Friday, December 24, 2010

in which more evidence accumulates for utility of calcium channel blockers in treating Parkinson's disease

Neurodegeneration in Parkinson's disease is known to be specific to a group of dopamine neurons originating in the substantia nigra pars compacta (SNpc).  In  nearby region, the ventral tegmental area (VTA), dopamine neurons are all but unaffected by disease progression.  This selectivity has generated great interest from the PD research community.  In  a study out of Dr. D. James Surmeier's lab at Northwestern University, this selectivity was suggested to be related to calcium channel activity.

 Neural pacemaking, or the rhythmic signalling common to neurons in the motor circuit, involves the influx of calcium into the cell.  Pacemaking in juvenile SNpc dopamine neurons is similar to neurons in the VTA.  However, in mature SNpc neurons pacemaker firing opens many more L-type calcium channels than in VTA neurons.  This allows for greater influx of calcium to the cell, and puts a greater burden on the mitochondrial system in order to pump it out, fostering oxidative stress.  Therefore, basal oxidative stress is thought to be significantly higher in SNpc compared to VTA dopamine neurons.

The Surmeier team wanted to confirm the importance of the L-type calcium channel in producing the differences in oxidative stress levels between SNpc and VTA neurons.  In order to do this, they used a genetic knockout model of DJ-1 (or Park7), the popular gene linked to occurance of familiar Parkinson's disease.

In a beautiful study, they recorded intracellular calcium oscillations and oxidation of mitochondrial matrix proteins from SNpc dopamine neurons in mice with or without the DJ-1 gene, and found that oxidative stress was greater in SNpc neurons in DJ-1 knockouts compared to wild type.  They also showed that pretreatment with isradipine, an L-type calcium channel agonist, kept DJ-1 knockout oxidative stress levels near wild type levels.

The study also suggests that mitochondrial uncoupling protein (UCP) expression is greater in SNpc dopamine neurons compared to VTA, resulting in more frequent mitochondrial 'flickering', or transient depolarization.  In DJ-1 knockout mice, UCP expression was lower, suggesting that UCP expression in SNpc dopamine neurons contributes to oxidative stress.

Collectively, the restuls of the study indicate that high calcium entry to SNpc dopamine neurons through L-type channels during pacemaking activity leads to selectively elevated oxidative stress.  In turn, these SNpc dopamine neurons are made more susceptible to toxins, aging and the degenerative effects of DJ-1 mutations.  Several calcium blockers are currently used to treat conditions like cardiomyopathy and kidney disease, btu the current study suggests their use in Parkinson's disease in order to protect against oxidative stress to which these mature neurons are so vulnerable.
Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, & Surmeier DJ (2010). Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature, 468 (7324), 696-700 PMID: 21068725

Thursday, December 23, 2010

an instance of misconstrued media reporting: placebos

A most recent example of the media mis-representing scientific findings is the recent NPR report on placebos being equally effective in IBS patients as "the strongest prescription drugs", even when the patients knew that they were being given the placebo.  This coverage was a translation of a study out of Harvard Medical, and published in PLoS ONE.

The study, termed "honest placebo", didn't actually eliminate the deception for which placebo studies are renowned.  In the methodology, the researchers report telling the patients who received placebo treatment that “placebo pills, something like sugar pills, have been shown in rigorous clinical testing to produce significant mind-body self-healing processes.”  By this design, the patients may have received a similar benefit to what they would have experienced if they had expected that they were being given a strong prescription drug.  The patients were given the impression that the placebo would help them.  What would have contributed even greater meaning to this study is an additional group who were told that they were receiving a placebo drug, but not told that it was expected to help them.

As many of the comments on the NPR report echo, a strong component in placebo studies is the idea of holism and self-healing.  Dr. Ted Kaptchuk, a co-investigator in the Harvard study, states in his interview that the healing factor was assumed to be the "self-healing ritual" of dosing oneself twice daily, even with a placebo.  This scientist would suggest that self-healing is as likely to take place due to the belief that a placebo had been reported helpful as it is to be due to the ritual of pill-taking.

