Calcium channels and vulnerable neurons

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

C. Savio Chan, Jaime Guzman, D. James Surmeier and colleagues at Northwestern University, "'Rejuvenation' protects neurons in mouse models of Parkinson's disease" (Nature 447:1081–1086, June 2007). PubMed lists US NIH extramural support; the exact grants were not checked.

What happened

Most neurons fire using sodium channels. Chan et al. found that adult nigral dopamine neurons keep their steady "pacemaker" firing largely through L-type calcium channels, notably Cav1.3, while young neurons used sodium. Isradipine, an L-type blocker, switched adult cells back to the sodium-dependent young mode ("rejuvenation"). Chronic isradipine protected these neurons from the toxin MPTP (landmark 2) in mice. The authors argued that constant calcium entry burdens these cells, and that this physiology, not dopamine chemistry, explains why they die first. Human evidence at the time was thin: a 1999 review asked whether calcium blockers might protect (Rodnitzky, Drugs). A later Danish registry study of 1,931 patients and 9,651 controls found people prescribed dihydropyridine blockers that cross into the brain (not amlodipine) were less likely to develop Parkinson's (odds ratio 0.73, 95% CI 0.54–0.97), which fits the idea but cannot show cause (Ritz 2010, Ann Neurol). In 2010 the same Northwestern lab reported that Cav1.3-driven pacemaking raises oxidant stress in the mitochondria of these neurons (Guzman 2010, Nature 468:696–700; it has a 2015 corrigendum, which does not concern the 2007 paper). No correction or retraction was found for the 2007 paper (Crossref, Europe PMC).

Why it moved us toward a cure

It offered an answer to a core question: why do these particular neurons die? The idea was tested directly in a 336-person Phase 3 of isradipine, which found no benefit (landmark 144).

Outcome

Open. The mechanism is supported by the Northwestern lab's own follow-up and one registry study, but it is unproven in people, and isradipine itself is a dead end (landmark 144). That trial shows that this drug at that dose did not slow progression, not that calcium stress is irrelevant: dose, brain delivery, timing in disease, and the mouse-to-human gap are all possible reasons. Surmeier is also an author of landmark 58, which includes mitochondrial oxidant stress; see also landmark 11.

Sources

• Chan et al., Nature 2007;447:1081–1086, DOI 10.1038/nature05865 (PubMed 17558391) · Alzforum summary, "Teaching Old Neurons Young Tricks"
• Ritz et al., Ann Neurol 2010;67:600–606, DOI 10.1002/ana.21937 · Guzman et al., Nature 2010;468:696–700, DOI 10.1038/nature09536 · Rodnitzky, Drugs 1999;57:845–849 (PubMed 10400399)
• Isradipine Phase 3 sources are in landmark 144.
• Not yet verified: independent (non-Northwestern) replication of the rejuvenation experiments; the Chan paper's full text (abstract read).