title: Genomic and biochemical approaches in the discovery of mechanisms for selective neuronal vulnerability to oxidative stress.
abstract: BACKGROUND
  Oxidative stress (OS) is an important factor in brain aging and neurodegenerative diseases. Certain neurons in different brain regions exhibit selective vulnerability to OS. Currently little is known about the underlying mechanisms of this selective neuronal vulnerability. The purpose of this study was to identify endogenous factors that predispose vulnerable neurons to OS by employing genomic and biochemical approaches.
  
  
  RESULTS
  In this report, using in vitro neuronal cultures, ex vivo organotypic brain slice cultures and acute brain slice preparations, we established that cerebellar granule (CbG) and hippocampal CA1 neurons were significantly more sensitive to OS (induced by paraquat) than cerebral cortical and hippocampal CA3 neurons. To probe for intrinsic differences between in vivo vulnerable (CA1 and CbG) and resistant (CA3 and cerebral cortex) neurons under basal conditions, these neurons were collected by laser capture microdissection from freshly excised brain sections (no OS treatment), and then subjected to oligonucleotide microarray analysis. GeneChip-based transcriptomic analyses revealed that vulnerable neurons had higher expression of genes related to stress and immune response, and lower expression of energy generation and signal transduction genes in comparison with resistant neurons. Subsequent targeted biochemical analyses confirmed the lower energy levels (in the form of ATP) in primary CbG neurons compared with cortical neurons.
  
  
  CONCLUSIONS
  Low energy reserves and high intrinsic stress levels are two underlying factors for neuronal selective vulnerability to OS. These mechanisms can be targeted in the future for the protection of vulnerable neurons.
authors.affiliation: Higuchi Biosciences Center, University of Kansas, Lawrence, KS 66047, USA. xwang@ku.edu
authors.forename: Xinkun
authors.initials: X
authors.lastname: Wang
authors.forename: Asma
authors.initials: A
authors.lastname: Zaidi
authors.forename: Ranu
authors.initials: R
authors.lastname: Pal
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Garrett
authors.forename: Rogelio
authors.initials: R
authors.lastname: Braceras
authors.forename: Xue-wen
authors.initials: XW
authors.lastname: Chen
authors.forename: Mary L
authors.initials: ML
authors.lastname: Michaelis
authors.forename: Elias K
authors.initials: EK
authors.lastname: Michaelis
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D018929:Cell Culture Techniques; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D015870:Gene Expression; D016678:Genome; D006624:Hippocampus / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000235:genetics; D010269:Paraquat / Q000633:toxicity; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D010269:Paraquat