Increase in Cerebellar Neurotrophin-3 and Oxidative Stress Markers in Autism

Sajdel-Sulkowska, Elizabeth M.; Xu, Ming; Koibuchi, Noriyuki

doi:10.1007/s12311-009-0105-9

Cited by 108 publications

(81 citation statements)

References 48 publications

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“…Within our autism cohort, nitrotyrosine was positively correlated with percent oxidized glutathione (r = 0.50; p \ 0.001). Supporting our observations in plasma, a recent preliminary study found increased levels of nitrotyrosine in autism post-mortem brain (Sajdel-Sulkowska et al 2009). …”

supporting

confidence: 90%

Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

James¹

2012

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY) 2012 REPORT TYPE Final DATES COVERED (From -To) TITLE AND SUBTITLE Redox Abnormalities as a Vulnerability Phenotype for Autism 5a. CONTRACT NUMBERand Related Alterations in CNS Development 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER AUTHOR(S)Sandra Jill James, Ph.D.5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERArkansas Children's Hospital Research Institute Little Rock, AR 72202 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel CommandFort Detrick, MD 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release; distribution unlimited SUPPLEMENTARY NOTES ABSTRACT:We hypothesize that low systemic redox potential (GSH/GSSG; cysteine/cystine) reflects a vulnerability phenotype that is associated with regressive autism and is predictive of the risk of developing autism. The redox vulnerability phenotype is associated with epigenetic alterations in primary immune cells that may be reversible with restoration of intracellular redox potential. The hypothesis predicts that children with regressive autism and high risk (developmentally-delayed) children who are subsequently diagnosed with autism will exhibit lower redox potential compared to age-matched unaffected control children. It also predicts that low redox potential from these children will be associated with epigenetic modifications in DNA methylation and histone acetylation/methylation that are reversible with treatment to restore redox potential. In Aim 1 we will determine whether redox potential in immune cells can be used as a biomarker for regressive autism and whether it is predictive of the subsequent diagnosis of autism. We will also evaluate immune redox potential from high risk developmentally delayed children to determine whether redox status is predictive of subsequent development of autism. In Aim 2, we will determine whether immune cells from autistic children are associated with altered cytokine patterns,...

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confidence: 90%

Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

James¹

2012

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“…In that context it is important to point out that we previously reported that perinatal exposure to hypergravity resulted in the increase in oxidative stress [56] and suggested that oxidative stress may contribute to the decrease in Purkinje cell number and the impairment of motor coordination in hypergravity-exposed rat neonates [8]. More recently we have reported on the relationship between oxidative stress and the disruption of neurotrophin expression in the human brain under pathological conditions [18]. It is thus possible that the changes in neurotrophin levels observed in hypergravity-exposed rats may result from increased oxidative stress but the mechanism involved in this process is not yet understood.…”

Section: Possible Involvement Of Oxidative Stress In Altered Neurotromentioning

confidence: 94%

“…Cerebellar BDNF, NGF, and NT-3 were measured in homogenates prepared according to the procedure previously described [18]. In brief, the homogenates were prepared in phosphate-buffered saline containing protease inhibitors (Complete, EDTA-free protease inhibitor cocktail, Roche Diagnostics, Germany), 0.5% Nonident P40, 5% sodium dodecyl sulfate (SDS, Sigma, St. Louis, MO).…”

Section: Analysis Of Cerebellar Neurotrophins' Levelsmentioning

confidence: 99%

Cerebellar Brain-Derived Neurotrophic Factor, Nerve Growth Factor, and Neurotrophin-3 Expression in Male and Female Rats Is Differentially Affected by Hypergravity Exposure During Discrete Developmental Periods

