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A New Piece of the Parkinson’s Puzzle

Here’s some more news on the Parkinson’s front, with a possible risk factor (and possible protective agent) both coming from an unexpected direction. It’s been known for quite a while now that the alpha-synuclein protein is deeply involved in the pathology of the disease – precipitated masses of it are found apparently killing off cells in the affected region of the brain (it’s the main constituent of Lewy bodies), and people with higher copy numbers of the gene for it are at greater risk for developing the disease in the first place. But just what goes wrong with its production and handling in Parkinson’s is still a matter of debate.

A large multicountry research team reports that the beta-2 receptor, of all things, is a regulator of the SNCA gene that codes for the synuclein protein. A screen for alpha-synuclein protein expression was developed in neuronal cell cultures, and on testing a large selection of known drugs and biomolecules, metaproteronol (a beta-2 agonist) turned out to significantly lower the levels of the protein and its associated mRNA. Other beta-2 agonists replicated the result, fortunately including ones with better brain penetration, and with these the effect also carried over into whole-animal studies in mice. It worked the other way, too – propranolol, a classic beta-antagonist, actually raised alpha-synuclein levels in the same fashion. The same effects were even more pronounced in cells derived  from a patient carrying a triplication of the SNCA gene, and administration of an agonist even protects mice neurons to exposure to MPTP, the classic Parkinson’s-inducing model. Digging deeper, this all seems to be mediated by epigenetic marking (acetylation) on lysine-27 of histone-3 protein, which the promoter region of the SNCA gene appears to be very sensitive to.

What’s most remarkable about this paper, though, is that it comes with human data. “How so?”, you’re probably wondering, given the time and expense it takes to get a trial launched. But the Norwegian co-authors provide data from that country’s public health system. Scanning across the entire population of Norway, they find that use of salbutamol (a common beta-2 agonist, often prescribed for asthma) is associated with lower risk of Parkinson’s, and that propranolol, the antagonist, is associated with an even higher risk of developing the disease. The team does a good job of trying to account for other possible confounding factors (asthma itself, education and economic levels, history of smoking and other risk factors, etc.), and the correlations stand up to all of these.

This is definitely something to think about, then. A trial of beta-adrenoceptor ligands in Parkinson’s patients would be comparatively easy to get off the ground, and I hope that something like this is in the works now. It’s going to be a balancing act between their apparent effects on alpha-synuclein and their other effects (cardiovascular, etc.), but this hypothesis is very much worth testing. And if it continues to hold up, then it’s likely to affect clinical practice, too – at the very least, anyone who might be otherwise at risk for Parkinson’s should avoid beta-antagonists.

27 comments on “A New Piece of the Parkinson’s Puzzle”

  1. Pharminthecountry says:

    Very interesting Derek, especially the healthcare data. You have a typo in para 3… “propranolol, the agonist, is associated with an even higher risk” – propranolol is an antagonist, as you note elsewhere.

    1. Derek Lowe says:

      Typoed it while eating breakfast at the same time. At least I got it right in the paragraphs above that part! Thanks.

  2. whitequark says:

    Are you sure you didn’t mix up “agonist” and “antagonist” in a few places? I don’t understand the logic otherwise.

    > Administration of an antagonist even protects mice neurons to exposure to MPTP, the classic Parkinson’s-inducing model

    If a beta-2 antagonist induces SNCA, shouldn’t it sensitize neurons to MPTP?

    > and that propranolol, the agonist, is associated with an even higher risk of developing the disease

    Propranolol is a beta-2 antagonist…

    1. Derek Lowe says:

      A typo, now fixed – which should come as a relief, since indeed it makes no sense as written.

  3. Anon says:

    typo: …that propranolol, the ANTagonist, is associated…

  4. luysii says:

    Because I started treating people with Parkinson’s disease when it was first became available in the USA (1972), I read everything I could about it when in practice. Beta-2 agonists had been tried before. So I sent the lead author the following

    Dr. Snyder:

    A small study on 8 patients with Parkinson’s disease gave Albuterol because beta adrenergic drugs were said to increase the transort of aromatic and branched chain amino acids into the brain, hopefully increasing the amount of dopamine present [ Neurology vol. 44 pp. 1511 – 1513 ’94 ]. All showed improvement. 3/8 were still taking the medication at the time of publication. I found it surprising as one would expect adrenergic drugs to worsen tremor. As far as I can tell nothing was done in followup.

    He responded

    Very interesting observation. Thanks for bringing this paper to my attention. I will look into it. It does seem likely that a much larger clinical trial looking at beta-agents will be in the offing. The mechanism of action you cited is interesting and I likely should have mentioned it as a potential basis for the reported observations.
    Thanks again for your interest and thoughtful response.
    Cheers,
    Evan

    1. SquirrelPhilips says:

      See also Clinical Neuropharmacology. 26(4):207-12, JUL 2003

      ” This open-label pilot study suggests that albuterol increases muscle mass and improves the therapeutic response to levodopa in patients with fluctuating PD. A double-blind, placebo-controlled study is needed to confirm the effects and safety profile of beta(2)-agonists in PD.”

      Presumably the salbutamol-users in this Science paper were administered through an inhaler device. The direct inhalation has an excellent and rapid effect on bronchioles, but I wonder if this is necessarily the best route of administration for PD patients, and what improvements could be made using oral/IV administration. Either way, salbutamol is going to hit a lot of other targets along the way.

