In the upcoming print issue of the Journal of Medicinal Chemistry, Italian researchers led by Allesandro Dalpiaz are reporting initial success in using Vitamin C to ferry drugs through the blood-brain barrier, an obstacle in the development of drugs against Alzheimer's and other central nervous system diseases. Published online last month, the paper is discussed below by Patrick May, who leads pre-clinical AD programs at Eli Lilly and Company.—Gabrielle Strobel

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  1. In developing small molecule therapeutics, drug hunters targeting neurodegenerative diseases have to overcome an added barrier, both figuratively and literally. In general, the experimental therapeutic must pass the blood-brain-barrier (BBB) in order to interact with their molecular targets within the brain. Several groups are targeting various specific transporters to aid delivery of compounds across the BBB.

    Stefano Manfredini and colleagues propose exploiting a newly described family of ascorbic acid transporters to enhance uptake of pro-drugs into brain. Using human retinal pigmented epithelial cells that endogenously express the SVCT2 ascorbate transporter subtype, they demonstrate that pro-drugs consisting of ascorbic acid-conjugates of nipecotic acid, kynurenic acid, and diclofenamic acid interfere with [14C]-ascorbate cellular transport. For an in vivo proof-of-principal, they demonstrate that intraperitoneal administration of a nipecotic acid-ascorbate pro-drug delayed the onset of pentylenetetrazole (PTZ)-induced seizures in mice compared to saline or unconjugated nipecotic acid.

    This latter experiment demonstrates both the promise and limitations of pro-drug approaches. Clearly the pro-drug afforded some efficacy over the parent drug, although bona fide brain exposure data for pro-drug and parent would have been informative, if not persuasive. However, many efficacious drugs in this standard anti-convulsant model already afford full protection against seizures rather than delaying their onset. The relatively weak efficacy shown in this assay may speak to the short half-life of the pro-drug once it is absorbed into the bloodstream. Moreover, the pro-drug was administered intraperitoneally, since little pro-drug would likely survive the rapid metabolism in the gut following oral administration.

    Despite these criticisms, exploiting ascorbate transporters as an entrĂ©e into the brain is an attractive approach, as the high levels of ascorbate in the brain suggest a robust uptake system. Manfredini et al. have laid the groundwork for future refinements to this strategy, which should strive to optimize the oral bioavailability and stability of the pro-drug while in the systemic circulation, coupled with an efficient conversion to active parent once the pro-drug passes the BBB.

    References:

    . Design, synthesis and activity of ascorbic acid prodrugs of nipecotic, kynurenic and diclophenamic acids, liable to increase neurotropic activity. J Med Chem. 2002 Jan 31;45(3):559-62. PubMed.

  2. I have been giving my dad vitamin C bid for the last 2 weeks, along with his namenda, and there is a mini improvemnt in his behavior. Too soon for any excitement over it . Taking one day at a time.

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Primary Papers

  1. . Design, synthesis and activity of ascorbic acid prodrugs of nipecotic, kynurenic and diclophenamic acids, liable to increase neurotropic activity. J Med Chem. 2002 Jan 31;45(3):559-62. PubMed.