Sajdel-Sulkowska

Koibuchi

2009

Cerebellum

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We previously reported that the effects of perinatal exposure to hypergravity on cerebellum and motor functions in rat neonates are strongly dependent on the specific developmental period of exposure. In the present study, we explored the hypothesis that neurodevelopmental changes are associated with altered expression of brain neurotrophins critical for normal brain growth and differentiation. We compared the effects of hypergravity exposure during four developmental periods: period I extended from gestational day (G) 8 through G15; period II from G15 to birth, period III from birth to postnatal day (P) 6; and period IV extended from G8-P12. For comparison we used stationary control (SC) neonates not exposed to hypergravity. Neurotrophins, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin 3 (NT-3) levels were measured in cerebellar homogenates prepared from postnatal day 12 male and female rat neonates using specific ELISAs. Hypergravity exposure affected individual neurotrophins differently and the effect was further determined by the period of hypergravity exposure. ANOVA showed: (1) a significant effect of the period of exposure to hypergravity on cerebellar BDNF (p = 0.009), with maximal decrease of 28.7% in males and 32.1% in females following exposure during period III; (2) a significant effect on NGF (p < 0.0001), with maximal decrease of 35.6% in male and 48.8% in female neonates following exposure during period III; (3) no statistically significant effect on NT-3 expression with a trend towards decreased expression in female rats following exposure during period IV. Although the molecular mechanisms underlying the differential neurotrophins' response to hypergravity are not clear, an altered pattern of their expression is likely to contribute to neurodevelopmental changes and impaired sensorimotor behavior in exposed neonates.

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“…A marker, 3-nitrotyrosine (3-NT), is specific for oxidative stress damage to proteins mediated by peroxynitrite, which is formed by the reaction of superoxide with nitric oxide on tyrosine residues in proteins [7]. Increase in 3-NT has been observed in over 50 different pathologies including Alzheimer's disease (AD [8,9]), Parkinson's disease [8][9][10], and autism [11][12][13]; 3-NT is a well-accepted marker of oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Brain Region-Specific Changes in Oxidative Stress and Neurotrophin Levels in Autism Spectrum Disorders (ASD)

Sajdel-Sulkowska

McGinnis³

et al. 2010

Cerebellum

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Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by social and language deficits, stereotypic behavior, and abnormalities in motor functions. The particular set of behavioral impairments expressed in any given individual is variable across the spectrum. These behavioral abnormalities are consistent with our current understanding of the neuropathology of ASD which suggests abnormalities in the amygdala, temporal and frontal cortexes, hippocampus, and cerebellum. However, regions unrelated to these behavioral deficits appear largely intact. Both genetic predisposition and environmental toxins and toxicants have been implicated in the etiology of autism; the impact of these environmental triggers is associated with increases in oxidative stress, and is further exacerbated when combined with genetic susceptibility. We have previously reported increased levels of 3-nitrotyrosine (3-NT), a marker of oxidative stress, in ASD cerebella. We have also shown that this increase was associated with an elevation in neurotrophin-3 (NT-3) levels. The objectives of the current study were to determine whether the increase in oxidative stress in ASD is brain region-specific, to identify the specific brain regions affected by oxidative stress, and to compare brain region-specific NT-3 expression between ASD and control cases. The levels of 3-NT and NT-3 were measured with specific ELISAs in individual brain regions of two autistic and age- and postmortem interval (PMI)--matched control donors. In the control brain, the levels of 3-NT were uniformly low in all brain regions examined ranging from 1.6 to 12.0 pmol/g. On the other hand, there was a great variation in 3-NT levels between individual brain regions of the autistic brains ranging from 1.7 to 281.2 pmol/g. The particular brain regions with the increased 3-NT and the magnitude of the increase were both different in the two autistic cases. In the older autistic case, the brain regions with highest levels of 3-NT included the orbitofrontal cortex (214.5 pmol/g), Wernicke's area (171.7 pmol/g), cerebellar vermis (81.2 pmol/g), cerebellar hemisphere (37.2 pmol/g), and pons (13.6 pmol/g); these brain areas are associated with the speech processing, sensory and motor coordination, emotional and social behavior, and memory. Brain regions that showed 3-NT increase in both autistic cases included the cerebellar hemispheres and putamen. Consistent with our earlier report, we found an increase in NT-3 levels in the cerebellar hemisphere in both autistic cases. We also detected an increase in NT-3 level in the dorsolateral prefrontal cortex (BA46) in the older autistic case and in the Wernicke's area and cingulate gyrus in the younger case. These preliminary results reveal, for the first time, brain region-specific changes in oxidative stress marker 3-NT and neurotrophin-3 levels in ASD.

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Increase in Cerebellar Neurotrophin-3 and Oxidative Stress Markers in Autism

Cited by 108 publications

References 48 publications

Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

Cerebellar Brain-Derived Neurotrophic Factor, Nerve Growth Factor, and Neurotrophin-3 Expression in Male and Female Rats Is Differentially Affected by Hypergravity Exposure During Discrete Developmental Periods

Brain Region-Specific Changes in Oxidative Stress and Neurotrophin Levels in Autism Spectrum Disorders (ASD)

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