. Does NSAID use modify cognitive trajectories in the elderly? The Cache County study. Neurology. 2007 Jul 17;69(3):275-82. PubMed.

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  1. 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:

    . 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.

    . 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.

    . Ginkgo for memory enhancement: a randomized controlled trial. JAMA. 2002 Aug 21;288(7):835-40. PubMed.

    . 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.

    . 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.

    . Terpene trilactones from Gingko biloba: from ancient times to the 21st century. Bioorg Med Chem. 2005 Sep 1;13(17):4987-5000. PubMed.

    . 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.

    . 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.

    . 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.

    View all comments by Yuan Luo
  2. This paper from the Cache County Investigators reports an association between long-term NSAID use and slow cognitive decline on the 3MS in individuals who started NSAIDs at a young age and carry the ApoE4 allele. As the authors point out, though the findings are interesting, this is an observational study that cannot yield conclusive evidence of a neuroprotective effect. Further, the randomized study necessary to demonstrate such an effect would be essentially unfeasible. So we are left with intriguing results that should not be used to guide treatment recommendations. In fact, since almost all randomized controlled trials suggest that any effect of NSAIDs on neurodegenerative disease is more likely harmful than beneficial, it may be reasonable to attribute the apparent protective effects reported here to biases that could not be fully controlled for in the analyses. Perhaps there are biological, cognitive, behavioral, or socioeconomic factors linked to long-term NSAID use that influence likelihood of cognitive decline.

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