The incidence of Alzheimer's disease (AD) has steadily increased in the United States as our average lifespan has lengthened. Thus, the means to prevent or reduce the rate of this disorder is a high priority for medical research. A standardized extract of Ginkgo biloba leaves (EGb 761) has been used for treatment of certain cerebral dysfunctions and dementias associated with aging and AD. Substantial evidence indicates that EGb 761 has neuroprotective effects. The action mechanisms of the extract are, however, poorly understood. Our previous studies funded by the National Institutes of Health provided evidence for the anti-amyloid beta (A beta) aggregation and anti-apoptotic properties of EGb 761 in vitro, which hold promise as potentially important neuroprotective mechanisms of action. ? The goal of this interdisciplinary project is to further our understanding of the neuroprotective mechanisms of EGb 761 in vivo. We will continue to test the hypothesis that the neuroprotective effect of EGb 761 is achieved by inhibition of A beta oligomerization, antioxidative properties and augmentation of an organism's endogenous stress-response. We will use transgenic C. elegans models in conjunction with a transgenic mouse model of AD to study possible links between A beta aggregation, oxidation and toxicity.
The specific aims of the present project are: 1) to correlate effects of EGb 761 on A beta aggregation and toxicity through fluorescence staining of A beta deposits and behavioral analysis of A beta-induced paralysis in the transgenic C. elegans expressing human A beta; 2) to define activities of single constituents of Egb 761 against A beta-induced oxidation through kinetic study of protein carbonyls in an inducible transgenic C. elegans; 3) to implicate changes in gene transcription profile induced by EGb 761 in the wild type and the transgenic C. elegans, using DNA microarray method, 4) to determine effects of EGb 761 on cognitive impairment through testing hippocampus-dependent spatial learning in a transgenic mouse model of AD. Previous results and preliminary data show the feasibility of this project. A better understanding of the 'mechanisms of EGb 761 neuroprotection will be important for understanding of the underlying neurodegenerative processes and for designing therapeutic strategies that target neurodegenerative disorders ? ?

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
1R01AT001928-01A1
Application #
6827981
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Sorkin, Barbara C
Project Start
2004-09-15
Project End
2008-05-31
Budget Start
2004-09-15
Budget End
2005-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$243,439
Indirect Cost
Name
University of Southern Mississippi
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
623335775
City
Hattiesburg
State
MS
Country
United States
Zip Code
39406
Aboukhatwa, Marwa; Luo, Yuan (2011) Antidepressants modulate intracellular amyloid peptide species in N2a neuroblastoma cells. J Alzheimers Dis 24:221-34
Wu, Yanjue; Cao, Zhiming; Klein, William L et al. (2010) Heat shock treatment reduces beta amyloid toxicity in vivo by diminishing oligomers. Neurobiol Aging 31:1055-8
Madgula, Vamsi L M; Avula, Bharathi; Yu, Young-Beob et al. (2010) Intestinal and blood-brain barrier permeability of ginkgolides and bilobalide: in vitro and in vivo approaches. Planta Med 76:599-606
Yu, Young-Beob; Dosanjh, Laura; Lao, Lixing et al. (2010) Cinnamomum cassia bark in two herbal formulas increases life span in Caenorhabditis elegans via insulin signaling and stress response pathways. PLoS One 5:e9339
Hou, Yan; Aboukhatwa, Marwa A; Lei, De-Liang et al. (2010) Anti-depressant natural flavonols modulate BDNF and beta amyloid in neurons and hippocampus of double TgAD mice. Neuropharmacology 58:911-20
Dosanjh, Laura E; Brown, Marishka K; Rao, Gautam et al. (2010) Behavioral phenotyping of a transgenic Caenorhabditis elegans expressing neuronal amyloid-beta. J Alzheimers Dis 19:681-90
Hou, Yan; Wei, Huailing; Luo, Yuan et al. (2010) Modulating expression of brain heat shock proteins by estrogen in ovariectomized mice model of aging. Exp Gerontol 45:323-30
Keowkase, Roongpetch; Aboukhatwa, Marwa; Luo, Yuan (2010) Fluoxetine protects against amyloid-beta toxicity, in part via daf-16 mediated cell signaling pathway, in Caenorhabditis elegans. Neuropharmacology 59:358-65
Tchantchou, Flaubert; Lacor, Pascale N; Cao, Zhiming et al. (2009) Stimulation of neurogenesis and synaptogenesis by bilobalide and quercetin via common final pathway in hippocampal neurons. J Alzheimers Dis 18:787-98
Brown, Marishka K; Luo, Yuan (2009) Bilobalide modulates serotonin-controlled behaviors in the nematode Caenorhabditis elegans. BMC Neurosci 10:62

Showing the most recent 10 out of 20 publications