Why do we give levodopa to people with Parkinson’s disease instead of dopamine? After all, loss of dopamine, a major neurotransmitter in the brain, characterizes Parkinson’s disease.
Levodopa vs Dopamine
Well, the answer is simple, if surprising. It turn out that dopamine cannot cross the blood brain barrier (BBB). The BBB is a filter between peripheral blood in the body and blood in the brain itself. The BBB works a little bit like a water purification filter. Of course, in the brain the filtration process is a whole lot more complex. Tightly connected endothelial cells line the brain’s blood vessels to form the BBB. Helpfully, the BBB prevents harmful substances from entering the brain.
The BBB favours fat-soluble (lipophilic) substances that can dissolve in the membrane of endothelial cells and pass through more easily. However, dopamine is a water-soluble (hydrophilic) molecule with polar hydroxyl groups (-OH). It is dopamine’s polarity that limits its ability to diffuse through the lipophilic environment of the BBB.
Discovery of Dopamine
Fortunately for people suffering from Parkinson’s disease, in 1957 a Swedish neuropharmacologist, Arvid Carlsson, discovered that dopamine was not just a precursor to noradrenaline, but was a neurotransmitter in its own right. Subsequent research by Carlsson showed that depleting dopamine caused impairments of movement control, like that seen in Parkinson’s disease.
He went on to show that the administration of the levodopa, a metabolic precursor of dopamine, was effective for treating movement disorders in animals. Carlsson was awarded the Nobel Prize in Physiology and Medicine in 2000 for these amazing discoveries, together with colleagues Paul Greengard and Eric Kandel. Oleh Hornykiewicz, an Austrian biochemist, was instrumental in proving the effectiveness of levodopa in treating Parkinson’s disease in humans.
To this day, the administration of levodopa remains the primary treatment for Parkinson’s disease. An enzyme called DOPA decarboxylase converts levodopa into dopamine. If this conversion happens outside of the brain, it causes a whole lot of unpleasant side-effects, such as nausea, vomiting, and low blood pressure. We combine levodopa with a DOPA decarboxylase inhibitor. Carbilev uses carbidopa to block DOPA decarboxylase in the peripheral blood stream. That prevents conversion of levodopa to dopamine outside the brain. This allows more levodopa to reach the brain, enhancing its therapeutic effects and reducing peripheral side effects. Similarly, Madopar uses benserazide to inhibit peripheral DOPA decarboxylase and achieve the same effect.
Thank you, Professors Carlsson and Hornykiewicz. Without your insights, we would be in deep trouble.
