Wednesday, April 7, 2010

Calcium Channel Blockers Crossing the Blood Brain Barrier for Parkinson's Disease

BBBs and the L-type CCBs that cross them

If you've ever looked at the common questions about Parkinson's disease and dopamine as asked in the classroom or in homework help on Yahoo!Answers, you have already seen the most common question goes something like, "Why does dopamine die in PD?"  And that's a biggie, misleading but still a $64 million dollar question.

One interesting thing about Parkinson's disease is that although dopamine is produced in several areas of the body including the brain in the substantia nigra and the ventral tegmental area, the VTA does not appear to be susceptible to over-expression of alpha synuclein. Which means there is yet another research area for the potential of grafting - or stem cell therapy.  Moreover, not that much dopamine is metabolized to norepinephrine which explains why PD may not begin officially until the number of norepinephrine neurons also diminish.

But that's not our question for today. What do we know know about saving dopamine neurons in the substantia nigra?

Mouse PD models have already demonstrated that cell "rejuvenation" protects neurons in studies at Northwestern University.  Most human cells use either potassium or sodium channels when they are young but as the body ages, the dopamine cells switch to calcium channels. By blocking the calcium channel may give the cell a chance to rest and recover which is healthier than cell death and essential for PD.  In 2007 Steve read at least two abstracts by Dr DJ Surmeier etal about this very subject.
In the first abstract it was the statement: "Our studies suggest that the unusual reliance of these neurons on L-type Ca(v)1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression." 
And in the second:
"The Ca(2+) channels underlying autonomous activity in dopaminergic neurons are closely related to the L-type channels found in the heart and smooth muscle. Systemic administration of isradipine, a dihydropyridine blocker of L-type channels, forces dopaminergic neurons in rodents to revert to a juvenile, Ca(2+)-independent mechanism to generate autonomous activity. More importantly, reversion confers protection against toxins that produce experimental parkinsonism, pointing to a potential neuroprotective strategy for Parkinson's disease with a drug class that has been used safely in human beings for decades."

In order to stay on target we have to mention the arguments. 
From DJ Surmeier in Neuron: "The controversy about whether dopamine contributes to cell loss in Parkinson's disease takes a new turn as Mosharov et al. in this issue of Neuron demonstrate that Ca2+ influx through L-type channels elevates dopamine synthesis to potentially toxic levels in vulnerable ventral mesencephalon neurons."

In the study entitled "Interplay between Cytosolic Dopamin(e), Calcium, and alpha-synuclein causes selective death of Substantia Nigra Neurons"
"They attribute this specific elevation of cytosolic dopamine in SN neurons to the presence of a pace-making L-type calcium channel as a source of calcium entry, present in SN, but not VTA, neurons. Blockade of this channel, as well as treatment with intracellular calcium chelators protects SN neurons from cytosolic dopamine build-up....the pace-making L-type Ca channel may prove to be a useful therapeutic target in PD"
Faculty of 1000 Biology: evaluations for Mosharov EV et al Neurorn 2009 62 :218-229
 
We've written before about the studies which found that neurons die because calcium channels lead to an increase of dopamine inside the cell; excess dopamine then reacts with alpha-synuclein to form inactive complexes; and then the complexes gum up the cell's ability to dispose of toxic waste accumulating in the cell over time. The waste eventually kills the cell. Put another way, Dopamine in presynaptic terminals prior leaving the vesicle, signal the post synaptic terminal.  "A better treatment may be to push more dopamine into the compartments where it has no toxic effect on the cell" according to Eugene Mosharov, Ph.D., associate research scientist, and David Sulzer, Ph.D., professor of neurology; psychiatry at Columbia University Medical Center.

The question is why? And that is the answer being sought in the Calcium Channel inhibitor research - does the Ca inhibitor restore a more youthful saline condition to the cell in order to prevent cytosolic death?  And if so what is required of that inhibitor?  It has been proposed that the inflow of calcium is the last pathway "for irreversible neuronal injury" because the oxidative stress of free radicals "prevents neurons from maintaining ionic homeostasis."  One result is that neuronal depolarization triggers an action potential which opens the Ca channels. So what we need is a way to prevent the floodgates from opening to cause that neuron damage.

The first thing that this CCB must be able to do is get to the brain in order to work. Crossing the blood brain barrier (BBB) depends upon lipid solubility of small molecular size. To be lipid soluble means that it must be rendered more polar by metabolism prior to excretion in urine. Where can we find those small lipid soluble molecules? 
 
Within the dihydropyridine class of CCBs is a subtype of L-type (L representing long-lasting length of activation - slow CA channels in the cell membranes) voltage-gated calcium channel blockers. These L-type Ca blockers exert an anti-inflammatory effect and we know that some scientists have referred to PD as an inflammatory disease. As it happens, neurons which die in Parkinson's also contain a type of L-type calcium channel. CCBs affect SN neurons in a manner similar to the way they affect the heart. 
  
Now it happens that the channels are not identical.  In the substantia nigra we find a CaV1.3 channel.  The current drugs in the L-type class happen to prefer CaV1.2 channels so we aren't there yet.  As a matter of fact, there is an open door for more R&D in this area.  But if you have PD, you often try what is available. 
 
Research at Northwestern University, at Emory University, at Columbia University may find the precise answer.  Meanwhile at Northwestern Dr Surmeier has explained, "...partial blockade of Cav1.3 channels is sufficient to provide protection against a toxin challenge... We also know from epidemiological studies (Becker et al., 2008 and a study by Ritz et al. in press) that dihydropyridine use for hypertension is associated with a significantly reduced risk of Parkinson’s disease...If it turns out that more complete antagonism of Cav1.3 channels is necessary to achieve protection in humans, then more selective drugs would have to be developed that spare the cardiovascular system."

Of the dihydropyridine class (note that they all end in "dipine"), the L-type inhibitors which cross the blood brain barrier are: Amlodopine, Azenlnipidine, Clevidipine, Felodipine, Isradipine, Nicardipine, Nefedipine and Nimodipine.

additional reading:
Neurons and action potential - scroll down the page
Neurotransmitters and their molecules  
Brain diagrams: the basal ganglia and the cerebellum  sorry to say this link no longer works
A unique interactive brain diagram thanks to Open Colleges
Previous posts and comments:
The PD Triangle for cell death
DynaCirc or Isradipine - generic vs brand
Switching back to DynaCirc Cr      
The Future of Isradipine and PD

April is Parkinson's Awareness Month
Visit PDF for suggestions of group activities

And if you live in Northeast Ohio
There is a Benefit Recital
for Parkinson's Disease
to be given by Clair Allen, violinist
whose Father passed away earlier this year
following a long battle with PD.
Claire is dedicating her Senior Recital to his honor.
Donations will go to the Michael J Fox Foundation
to support Parkinson's research.
Works by Schumann, Bach, Dvorak and Bartok
Sunday, April 11th, 2010 at 2:00pm
To make a donation follow the links at TeamFox.org

1 comment:

  1. Recent medical developments might help ease out the chemical reaction happening.

    ReplyDelete

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