New evidence suggests that Parkinson disease may have more to do with age-related calcium signaling than dopamine dysfunction. The finding, which is reported in the June 28 issue of Nature, resounds with emerging evidence that calcium toxicity contributes to cell death associated with Alzheimer disease (see ARF related news story) and suggests that calcium channel blockade may be an effective treatment for PD. A similar therapeutic strategy is being pursued for AD (see ARF drugs in clinical trials).
Researchers led by D. James Surmeier at Northwestern University, Chicago, Illinois, investigated what makes dopaminergic neurons in the substantia nigra pars compacta (SNc) selectively vulnerable to cell death. “There’s a fair amount of debate in Parkinson disease in selective vulnerability,” Surmeier said. “Some think the disease doesn’t just affect dopaminergic neurons, but affects a broad group of neurons. And, that may be true.” That is, predisposition to cell death in Parkinson disease may be due to more than simply possessing dopamine, which has been linked to oxidative damage (see ARF related news story). In fact, the physiology—not the chemistry—of these dopaminergic neurons may underlie their selective susceptibility.
The basic physiology of SNc dopaminergic neurons shows a key difference from many other neurons. “What was immediately apparent to us is that they use calcium ions to maintain autonomous activity,” Surmeier said. First author C. Savio Chan and colleagues observed that rhythmic pacemaking activity ceased when they bathed the cells in L-type calcium channel antagonists, such as isradipine, nimodipine, and other members of the dihydropyridine family. On the other hand, blocking sodium channels with tetrodotoxin did not abolish the pacemaking rhythm.
The calcium-dependent nature of the pacemaking served as a red flag to the researchers, because it hinted at the potential for cell death due to calcium toxicity. To investigate the role of L-type calcium channels in SNc dopaminergic neurons, Surmeier examined mice with genetic deletions of the L-type channel subunit Cav1.3, which is highly expressed in the SNc neurons. “We looked at dopaminergic cells and much to our surprise those cells were firing at a perfectly normal rate but were using sodium not calcium,” Surmeier said.
Further experiments showed that age determined whether pacemaking was governed by sodium or calcium. Recordings of SNc dopaminergic neurons from wild-type mice less than 3 weeks old showed a dependency on sodium that waned with age as calcium channels took over the pacemaking activity. Therefore, deleting the Cav1.3 calcium channel allowed the cells to retain their youthful ways. “The genetically modified mouse stayed in a young mode of behaving,” Surmeier said. “It never switched, because it couldn’t make the protein for this [calcium] channel.”
But, could the juvenile, sodium-dependent pacemaking be obtained or preserved with a pharmacological rather than a genetic intervention? To test this, the researchers applied the calcium channel blocker isradipine to SNc dopaminergic neurons taken from wild-type mice, then sat back and waited. Cells remained silent for 30 minutes after the calcium channel blockade. After around an hour some cells twitched to life, and within a few hours nearly all the examined neurons regained pacemaking activity. “It was like you had taken childhood toys and put them on a shelf,” Surmeier said. The calcium blockade forced the cells to revert to their younger way of sodium-dependent pacemaking that had lain latent after the calcium signaling came to dominate.
Having observed that SNc neurons could be swayed from their potentially vulnerable calcium-dependent state, the researchers studied whether the juvenile, sodium-dependent pacemaking approach could protect the cells from Parkinson disease. Treating brain tissue slices with isradipine for 2 hours before adding the pesticide rotenone, which produces Parkinson-like characteristics—including preferential SNc dopaminergic cell loss and accumulation of Lewy-like bodies—decreased rotenone-induced stress on dendrites. Further, Chan and colleagues found that they could protect mice by rejuvenating dopaminergic neurons in vivo. Administering chronic isradipine with subcutaneous pellets shifted pacemaking from calcium- to sodium-dependent channels and protected against SNc cell loss when combined with MPTP treatment, a predominant animal model for Parkinson disease.
Whether the mouse data suggest a viable treatment strategy in humans remains unclear. But there is reason for optimism. Some data suggest that patients taking the calcium channel blocker israpidine for hypertension or stroke may be protected against PD (see Rodnitzky, 1999).—Molly McElroy
Molly McElroy is a freelance writer based in Melbourne, Florida.
- Aβ Oligomers and NMDA Receptors—One Target, Two Toxicities
- Dopamine Renders α-Synuclein Toxic to Neurons
- Rodnitzky RL. Can calcium antagonists provide a neuroprotective effect in Parkinson's disease?. Drugs. 1999 Jun;57(6):845-9. PubMed.
- Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, Meredith GE, Surmeier DJ. 'Rejuvenation' protects neurons in mouse models of Parkinson's disease. Nature. 2007 Jun 28;447(7148):1081-6. PubMed.