      1. Barry says:

        It was my understanding that salbutamol was given by inhaler to spare the patient the adverse effects of systemic beta-agonism. Finding a beta-agonist that acts behind the blood-brain-barrier but but not in the periphery (if that’s what’s indicated) would be very difficult.
        But maybe a beta-agonist that gets across the blood-brain-barrier could be balanced against a beta-antagonist that doesn’t get across?

  5. Peter S. Shenkin says:

    In the early stages of my wife’s Parkinson’s, she was prescribed propranolol to mitigate the symptoms. Apparently, it’s commonly used. She wasn’t on it for long. Apparently, short-term mitigation works in a direction opposite to long-term deleterious effects.

  6. Dario says:

    Very interesting!

    Incidentally, the website of the Norwegian Prescription Database (http://www.norpd.no) is currently unavailable, probably due to the multiple requests

  7. David says:

    Public health data for the win!

  8. milkshaken says:

    two comments of caution on Parkinson: 1) MPTP model in mice is not reliable, mice do not have the same transport mechanism to dopaminergic neurons as primates and they also lack MAO needed for activation of MPTP to active metabolite MPP+ You can kill neurons in mouse brain by giving them much higher relative dose of MPTP but the produced lesions are a poor analog of Parkinson. You would needed to use monkeys with MPTP, or a different neurotoxin with mice. 2)By the time Parkinson manifests itself maybe 80 or 90% of dopamine-producing neurons is already dead and he rest is not doing great either, the underlying neurodegeneration has been ongoing for many years already. It is important not to have unrealistic expectations. But maybe if you could stop the remaining neurons from dying and prevent inflammation and vascular disease that they can very slowly regenerate, and this would stabilize the patients

    1. luysii says:

      The humans who took MPTP developed very severe Parkinsonism almost immediately. Their suffering told us a lot about the side effects of L-DOPA (on off effects, dyskinesia). They had the side effects almost immediately showing that they were a symptom due to disease severity and not some weird toxic long term toxic effect of L-DOPA. As mentioned above, L-DOPA is purely symptomatic treatment, while all the time dopamine neurons continue dying.

  9. pete says:

    What surprises me about the propranolol risk is that it hasn’t been noted before. For example, propranolol is commonly prescribed for reducing tremor among pts. with Essential Tremor, aka Benign or Familial Tremor. That’s a big enough patient population that you’d think clinicians might have seen a disturbing trend toward flipping into Parkinsonism based on chronic high doses of propranolol, or of similar beta-antagonists.

    1. tangent says:

      It would be interesting to collect historical examples, how big a relative risk does it take for clinicians to notice the effect out of the blue? Or how big an effect size for a non-binary outcome.

  10. John Francini says:

    Since the article is paywalled, I have a question for Derek, Luysii, or others who have read it. Is there any indication in the report of how much additional risk above baseline the Norwegian co-authors saw of developing PD when taking propranolol (Inderal in the US) long term for blood pressure control/migraine prevention?

    1. luysii says:

      I had a bunch of people with essential tremor on Inderal followed for ‘up to’ 15 years. None developed Parkinsonism.

  11. Peter S. Shenkin says:

    What I find is that the most common side effect of salbutamol is tremors; yet long-term, it lowers the likelihood of getting Parkinson’s. With propanolol, it’s the opposite. It’s used in early-stage Parkinson’s (as well, as noted above by @pete, for Essential Tremor) because it reduces tremor; yet long-term, in increases the likelihood of getting Parkinson’s.

  12. Peter S. Shenkin says:

    (I meant to say, “What I find interesting”….)

  13. sonicare says:

    salbutamol use can have short and long term refractory effects on pulmonary receptors. Makes me wonder if it also downregulates receptors involved in PD pathology

  14. Ann says:

    Norwegians may not be a typical population of salbutamol users. They are born on cross country skis and are very fit as a population. I suspect that more Norwegians are prescribed salbutamol because of exercise- and cold air-induced asthma than you might find in the population of the USA or most of Europe. It will be interesting to find out if the large effect of long-term salbutamol is seen elsewhere.

    1. pete says:

      @Ann — good point, esp. in light of the neuro-protective benefits of exercise.

  15. sgcox says:

    Looks like transcription suppression by beta-2 agonists is not limited to alpha-syn in neurons. Here is a very recent paper about a completly different system. Looks like the real thing !
    https://www.ncbi.nlm.nih.gov/pubmed/28870238
    Raises the question abut general side effects of long term use though..

    1. tangent says:

      First Law of Drugging: Everything Hits Everything.

      It’s a weirdly small world out there.

  16. sailbillcom says:

    In 2009 my PCP diagnosed my then-slight hand tremor as ET-familial and prescribed propranolol. This was 90% effective for two weeks, then quickly lost effect. Follow-up testing by a neurologist yielded a definitive (90% certainty) diagnosis of PD.

  17. Barry says:

    There’s an opportunity for someone to bring a new-generation beta-blocker to market with reduced brain penetrance. But I don’t know that the proper clinical study could be run ethically in the U.S., if the expectation is that the control would suffer increased risk of PD. And such a study would have to run many years.

  18. Barry says:

    When beta-adrenergic signals stop,
    synuclein expression compensates
    although systolic pressure’s quick to drop,
    grey Lewys body gunk accumulates.
    Substantia nigra’s killed off year by year
    asymptomatic ’til it’s almost dead
    until the tremors suddenly appear
    and dopa must come in PO, instead.
    ‘Though anti-hypertensives quell stage-fright
    they take a toll within our CNS
    musicians damping down their “fight or flight”
    can compromise their motor fine finesse.
    Such pharmacology’s a parlous art
    to balance risk, and salve to head, and heart.

    http://mobilesonnets.blogspot.com/search/label/biology

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