Brain gene expression is modified by Gingko biloba extract EGb 761 and in a-tocopherol deficient mice
1Kishorchandra Gohil and 2Lester Packer
1University of California Davis, School of Medicine, Dept Internal Medicine, Davis, CA. 2University of Southern California, School of Pharmacy, Dept Molecular Pharmacology and Toxicology Los Angeles, CA USA.
Aging and disease prevention by antioxidant nutrition is increasingly a subject of academic research and public health interest. Antioxidants play an important role in maintaining the physiological redox status of cellular constituents against free radicals. Antioxidants may change their redox state, be targeted for destruction, and regulate oxidative processes involved in signal transduction and gene expression. An intriguing possibility is that dietary supplements may normalize deregulated transcriptomes of degenerative human diseases and aging. This presentation will review recent studies of effects on gene expression by botanical extracts and in vitamin E deficiency.
.Reports of Gingko biloba extract EGb 761 action on preventing brain mitochondria and cognitive dysfunction during aging led us to investigate its effects on gene expression. Mice were fed a diet containing EGb 761 and then RNA isolated from two brain regions and analyzed using affymetrix high density oligomeric microarrays for 12,000 mouse genes. Genes which showed changes in expression of at least three-fold or more in the cortex and hippocampus were analyzed; 9 genes and one gene respectively were up-regulated, and included genes for transcription, hormones, and proteins which are hallmarks of neurodegenerative disease.
In human T24 bladder cancer cells functional classification of the Ginkgo biloba sensitive genes enabled grouping into several distinct classes such as transcription factors, heat shock and antioxidant transcripts, mitochondrial, cell cycle and transcripts for DNA repair enzymes. The GeneChip assay detected ~ 2000 distinct mRNA's showing that only a small fraction of the human transcriptome can be analyzed. Differential analysis if the affected genes (>2-fold change) showed that only a small fraction of the genes were affected by the extract. The induction of transcripts encoding mitochondrial proteins was remarkable, suggesting an activation of selected mitochondrial genes in the nucleus. This implies that the extract induces "mitochondrial differentiation"; the mitochondrial biochemical composition from untreated cells is different from that of Ginkgo biloba treated cells.
Mutations in the gene for a-tocopherol-transfer-protein (TTP) result in Vitamin E deficiency and neurodegenerative disease. Expression profiles of ~5000 genes from brain cortex from TTP-null mice showed there a net increase in genes expressed compared to wild type mice. A large number of the induced transcripts encoded enzymes of the mitochondrial electron transport chain and its regulatory proteins. Two mRNA's for protein kinase C were down regulated in cortex of TTP null mice. . Particularly noteworthy was repression of the mRNA for proteolipid protein that is essential for the synthesis of myelin suggesting an important role of the TTP-gene in the function of myelinated neurons The data identify possible genomic targets of vitamin E in vivo and demonstrate its essential role in cell signaling, mitochondrial functions, and lipid metabolism.
. These observations demonstrate that nutritional antioxidants target molecular pathways that may be causatively associated with neurodegeneration and aging.
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