Ambushing brain damage

Nature Reviews Neuroscience has a fascinating article on drugs that remain dormant in the brain and only respond when damage occurs.

They’ve been christened pathologically activated therapeutic (PAT) drugs and rely on the fact that brain damage triggers specific chemical changes and drugs can be designed to take advantage of these processes.

For example, memantine is a type of drug that antagonises (blocks) the NMDA receptor which is activated by the neurotransmitter glutamate.

Important, because this receptor is known to be activated to excess in conditions like Alzheimer’s and Parkinson’s disease.

Several drugs block this receptor, including ketamine and PCP (‘Angel dust’), but they block the receptor as soon as they arrive.

Memantine is different – it doesn’t do its job unless the receptor has already been activated or ‘opened’ at least once already – making it a ‘non-competative antagonist’ – in other words, it doesn’t compete with the neurotransmitter, it waits until it’s been and gone.

It’s as if you wanted to prevent postmen from delivery their parcels by bricking up each door, but the householders will only open their door to the postmen.

So you hang around, wait for the postman to call, and then get in the doorway and block it. You’re not fighting the postmen while they deliver the letter, you’re avoiding conflict and taking advantage of what they already do.

This gives memantine a very important property. It blocks more receptors the more glutamate is about, or to return to our analogy, it can block more doors when there are more postmen about.

This means the drug ‘lies in wait’. As more NMDA receptors are activated owing to Alzheimer’s disease, the more it steps in to calm the situation down and prevent constant activation which is what is thought to cause the most damage.

The article outlines several other neurochemical processes that allow drugs to seemingly ‘lie in wait’ and only react to damage, rather than affecting the brain regardless of what else is happening.

It’s an interesting, clever and potentially very important twist on drug design that takes advantage of our growing knowledge of how the brain works in both illness and health.

Link to abstract of scientific paper.

2 Comments

  1. Posted September 28, 2007 at 10:35 am | Permalink

    This sounds like a really exciting development – thanks for sharing. Cool analogy too.

  2. Stephen Norton
    Posted April 27, 2011 at 2:42 pm | Permalink

    The spice Rosemary contains carnosic acid which is also a pathologically activated therapeutic (PAT)substance.

    http://www.sciencedaily.com:80/releases/2007/10/071030102210.htm

    The active ingredient in rosemary, known as carnosic acid (CA), can protect the brain from stroke and neurodegeneration that is due to injurious chemical free radicals. These radicals are thought to contribute not only to stroke and neurodegenerative conditions such as Alzheimer’s, but also to the ill effects of normal aging on the brain.
    In two expedited publications by The Journal of Neurochemistry and Nature Reviews Neuroscience, the scientists report for the first time that CA activates a novel signaling pathway that protects brain cells from the ravages of free radicals. In animal models, the scientific group, led by Drs. Takumi Satoh (Iwate University, Japan) and Stuart Lipton (Burnham Institute), found that CA becomes activated by the free radical damage itself, remaining innocuous unless needed, exactly what is wanted in a drug.
    The scientists call this type of action a “pathological-activated therapeutic” or PAT drug. A “pat” represents a gentle tap and not the heavy sledge hammer that some drugs produce, including significant side effects in areas of the body where their effects are not needed and not wanted.
    “This new type of drug works through a mechanism known as redox chemistry in which electrons are transferred from one molecule to another in order to activate the body’s own defense system,” said Stuart A. Lipton, MD, PhD, the senior author on the paper and Director, Professor, and Senior Vice President at the Burnham’s Del E. Webb Neuroscience, Aging, and Stem Cell Research Center.
    “Moreover, unlike most new drugs, this type of compound may well be safe and clinically tolerated because it is present in a naturally-occurring herb that is known to get into the brain and has been consumed by people for over a thousand years.” Dr. Lipton is also a practicing neurologist at the University of California, San Diego, and therefore knows first-hand that such drugs are critically needed for care of the aging and neurologically-ill patients.


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