Calcium activity in the brain plays an important role in the onset of Parkinson’s disease, according to a study in mice. The finding helps explain why common calcium-blocking drugs, such as those used to control blood pressure, appear to protect against the disease.

Damage to dopamine-releasing cells in a brain area called the substantia nigra (SN) is known to be involved in the onset of Parkinson’s disease. “Pacemaking” cells in this area release pulses of dopamine, a hormone crucial for movement and balance. so damage to these cells leads to the symptoms of Parkinson’s – such as tremors and stiffness.

A key question is why cells of the SN are so much more susceptible to damage than those in surrounding areas. Now it seems that calcium, which enters these cells to regulate their activity, is the culprit.

Jaime Guzman from Northwestern University in Chicago and colleagues compared the effect of calcium activity in two brain areas in mice – the pacemaking SN and a neighbouring area where there was no pacemaking activity.

Oxidative stress

They found that the calcium influx in the SN caused much higher levels of oxidative stress – pressure on cells to counteract the effects of molecules such as free radicals, that can damage proteins and DNA. Oxidative stress is thought to be the source of the cell damage that leads to Parkinson’s disease.

“Although calcium channels normally participate in pacemaking, they aren’t essential as other ion channels can pick up the slack,” says James Surmeier, who was part of the team. Treating mice that had Parkinson’s disease with calcium-channel-blocking drugs might therefore prevent cell damage without hindering essential pacemaking activity.

To investigate this possibility, the team used mice lacking a gene called DJ-1. The absence of this gene causes early onset Parkinson’s disease, and mice who lacked the gene showed much higher levels of damage to the dopamine-releasing cells of the SN than normal mice. When treated with drugs that block calcium channels, however, the degree of cell damage dropped to levels seen in other types of brain cells that are relatively resistant to oxidative stress.

The right drug

The findings explain why previous research conducted by Christoph Meier at University Hospital Basel in Switzerland showed that calcium-blocking hypertension drugs reduced the risk of Parkinson’s disease, while other types of drug used to treat high blood pressure did not.

“A lot seems to point towards a potential benefit of calcium-channel blockers in Parkinson’s disease,” says Meier, “but it’s too early to tell whether they help prevent the disease or could improve the situation of patients who already have a diagnosis.”

Surmeier is more confident. “We think that anyone at risk of developing Parkinson’s disease should benefit by the use of calcium blockers such as isradipine,” he says, as it appears that the dopamine-producing cells in the SN begin to disappear well before the onset of symptoms.

Isradipine is already in a phase II clinical trial for people with early stage Parkinson’s disease, and Surmeier is now planning to investigate more selective and potent drugs.

Journal reference:

Nature, DOI: 10.1038/nature09536

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