The current available drugs for Alzheimer disease (AD) only confer modest benefits. Additional AD therapies are urgently needed. Ginkgo biloba leaf extract, EGb 761, has been used as a dietary supplement in the U.S. for Alzheimer dementia. Several clinical trials have provided evidence of efficacy comparable to donepezil (Mazza et al., 2006) for treatment of mild to moderate AD. The evidence for EGb 761 enhancing learning in healthy humans is inconclusive (LaBar et al., 1997; Solomon, et al., 2002). A well-controlled study supported by the NIH is underway (DeKosky et al., 2006). Although the extract EGb 761 has been substantially studied at all levels of biological systems (Christen, 2002), its neuroprotective mechanisms and pharmacological evaluation of the active components remain puzzling to the scientific community. Two major constituents of EGb 761, flavonoids (24 percent) and terpenoids (6 percent) have been actively investigated (DeFeudis, 1998). The terpenoid fraction primarily contains ginkgolides A, B, C, J, and M, and bilobalide, which are specific to the ginkgo biloba tree (Nakanishi, 2005). The ginkgolide B is known as a potent antagonist of platelet activating factor receptor (PAFR) (Smith et al., 1996). The flavonoids impart antioxidative properties to EGb 761. In this paper, Ottavio Vitolo and colleagues in Michael Shelanski’s laboratory reported a very elegant study demonstrating that a terpene trilactone-enriched EGb 761, P8A, completely blocked Aβ-induced LTP reduction and neuronal cell death, two systems that have been considered to be related to AD. A single constituent of EGb 761, ginkgolide J, exhibited the most potent effect on LTP among other EGb 761 components. This observation is consistent with a previous finding that ginkgolide A and J alleviated Aβ-induced pathological behaviors in a C. elegans model (Wu et al., 2006) and enhanced adult neurogenesis and phosphorylation of CREB in a mouse model of AD (Tchantchou et al., 2007). The novelty of this study is that they employed LTP or long-term potentiation, a well-accepted, sophisticated cellular model for neuroplasticity, to investigate a challenging question of complexity. Their results provided initial identification of the key compounds of the extract that affects synaptic function, and provided the rationale for future medicinal chemistry studies based on the chemical structures derived from the extract. The use of mouse hippocampus slices allows for screening of compounds that target at early synaptic and cognitive changes in relation to AD. Compound(s) identified in this model could implicate potential enhanced efficacy of ginkgolide J to the mammalian model of AD and clinical studies. The unique structure of ginkgolides, their bioavailability, combined with its effects on synaptic dysfunction demonstrated by Vitolo et al. (2007) makes them a promising source of novel therapeutic candidates. Neurotoxicity and the natural resource of ginkgolide J is the next issue to be addressed.
See also:
DeFeudis, F.V., Ginkgo biloba extract (EGb 761): from chemistry to clinic. 1998: Publi Ullstein Med. Weisbaden, Germany.
References:
Mazza M, Capuano A, Bria P, Mazza S.
Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study.
Eur J Neurol. 2006 Sep;13(9):981-5.
PubMed.
Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF.
A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group.
JAMA. 1997 Oct 22-29;278(16):1327-32.
PubMed.
Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R.
Ginkgo for memory enhancement: a randomized controlled trial.
JAMA. 2002 Aug 21;288(7):835-40.
PubMed.
Dekosky ST, Fitzpatrick A, Ives DG, Saxton J, Williamson J, Lopez OL, Burke G, Fried L, Kuller LH, Robbins J, Tracy R, Woolard N, Dunn L, Kronmal R, Nahin R, Furberg C, .
The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia.
Contemp Clin Trials. 2006 Jun;27(3):238-53.
PubMed.
Christen Y, Maixent JM.
What is Ginkgo biloba extract EGb 761? An overview--from molecular biology to clinical medicine.
Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):601-11.
PubMed.
Nakanishi K.
Terpene trilactones from Gingko biloba: from ancient times to the 21st century.
Bioorg Med Chem. 2005 Sep 1;13(17):4987-5000.
PubMed.
Smith PF, Maclennan K, Darlington CL.
The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor (PAF).
J Ethnopharmacol. 1996 Mar;50(3):131-9.
PubMed.
Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL, Link CD, Luo Y.
Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans.
J Neurosci. 2006 Dec 13;26(50):13102-13.
PubMed.
Tchantchou F, Xu Y, Wu Y, Christen Y, Luo Y.
EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer's disease.