The great value of this study's conclusions is lost in the media translation: there is healing potential in having the expectation that your therapy will work. 
 NPR does the courtesy of acknowledging that "placebos don't shrink tumors or stop multiple sclerosis in its tracks".  However, particularly for conditions such as IBS, which have consistently shown to be negatively effected by stress and proactive treatment, this study's findings are important to treatment development.

ResearchBlogging.orgTed J. Kaptchuk, Elizabeth Friedlander, John M. Kelley, M. Norma Sanchez, Efi Kokkotou, Joyce P. Singer, Magda Kowalczykowski, Franklin G. Miller, Irving Kirsch, Anthony J. Lembo (2010). Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome PLoS

Thursday, December 2, 2010

VEGF-B as a therapeutic intervention for Parkinson's disease

Since it was discovered that the brain had tremendous neuroregenerative potential, growth factors have been highly speculated as therapeutic tools.  The vascular endothilial growth factor (VEGF) family, and particularly VEGF-B, has recently been distinguished as having a neuroprotective role in the Parkinsonian brain.

Carolina Hagberg et al. published the findings in Nature Letters earlier this year that VEGF-B was tightly co-expressed with several mitochondrial genes, suggesting a role for this growth factor in metabolism.  VEGF-B was specifically found to regulate endothilial fatty acid transport (uptake) proteins, and thus, the uptake of fatty acids into peripheral and heart muscle, and brown adipose tissue.  The co-expression of VEGF-B and mitochondrial proteins suggests a coordination of endothilial lipid uptake and mitochondrial lipid use, which is why it is an attractive intervention for PD, wherein it is thought that dopaminergic neurons die by dysfunction of mitochondrial metabolism.

This mechanistic information provides support for work lead by Torsten Falk at the University of Arizona suggesting a role for VEGF-B in the Parkinsonian brain.  In a 2009 study, a midbrain cell culture showed upregulation of the VEGF-B gene following treatment with rotenone (a pesticide specifically toxic to dopaminergic neurons, and commonly used in non-primate animal models of PD).  Additionally, application of exogenous VEGF-B to cell cultures resulted in neuroprotection from rotenone toxicity.

More recently, Falk et al. have shown exogenous VEGF-B to be neuroprotective in vivo.  From a 2006 study by Sun et al., intraventricularly administered VEGF-B restored neurogenesis to wild-type levels in VEGF-B knockout mice.

In corroboration with the Hagberg study, there is a strong suggestion that VEGF-B may be neuroregenerative via direct effect on mitochondrial function.  Correlative studies associating VEGF-B expression with midbrain mitochondrial un-coupling proteins, Complex I, or apoptotic cascades remain to be seen.  Additionally, there are no reports of VEGF-B's capacity to be neurorestorative, or slow dopaminergic neurodegeneration in a progressive PD model.
Hagberg, C., Falkevall, A., Wang, X., Larsson, E., Huusko, J., Nilsson, I., van Meeteren, L., Samen, E., Lu, L., Vanwildemeersch, M., Klar, J., Genove, G., Pietras, K., Stone-Elander, S., Claesson-Welsh, L., Ylä-Herttuala, S., Lindahl, P., & Eriksson, U. (2010). Vascular endothelial growth factor B controls endothelial fatty acid uptake Nature, 464 (7290), 917-921 DOI: 10.1038/nature08945

T. A. FALK, X. YUE, S. ZHANG, S. J. SHERMAN (2010). Evidence for neuroprotection after treatment with Vascular Endothelial Growth Factor-B in vivo in the 6-hydroxydopamine rat model of Parkinson’s disease Society for Neuroscience 2010 Abst.

Sun, Y., Jin, K., Childs, J., Xie, L., Mao, X., & Greenberg, D. (2006). Vascular endothelial growth factor-B (VEGFB) stimulates neurogenesis: Evidence from knockout mice and growth factor administration Developmental Biology, 289 (2), 329-335 DOI: 10.1016/j.ydbio.2005.10.016