Smuggling drugs into the brain

Open-access science journal PLoS Biology has a fascinating article on the latest developments in getting drugs across the blood-brain barrier – the body’s strict border control that keeps the brain free of foreign substances.

The blood-brain barrier is a filtering system in the capillaries, the smallest blood vessels in the brain, to prevent molecules over a certain size reaching the brain itself (click image for larger version).

This makes good biological sense as it keeps the brain free of a whole range of potential poisons and infections but is a pain for drug designers.

There are many drugs which would have an effect but can’t get from the blood into the brain because the molecules are too big.

For example, Parkinson’s disease involves the death of dopamine neurons in the nigrostriatal pathway of the brain – a key circuit for movement – which is partly why the disease causes tremor and rigidity.

The obvious thing to do would be to give people dopamine to make up for the lost neurons, but it turns out that dopamine molecules are too big to cross the blood-brain barrier. If you swallow a dopamine pill, it won’t reach the brain.

Eventually someone hit on the idea of giving people levodopa or L-DOPA – a molecule that the body eventually transforms into dopamine and is small enough to cross the barrier.

So, you swallow an L-DOPA pill, it crosses the barrier and is changed into dopamine inside the brain itself. Clever.

Substances given with the intention that the body will transform them into the desired drug are called prodrugs and finding prodrugs small enough to cross the blood-brain barrier is one method for getting round the delivery problem.

This is fine if what you’re trying to deliver can be transformed into something useful but for many drugs this isn’t possible, so other methods have to be found.

New techniques are being developed which take advantage of the fact that the blood-brain barrier makes special exceptions for certain essential proteins.

The idea is that a drug molecule will be ‘wrapped up’ in a familiar protein and so will be smuggled across the barrier, only to be released when it reaches the other side.

Other techniques involve a mechanical approach to the problem where a device is implanted to pump the drug straight into the brain. Needless to say this direct intervention approach is favoured by neurosurgeons (the armed wing of the neuroscience world).

The PLoS Biology article discusses these are other developments and looks at how this problem is now becoming a core focus of drug development as useful medicines have sometimes been invented only to be found to be unusable in practice.

Link to PLoS Biology article ‘Bridging the Blood-Brain Barrier’.

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