor-j B (NF-jB, a transcription factor for a wide variety of proinflammatory cytokine genes) (Kotake et al, 1998;Sang et al, 1999), and its anti-apoptosis properties (Li et al, 2001;Lee and Park, 2005). Results from this study support the involvement of these factors in the neuroprotective action of PBN.…”

Section: Discussionmentioning

confidence: 99%

α‐Phenyl‐n‐tert‐butyl‐nitrone reduces lipopolysaccharide‐induced white matter injury in the neonatal rat brain

Fan

Mitchell

Tien

et al. 2007

Developmental Neurobiology

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Lipopolysaccharide (LPS)-induced white matter injury in the neonatal rat brain is at least partially associated with oxidative stress. alpha-Phenyl-n-tert-butyl-nitrone (PBN) (100 mg/kg) significantly attenuated LPS (1 mg/kg)-induced brain injury, as indicated by the reduction in bilateral ventricular enlargement, apoptotic cell death of oligodendrocytes (OLs), and the loss of OL immunoreactivity in the neonatal rat brain. Protection of PBN was linked with the attenuated oxidative stress induced by LPS, as indicated by the decreased elevation of 8-isoprostane content and by the reduced number of 4-hydroxynonenal or malondialdehyde positive OLs following LPS exposure. Interestingly, while LPS exposure elevated, rather than depleted, levels of the reduced glutathione (GSH) and the GSH/GSSG (oxidized form) ratio, LPS exposure significantly suppressed glutathione peroxidase activity in the rat brain. PBN attenuated LPS-induced alterations in glutathione homeostasis in the rat brain. Additionally, the inflammatory responses were also reduced in the PBN-treated brain, as indicated by the decreased number of activated microglia following LPS exposure and by the consequently decreased elevation of interleukin1-beta and tumor necrosis factor-alpha contents in the rat brain. The overall results suggest that antioxidant PBN, more than a straightforward free radical scavenger, may also involve anti-inflammatory and anti-apoptotic properties in protection of the neonatal rat brain from LPS-induced injury.

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“…As previously mentioned, many studies have demonstrated the efficacy of different antioxidants, including AA [Stamford et al, 1999;Henry and Chandy, 1998], DHLA [Prehn et al, 1992;Panigrahi et al, 1996;Cao and Phillis, 1995;Wolz and Krieglstein, 1996] and PBN [Phillis and Clough-Helfman, 1990;Cao and Phillis, 1994;Yang et al, 2000;Li et al, 2001], to reduce ischemic brain damage in models of global/forebrain ischemia in gerbils, as well as in models of both permanent and transient of focal ischemia in rats and mice. However, few studies have examined the effect of these antioxidants on mortality Fig.…”

Section: Discussionmentioning

confidence: 99%

“…[Floyd, 1990;Panigrahi et al, 1996;Li et al, 2001] and/ or functional outcome after ischemia [Cao and Phillis, 1995;Woltz and Krieglstein, 1996;Yang et al, 2000], and these have used only one measure of functional deficit (e.g., locomotor activity) to evaluate antioxidant neuroprotection.…”

Section: Discussionmentioning

confidence: 99%

Effect of ascorbic acid, dihydrolipoic acid, t‐Butylhydroquinone, and phenylbutylnitrone on mortality and neurological impairment induced by sequential common carotid artery sectioning in mice

Santiago‐Mejia¹,

Fuentes-Vargas²,

Rı́os

et al. 2004

Drug Development Research

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The efficacy of four antioxidant agents to reduce neurological deficits and mortality produced by sequential common carotid artery sectioning (SCAS) in mice was evaluated. Ascorbic acid (AA, 500 mg/kg), dihydrolipoic acid (DHLA, 100 mg/kg), tert-butylhydroquinone (t-BHQ, 100 mg/kg) or phenylbutylnitrone (PBN, 100 mg/kg) were injected ip 15 min after the second artery sectioning. Animals were evaluated at 24, 48, and 72 h after antioxidant or saline injection using two procedures: neurological examination and spontaneous motility. Based on neurological examination, a disability status scale was used to determine the degree of functional incapacity after brain ischemia for each animal. The scale comprised 10 progressive steps beyond 0 (normal) extending to status 10 (death due to SCAS). In this scale, the highest scores reflect greater neurological dysfunction. AA and DHLA but neither t-BHQ nor PBN decreased mortality and reduced neurobehavioral deficits caused by SCAS in mice. The observed 24-, 48-, and 72-h survival rates for AA were 86, 71, and 48% and for DHLA were 75, 65, and 65%, representing a significant prolongation of lifespan as compared with vehicle-treated animals (60, 35, 35%). The 24-, 48-, and 72-h neurological scores for AA of 5.2, 6.2, and 7.5 and for DHLA of 4.6, 5.3, and 5.8 as compared with the scores observed for the saline-treated control group (7.6, 8.6, and 8.6) indicate that administration of these antioxidants is beneficial for the neurological output of surviving animals. These antioxidants may have important neuroprotective properties, and indicate that a clinical trial, mainly of DHLA, in stroke patients should be considered. Drug Dev.

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Free radical spin trap α-phenyl-N- tert -butyl-nitron inhibits caspase-3 activation and reduces brain damage following a severe forebrain ischemic injury

Cited by 41 publications

References 41 publications

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

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

α‐Phenyl‐n‐tert‐butyl‐nitrone reduces lipopolysaccharide‐induced white matter injury in the neonatal rat brain

Effect of ascorbic acid, dihydrolipoic acid, t‐Butylhydroquinone, and phenylbutylnitrone on mortality and neurological impairment induced by sequential common carotid artery sectioning in mice

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