HYPE?

Media portrayal:

HOPE?

Scientific interpretation:

Neuroprotective effects of the anti-hypertension drug isradipine

Original article: Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress, The Journal of Clinical Investigation: June 1, 2018.

The takeaway

Chronic administration of the anti-hypertension drug isradipine was shown to improve several functions in dopamine neurons in mice. Isradipine effectively reduced calcium spikes and overall calcium levels, leading to reduced oxidative stress and mitochondrial damage.

Why is it important?

This study provides solid support for the STEADY-PD III trial currently underway to test the disease modifying potential of isradipine for Parkinson’s.

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IMPACT

  • Novelty 65% 65%
  • Proximity 80% 80%
  • Deliverability 80% 80%

Impact Opinion

“These exciting results provide us not only with further support for the ongoing STEADY-PD III clinical trial of isradipine in Parkinson’s, but also offers us further insights into the underlying biology of this condition. It will be interesting to see what else is learned before the results of the clinical trial become available in mid-2019.”

Background

Isradipine is a drug used to lower blood pressure and prevent cardiovascular disease by modulating the function of calcium channels in muscle. Dopamine neurons also express calcium channels, whose function is important in producing their regular, pacemaker-like firing patterns. Calcium in this context is helpful in that it stimulates energy production in mitochondria, the powerhouses of the cell; this is especially relevant for dopamine neurons which operate at near full capacity most of the time, enabling them to be maximally responsive. However, this process is not without cost, as it stimulates oxidative stress which is ultimately harmful.

Armed with this knowledge, as well as the observation that people treated chronically with isradipine were at lower risk for PD, a number of trials with isradipine have taken place, the most recent of which focused on establishing its neuroprotective potential in people with Parkinson’s in the STEADY-PD III trial. In the meantime however, there are a number of important open questions about its mode of action and its effects at therapeutic concentrations on calcium-triggered mitochondrial damage. This pre-clinical work addressed several of these important issues.

The details

This series of experiments examined the function of dopamine neurons in healthy mice treated chronically with isradipine. One of the main questions was to establish that the calcium channels in question are actually engaged by the drug at the clinically relevant doses used.

In one of the first studies ever to use a special kind of imaging, two-photon laser scanning microscopy, these researchers were able to actually measure the amount of calcium inside dopaminergic neurons. After treating young mice chronically with isradipine, intracellular calcium levels were reduced, calcium spikes were lowered and the compensatory increase in the number of calcium channels that was feared may occur did not.

 

In subsequent experiments, the researchers established that neurons from older animals had higher levels of calcium, which rendered them more vulnerable to damage, confirming the ageing effect which is known to increase risk for Parkinson’s. They also showed that it was primarily neurons from the substantia nigra, a key region implicated in the movement problems seen in the condition, which showed these elevated calcium levels, in comparison to the lower levels seen in another dopaminergic pathway.

Finally, both mitophagy, that is the removal/recycling of damaged mitochondria, as well as oxidative stress were reduced after chronic isradipine treatment, while the actual mass of mitochondria increased, indicating beneficial effects for metabolism. The effects of isradipine on calcium channel inhibition were also reversible at approx. one month after discontinuation of treatment. Isradipine was  well tolerated and there were no side effects.

Next steps

The results of the STEADY-PD III trial in humans are eagerly awaited and will be released in 2019. These will hopefully answer the all important question of this drug’s disease modifying potential in Parkinson’s.

Related work

https://clinicaltrials.gov/ct2/show/NCT02168842

https://steadypd3.com/

Original article: Guzman, J. N., Ilijic, E., Yang, B., Sanchez-Padilla, J., Wokosin, D., Galtieri, D., . . . Surmeier, D. J. June 1, 2018. Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress, The Journal of Clinical Investigation

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