Ginsenoside Rg3, Cynandione A, and p-methoxy-trans-cinnamic acid (MCA), all isolated from Oriental herbal medicines, attenate neurotoxicity induced by glutamate in vitro. Neoline, isolated from Aconiti tubers, protects short-term memory, possibly by influencing central cholinergic transmission. The present proposal is designed to elucidate the mechanisms of their neuroprotective activities in vitro as well as in vivo. The latter mandates transport of these agents across the blood-brain barrier (BBB). Thus, prodrug approaches are adopted for brain delivery. Specfic Aim 1 tests a hypothesis that Rg3 and MCA exet neuroprotective activities by inhibiting Ca ++ influx by determining their efects on Ca++ influx in vitro.
Aim 2 tests the hypothesis that Rg3, cynandione A and MCA exert neruoprotective activity by inhibiting neuronal apoptosis by assessing their effects on apoptosis and its markers in vitro and in vitro.
Aim 3 tests a hypothesis that neoline ameliorates deficits in short-term memory by influencing central cholinergic transmission in the brain. As such, we will determine its effects on muscarinic receptors in vitro and in vivo as, and Ach levels in vivo.
Aim 4 addresses issues involved in drug delivery across the BBB. To this end, we propose to synthesize a series of ester prodrugs of Rg3, and Rg3 analog (protopanaxadiol), and MCA.
Aim 5 concerns with development of injectable formulations for these test compounds. Note that they are all water-insoluble. The overall goal of this proposal is to identify novel strategies of blocking oxidative stress, which is the primary cause of neuronal death or memory impairment linked to neurodegeneration. Results of this three-way collaborative research are significant in that: I) these curative s have been used in Asian societies for centuries; ii) no effective treatments are currently available for such adult neurodegenerative disorders as Alzheimer's disease or for injuries to the CNS/stroke; and iii) the progressive memory loss observed in various dementia is extremely debilitating, making any palliative measure a major clinical development.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
5R01AT000106-03
Application #
6375409
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (06))
Program Officer
Hopp, Craig
Project Start
1999-09-30
Project End
2004-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
3
Fiscal Year
2001
Total Cost
$386,868
Indirect Cost
Name
University of Maryland Baltimore
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Kim, So Ra; Sung, Sang Hyun; Kang, So Young et al. (2004) Aristolactam BII of Saururus chinensis attenuates glutamate-induced neurotoxicity in rat cortical cultures probably by inhibiting nitric oxide production. Planta Med 70:391-6
Ma, Choong Je; Sung, Sang Hyun; Kim, Young Choong (2004) Neuroprotective lignans from the bark of Machilus thunbergii. Planta Med 70:79-80
Kang, So Young; Lee, Ki Yong; Park, Mi Jung et al. (2003) Decursin from Angelica gigas mitigates amnesia induced by scopolamine in mice. Neurobiol Learn Mem 79:11-8
Kim, So Ra; Kang, So Young; Lee, Ki Yong et al. (2003) Anti-amnestic activity of E-p-methoxycinnamic acid from Scrophularia buergeriana. Brain Res Cogn Brain Res 17:454-61
Kim, So Ra; Park, Mi Jung; Lee, Mi Kyeong et al. (2002) Flavonoids of Inula britannica protect cultured cortical cells from necrotic cell death induced by glutamate. Free Radic Biol Med 32:596-604
Jang, Young P; Kim, So R; Choi, Young H et al. (2002) Arctigenin protects cultured cortical neurons from glutamate-induced neurodegeneration by binding to kainate receptor. J Neurosci Res 68:233-40
Kim, So Ra; Sung, Sang Hyun; Jang, Young Pyo et al. (2002) E-p-methoxycinnamic acid protects cultured neuronal cells against neurotoxicity induced by glutamate. Br J Pharmacol 135:1281-91
Kim, Y; Park, E J; Kim, J et al. (2001) Neuroprotective constituents from Hedyotis diffusa. J Nat Prod 64:75-8
Lee, M K; Sung, S H; Lee, H S et al. (2001) Lignan and neolignan glycosides from Ulmus davidiana var. japonica. Arch Pharm Res 24:198-201
Lee, M K; Kim, Y C (2001) Five novel neuroprotective triterpene esters of Ulmus davidiana var. japonica. J Nat Prod 64:328-31

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