Hypertension drug shows positive Ph 3 Parkinson’s results in mice

The ability of the Cav1 channel inhibitor isradipine to slow the loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons and the progression of Parkinson’s disease (PD) is being tested in a phase 3 human clinical trial. But it is unclear whether and how chronic isradipine treatment will benefit SNc DA neurons in vivo.

To pursue this question, isradipine was given systemically to mice at doses that achieved low nanomolar concentrations in plasma, near those achieved in patients. The overall goal was to determine whether clinically relevant doses of isradipine effectively engaged Cav1 Ca2+ channels in brain SNc DA neurons in vivo and, if so, what the consequences of this engagement were. Optical tools were used to quantitatively measure intracellular Ca2+ concentrations as well as mitochondrial oxidant stress, turnover, and mass.

Results of the study:

This treatment diminished cytosolic Ca2+ oscillations in SNc DA neurons without altering autonomous spiking or expression of Ca2+ channels, an effect mimicked by selectively knocking down expression of Cav1.3 channel subunits. Treatment also lowered mitochondrial oxidant stress, reduced a high basal rate of mitophagy, and normalized mitochondrial mass — demonstrating that Cav1 channels drive mitochondrial oxidant stress and turnover in vivo. Thus, chronic isradipine treatment remodeled SNc DA neurons in a way that should not only diminish their vulnerability to mitochondrial challenges, but to autophagic stress as well.

The studies presented yielded 4 observations. First, cytosolic [Ca2+] during pacemaking was significantly higher in SNc DA neurons ex vivo than that in VTA neurons, rising from proximal to distal dendrites (P < 0.05). The oscillation in [Ca2+], which reached high nanomolar levels in distal dendrites, was dependent in large measure upon the opening of Cav1 Ca2+ channels, particularly those with a Cav1.3 pore-forming subunit. Second, chronic inhibition of Cav1 channels in vivo with the negative allosteric modulator isradipine led to a sustained reduction in cytosolic [Ca2+] in SNc DA neurons. This reduction was not accompanied by alterations in dopamine-dependent behavior, pacemaking rate, or the expression of Cav1 or Cav3 channel pore-forming subunit mRNAs. Third, chronic isradipine treatment significantly lowered somatodendritic mitochondrial oxidant stress, diminished a high basal rate of mitophagy, and increased mitochondrial mass in SNc DA neurons (P < 0.05). Fourth, with cessation of isradipine treatment, these effects reversed over the course of days. Together, these results fill an important gap in the researchers’ understanding of mechanisms underlying the ongoing clinical trial with isradipine and how Cav1 channel inhibition might alter PD pathogenesis.

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News Source: https://www.jci.org/articles/view/95898

Image Source: https://www.usnews.com/news/health-care-news/articles/2018-03-29/study-cancer-vaccine-cures-97-percent-of-tumors-in-mice-human-trials-to-begin-soon