Neuroprotective effects of the anti-hypertension drug isradipine
Why is it important?
- Novelty 65% 65%
- Proximity 80% 80%
- Deliverability 80% 80%
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.
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.
Where can I learn more?
The STEADYPD-III clinical trial results presented at the American Academy of Neurology’s 71st Annual Meeting (May 2019) suggest that isradipine did not show clinical benefit in people with Parkinson’s over the 3 years of the study. 336 people with early Parkinson’s took part in the study which was conducted by the Parkinson’s Study Group at 54 sites across the US and Canada.