by turning down the activity of voltage-dependent calcium channels responsible for an autonomous "pacemaking" function. That same function is performed in JUVENILE mouse neurons by another type of pacemaking channel which relies on sodium ions. This unique pacemaking activity is key to the steady release of dopamine by these neurons that is required for maintaining motor control. This "takeover" by these calcium channels in older mice is aggravated by the increased calcium inside the cells which can be caused by toxins (rotenone, MPTP, etc) that disrupt mitochondrial function and/or structural integrity. Other sources of increased intracellular calcium are also possible in highly metabolically active cells such as these under stress.

Presumably, in the absence of such challenges, the adult cells can go right on using their pacemaking calcium channels and remain healthy.

The drug (israpidine) binds to the calcium channels, forcing the neurons to revert to the juvenile sodium-dependent pacemaking channels which are still present but not dominant in the adult. The resulting drop in intracellular calcium apparently makes the neurons less susceptible to stress challenges, especially those which result in the production of superoxide ions and other reactive oxygen species which can cause cell damage and death.

What is not known is whether the same scenario prevails in primate/human dopaminergic substantia nigra neurons as in mice. If so, the drug could be useful for neuroprotection in people known to be susceptible to developing PD. It is unlikely that the drug can contribute to neuroregeneration, the replacement of neurons that have already died.

I was highly impressed with the science and experimental elegance of this work.

Robert