D-512: A Potential Dopamine Agonist for Parkinson's

An Investigational Drug That Battles Parkinson's Disease From the Beginning

Brain, neurons, synapses, neural network circuit of neurons, degenerative diseases, Parkinson
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Medications called dopamine agonists like Requip (ropinirole) and Mirapex (pramipexole) are commonly used to treat the symptoms of Parkinson's disease, especially in the early stages.

Dopamine agonists are usually prescribed by neurologists as either a means of lengthening the time it takes before a person has to start (or increase) their dose of levodopa. Levodopa is the most effective medication for Parkinson's, but its effectiveness decreases the longer someone is on the medication.

In addition to being inferior to levodopa in treating motor symptoms, dopamine agonists do nothing to slow down the disease.

These downsides have sparked researchers to develop a new dopamine agonist, called D-512, which not only appears superior to other dopamine agonists in terms of managing motor symptoms but may protect existing nerve cells, potentially putting the brakes on a person's disease (a remarkable feat).

It's important to understand that D-512 is in the very early phases of research. In fact, it's only been studied in animals. Still, it's a good first step towards finding a medication that battles Parkinson's disease from the beginning.

Overview of D-512

Parkinson's disease involves the loss of dopamine-producing nerve cells in a region of the brain called the substantia nigra. Since dopamine is a brain chemical (called a neurotransmitter) that is needed for the body to move, motor (movement-related) symptoms arise from this loss.

While there are a number of motor symptoms associated with Parkinson's disease, four cardinal ones are:

As a dopamine agonist, D-512 binds to dopamine receptors, or docking sites, in the brain. By directly stimulating these receptors, D-512 mimics the brain chemical dopamine (so the brain thinks it has dopamine when it really doesn't).

D-512 is different from other dopamine agonists, though, because it has a higher affinity for dopamine receptors. This means it can bind more easily and more tightly, which makes it last longer.

In addition to having a higher affinity for dopamine receptors, D-512 is believed to protect the dopamine-producing nerve cells that are still living, presumably by reducing oxidative stress (a key feature to the "why" behind Parkinson's disease). By reducing oxidative stress, D-512 would be considered to have antioxidant properties.

In other words, researchers believe D-512 could be a disease-modifying treatment for Parkinson's disease because it may slow down its progression.

The Science Behind D-512: An Animal Study

In one study in the British Journal of Pharmacologythe brains of rats were infused with 6-hydroxydopamine (a dopamine neurotoxin to mimic the disease of Parkinson's in humans). Then, the rats were given either D-512 or Requip (ropinirole), and the effects were compared.

Results

Study results revealed a higher brain uptake and blood levels of D-512 than ropinirole.

Moreover, while both D-512 and ropinirole increased spontaneous movements (in the rats) to a similar degree right after injection, the duration of motor activation was longer for D-512 than ropinirole.

More specifically, the anti-Parkinsonian effects of ropinirole lasted only about two hours whereas the anti-Parkinsonian effect of D-512 lasted for at least four hours.

Side Effect: Dyskinesia

D-512 was observed to cause dyskinesia, but to the same severity as Requip (ropinirole), in the rats. Dyskinesia refers to abnormal movements like writhing or twitching that are out of a person's control.

It's important to note that while dyskinesias are a common side effect of levodopa, occurring in around 50 percent of people with Parkinson's disease at five years, they are much less common in people taking dopamine agonists.

In fact, research reveals that dyskinesias, when a person is taking dopamine agonists alone, occur in about 5 to 7 percent of people with Parkinson's—and if dyskinesias do occur, they are generally milder in severity and occur later.

Bottom Line

All in all, dyskinesias are not a huge problem in people taking dopamine agonists alone (without levodopa), so there is still likely an improved benefit-side effect ratio of taking D-512, as compared to other dopamine agonists like Requip (ropinirole).

Remember, this is an animal study, so it's too early to make any conclusions yet. The bottom line here is that the effects of D-512 need to be translated into human use.

Dopamine Agonists and Their Role in Non-Motor Symptoms

In addition to treating motor symptoms in early-stage Parkinson's disease, scientific evidence suggests that dopamine agonists benefit non-motor symptoms, especially mood problems like anxiety, depression, and/or apathy.

Dopamine agonists may also improve certain autonomic problems like sexual function or sweating, as well as specific sleep problems in Parkinson's disease like restless leg syndrome or sleep fragmentation.

This is promising, as experts are focusing more and more on non-motor symptoms, as they often start earlier than motor symptoms and can be debilitating.

That said, it's unclear whether D-512 would be superior to traditional dopamine agonists like Requip (ropinirole) or Mirapex (pramipexole) in easing these non-motor symptoms.

A Word From Verywell

In the animal study mentioned, the biggest benefit of D-512 over Requip (ropinirole) is that it lasts longer and is better at its peak effect.

Still, more studies are needed to better understand if a compound like D-512 is truly better than current dopamine agonists for treating people with Parkinson's.

Besides motor symptoms and side effects, other factors need to be considered like a person's quality of life, the time postponed to starting levodopa, and whether D-512 is truly disease-modifying (can it protect the dopamine-producing nerve cells that are still living).

Sources:

Batla A, Stamelou M, Mencacci N, Schapira AH, Bhatia KP. Ropinirole monotherapy induced severe reversible dyskinesias in Parkinson's disease. Mov Disord. 2013 Jul;28(8):1159-60.

Lindenbach D, Das B, Conti MM, Meadows SM, Dutta AK, Bishop C. D-512, a novel dopamine D2/3 receptor agonist, demonstrates greate anti-Parkinsonian efficacy than ropinirole in Parkinsonian rats. Br J Pharmacol. 2017 Sep;174(18):3058-71.

Poewe W et al. Extended-release pramipexole in early Parkinson disease: a 33-week randomized controlled trial. Neurology. 2011 Aug 23;77(8):759-66.

The Michael J. Fox Foundation For Parkinson's Research. D-512: a Novel, Multifunctional D2/D3 Receptor Agonist for the Treatment of Parkinson's Disease.

Schaeffer E, Berg D. Dopaminergic therapies for non-motor symptoms in Parkinson's disease. CNS Drugs. 2017 Jul;31(7):551-70.

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