Adenosine: A Novel Drug Target in Parkinson's Disease

Blocking adenosine receptors in the brain may reduce symptoms

Nerve Cells in Parkinson's Disease


KATERYNA KON/SCIENCE PHOTO LIBRARY/Getty Images

Parkinson’s disease (PD) is a chronic neurological disease caused by the loss of dopamine-producing nerve cells in the brain. PD is marked by motor symptoms like tremor, stiffness, and slowed movements. Non-motor symptoms, like depression, sleep problems, and diminished cognitive function, are also common.

The current treatment of PD focuses on dopamine replacement, namely with the use of a drug called levodopa. While levodopa is the most effective drug for reducing symptoms and improving quality of life in patients with PD, it's associated with undesirable side effects, motor fluctuations (on-off), and involuntary movements (dyskinesia).

As a result, experts have been looking into other drug targets (besides dopamine) for reducing the symptoms of PD. One such emerging drug target is a brain chemical messenger called adenosine.

Adenosine and Parkinson's Disease

Adenosine is a molecule present in all body fluids and tissues and has been studied for decades for its therapeutic potential. Even though adenosine is found throughout the brain, its role is, unfortunately, still poorly understood, especially when it comes to Parkinson's disease and dopamine signaling.

That said, we do know that adenosine has four receptor (binding site) subtypes—A1, A2A, A2B, and A3.

The A2A receptors have piqued scientists' interest because they are found on dopamine-producing nerve cells in the area of the brain called the basal ganglia. These receptors uniquely interact with (and are conveniently located next to) dopamine receptors on the same cells.

Cause of Parkinson's Disease

The loss of dopamine-producing nerve cells in the substantial nigra (a region within the basal ganglia) is what causes the symptoms of Parkinson's disease. Scientists aren't sure exactly, but genes and environmental factors likely contribute to this nerve cell loss.

Researchers have found that by blocking ("antagonizing") the adenosine A2A receptors, the motor symptoms of patients with PD improve. As such, various drugs that target and block the adenosine A2A receptor have been examined in multiple human studies of patients with PD. 

One such drug—Nourianz (istradefylline)—is the first adenosine A2A receptor antagonist medication to be approved in the United States for the treatment of PD.

Nourianz: An Add-On Drug in PD

Nourianz is an oral drug taken once daily with or without food. It was approved in the United States in 2019 specifically as an add-on treatment to levodopa in patients with PD experiencing "off" episodes. 

"Off" episodes are a known long-term complication of levodopa that occur when PD-related symptoms reappear before the next scheduled levodopa dose is due. During an "off' episode, a person may feel stiff and slow, frozen in place, or like they cannot form words.

In studies examining thousands of patients with PD, Nourianz has been found to reduce these uncomfortable, distressing "off" episodes, so patients can feel energized for longer periods of time during the day.

In addition to the promising motor benefit of Nourianz, the drug is well-tolerated and appears safe. Across a series of studies, side effects like orthostatic hypotension (a sudden drop in blood pressure when going from sitting or lying down to standing), sleepiness, confusion, and psychosis—all known adverse effects related to levodopa, especially in older patients—were similar for patients receiving Nourianz and those receiving placebo.

Moreover, compared to levodopa, Nourianz has been found to be less likely to induce dyskinesia, which refers to twitching, jerking, twisting, or writhing muscle movements that are out of a person's control. Like "off" episodes, dyskinesia is a known complication of long-term levodopa use.

Levodopa-Induced Dyskinesia

It's not entirely clear why levodopa-induced dyskinesia occurs. Experts suspect that both disturbances in dopamine signaling between nerve cells (which lead to fluctuating dopamine levels in the brain) and the continued loss of dopamine-producing nerve cells play a role.

Keep in mind, though, Nourianz does not prevent the onset of dyskinesia caused by levodopa (and Nourianz is only approved to be taken with levodopa).

According to the drug manufacturer, common side effects associated with Nourianz include:

  • Dizziness
  • Constipation
  • Nausea
  • Hallucinations
  • Insomnia

Unusual urges or compulsive behaviors may also occur when taking Nourianz.

Other Benefits of Nourianz

It's important to mention that besides improving the motor symptoms of PD, there are other potential benefits to taking Nourianz (and perhaps other adenosine A2A receptor antagonists in the pipeline).

Research suggests that adenosine A2A receptor blockers have neuroprotective effects, meaning they may decrease the death rate of dopamine-producing nerve cells in the brain.

Supporting this neuroprotective role is the fact that the consumption of caffeine, which is a natural compound that blocks adenosine A2A receptors, is associated with a lower risk for developing PD in healthy individuals. Caffeine has also been found to reduce the progression or worsening of motor symptoms in patients with PD.

Adenosine A2A receptor antagonists may also improve mood disorders, which are common in PD. One study found that patients with PD taking Nourianz had an improvement in apathy and depressive-like symptoms.

While the precise effect of Nourianz on cognition dysfunction in patients with PD remains unknown, more studies on its therapeutic potentials will likely be done now that the drug is approved.

That said, in animal models of PD, the blockade of adenosine A2A receptors reversed working memory impairments. Caffeine consumption has also been linked to less severe cognitive symptoms in patients with PD, as well as a lower prevalence of lack of motivation and lack of pleasure compared to non-coffee drinkers.

Finally, small studies have revealed that Nourianz may reduce daytime sleepiness and freezing of gait (an abnormal walking pattern) and improve urinary dysfunction and postural abnormalities in patients with PD. More investigation with larger studies is needed to confirm these findings.

A Word From Verywell

Targeting adenosine offers a novel approach to optimally caring for patients with PD, especially older patients and those with advanced PD.

Also encouraging is the prospect that Nourianz and perhaps other future drugs that block the adenosine A2A receptor may improve non-motor symptoms, like mood or cognitive problems. These symptoms often unintentionally take a backseat in importance to the motor symptoms of Parkinson's disease, even though they can be equally if not more disabling.

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