FASEB J. 2007 Aug;21(10):2400-8.
PubMed.
Comments
University of Maryland
The current available drugs for Alzheimer disease (AD) only confer modest benefits. Additional AD therapies are urgently needed. Ginkgo biloba leaf extract, EGb 761, has been used as a dietary supplement in the U.S. for Alzheimer dementia. Several clinical trials have provided evidence of efficacy comparable to donepezil (Mazza et al., 2006) for treatment of mild to moderate AD. The evidence for EGb 761 enhancing learning in healthy humans is inconclusive (LaBar et al., 1997; Solomon, et al., 2002). A well-controlled study supported by the NIH is underway (DeKosky et al., 2006). Although the extract EGb 761 has been substantially studied at all levels of biological systems (Christen, 2002), its neuroprotective mechanisms and pharmacological evaluation of the active components remain puzzling to the scientific community. Two major constituents of EGb 761, flavonoids (24 percent) and terpenoids (6 percent) have been actively investigated (DeFeudis, 1998). The terpenoid fraction primarily contains ginkgolides A, B, C, J, and M, and bilobalide, which are specific to the ginkgo biloba tree (Nakanishi, 2005). The ginkgolide B is known as a potent antagonist of platelet activating factor receptor (PAFR) (Smith et al., 1996). The flavonoids impart antioxidative properties to EGb 761. In this paper, Ottavio Vitolo and colleagues in Michael Shelanski’s laboratory reported a very elegant study demonstrating that a terpene trilactone-enriched EGb 761, P8A, completely blocked Aβ-induced LTP reduction and neuronal cell death, two systems that have been considered to be related to AD. A single constituent of EGb 761, ginkgolide J, exhibited the most potent effect on LTP among other EGb 761 components. This observation is consistent with a previous finding that ginkgolide A and J alleviated Aβ-induced pathological behaviors in a C. elegans model (Wu et al., 2006) and enhanced adult neurogenesis and phosphorylation of CREB in a mouse model of AD (Tchantchou et al., 2007). The novelty of this study is that they employed LTP or long-term potentiation, a well-accepted, sophisticated cellular model for neuroplasticity, to investigate a challenging question of complexity. Their results provided initial identification of the key compounds of the extract that affects synaptic function, and provided the rationale for future medicinal chemistry studies based on the chemical structures derived from the extract. The use of mouse hippocampus slices allows for screening of compounds that target at early synaptic and cognitive changes in relation to AD. Compound(s) identified in this model could implicate potential enhanced efficacy of ginkgolide J to the mammalian model of AD and clinical studies. The unique structure of ginkgolides, their bioavailability, combined with its effects on synaptic dysfunction demonstrated by Vitolo et al. (2007) makes them a promising source of novel therapeutic candidates. Neurotoxicity and the natural resource of ginkgolide J is the next issue to be addressed.
See also:
DeFeudis, F.V., Ginkgo biloba extract (EGb 761): from chemistry to clinic. 1998: Publi Ullstein Med. Weisbaden, Germany.
References:
Mazza M, Capuano A, Bria P, Mazza S. Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study. Eur J Neurol. 2006 Sep;13(9):981-5. PubMed.
Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA. 1997 Oct 22-29;278(16):1327-32. PubMed.
Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R. Ginkgo for memory enhancement: a randomized controlled trial. JAMA. 2002 Aug 21;288(7):835-40. PubMed.
Dekosky ST, Fitzpatrick A, Ives DG, Saxton J, Williamson J, Lopez OL, Burke G, Fried L, Kuller LH, Robbins J, Tracy R, Woolard N, Dunn L, Kronmal R, Nahin R, Furberg C, . The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemp Clin Trials. 2006 Jun;27(3):238-53. PubMed.
Christen Y, Maixent JM. What is Ginkgo biloba extract EGb 761? An overview--from molecular biology to clinical medicine. Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):601-11. PubMed.
Nakanishi K. Terpene trilactones from Gingko biloba: from ancient times to the 21st century. Bioorg Med Chem. 2005 Sep 1;13(17):4987-5000. PubMed.
Smith PF, Maclennan K, Darlington CL. The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor (PAF). J Ethnopharmacol. 1996 Mar;50(3):131-9. PubMed.
Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL, Link CD, Luo Y. Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci. 2006 Dec 13;26(50):13102-13. PubMed.
Tchantchou F, Xu Y, Wu Y, Christen Y, Luo Y. EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer's disease. FASEB J. 2007 Aug;21(10):2400-8. PubMed.
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