Sunday, 30 August 2015

GABA as a neuroprotectant

Cawley N, Solanky BS, Muhlert N, Tur C, Edden RA, Wheeler-Kingshott CA, Miller DH, Thompson AJ, Ciccarelli O Reduced gamma-aminobutyric acid concentration is associated with physical disability in progressivemultiple sclerosis.Brain. 2015;138(Pt 9):2584-95. doi: 10.1093/brain/awv209.

Neurodegeneration is thought to be the major cause of ongoing, irreversible disability in progressive stages of multiple sclerosis. Gamma-aminobutyric acid is the principle inhibitory neurotransmitter in the brain. The aims of this study were to investigate if gamma-aminobutyric acid levels (i) are abnormal in patients with secondary progressive multiple sclerosis compared with healthy controls; and (ii) correlate with physical and cognitive performance in this patient population. Thirty patients with secondary progressive multiple sclerosis and 17 healthy control subjects underwent magnetic resonance spectroscopy at 3 T, to quantify gamma-aminobutyric acid levels in the prefrontal cortex, right hippocampus and left sensorimotor cortex. All subjects were assessed clinically and underwent a cognitive assessment. Multiple linear regression models were used to compare differences in gamma-aminobutyric acid concentrations between patients and controls adjusting for age, gender and tissue fractions within each spectroscopic voxel. When compared with controls, patients performed significantly worse on all motor and sensory tests, and were cognitively impaired in processing speed and verbal memory. Patients had significantly lower gamma-aminobutyric acid levels in the hippocampus (adjusted difference = -0.403 mM, 95% confidence intervals -0.792, -0.014, P = 0.043) and sensorimotor cortex (adjusted difference = -0.385 mM, 95% confidence intervals -0.667, -0.104, P = 0.009) compared with controls. In patients, reduced motor function in the right upper and lower limb was associated with lower gamma-aminobutyric acid concentration in the sensorimotor cortex. Specifically for each unit decrease in gamma-aminobutyric acid levels (in mM), there was a predicted -10.86 (95% confidence intervals -16.786 to -4.482) decrease in grip strength (kg force) (P < 0.001) and -8.74 (95% confidence intervals -13.943 to -3.015) decrease in muscle strength (P < 0.006). This study suggests that reduced gamma-aminobutyric acid levels reflect pathological abnormalities that may play a role in determining physical disability. These abnormalities may include decreases in the pre- and post-synaptic components of gamma-aminobutyric acid neurotransmission and in the density of inhibitory neurons. Additionally, the reduced gamma-aminobutyric acid concentration may contribute to the neurodegenerative process, resulting in increased firing of axons, with consequent increased energy demands, which may lead to neuroaxonal degeneration and loss of the compensatory mechanisms that maintain motor function. This study supports the idea that modulation of gamma-aminobutyric acid neurotransmission may be an important target for neuroprotection in multiple sclerosis.

So what this study says is is the GABA (an inhibitory neurotransmitter) levels may be associated with progressive disease. If you can image GABA you will see that people with low GABA are more likely to be progressive. Is this surprising?

It has been suggested, well over a decade ago, that too much nerve excitation can cause nerve damage. This is called excitotoxicity and is one of the nerve damaging mechanisms of stroke and it also believed to be part of MS. This was suggested following EAE in studies over a decade ago.

So what did this mean? 

Well if you block glutamate the major excitable neurotransmitter then it should block excitotoxicity. The only problem is that you need nerve function to live and if you block nerve function there are side effects. In fact quiet a lot of side effects. Anyone working with animals will tell you that is you block the AMPA glutamate receptors there are side-effects.

I wonder why company efforts to use AMPA antagonists have gone no-where?  Pharma make super strong blockers and in animals these types of drugs stop the receptors functioning and so they are useless. But weak blockers are what is needed for this type of target

So the other way to block glutamate is to block NMDA glutamate receptors and again if you use super strong antagonists it will send you doolally. There are some weak anatagonists and memantine is one of them. This drug can experimentally be shown to save nerves, but in the clinic this has not really been shown and again the problem is the balance of effect verses side-effect.

So if blocking the excitatory pathway has the problem of side effects then an alternative way is to boost the inhibitory pathways and the major inhibitory nerve is GABA.

It has long been known that MS there is often an imbalance of gluatamate and GABA and this an other studies indicate that people who progress more have lost GABAergic nerves and so the balance means there is less inhibition which will lead to more excitation and could lead to more nerve damage. This could be at the level of blocking energy deficits that were found some time ago and shown that GABA could block respiratory chain deficits in the mitochondria creating less energy loss so that nerves are better able to tolerate nerve insults.

The obvious lead on from this is that you can enhance GABAergic stimulation and this should be neuroprotective.

What may shock you is that despite thousands of people taking baclofen, there is no data I am aware of on whether it slows the development of MS. This is because pharma and neuros don't follow the people to collect this type of data, because it is viewed as a symptom control drug.

If there was a registry to which people with MS signed up to like the MS register (please sign up) which had access to treatment information may get this information in a few seconds. However, people with more advanced disease are more likely to have spasticity and will therefore be more likely to take baclofen.

Is GABA agonism neuroprotective in animals, it is already known that it can be but GABA is sedating, so it has be brought into the equation as sedation is stressful for animals and this is immunomodulatory. 

Will we be seeing a neuroprotective baclofen/GABApentin etc, trial? 

I suspect that baclofen is neuroprotective may slow progression, so you may have a useful drug already...but is it enough? 

I suscpect the answer is likely to be no because progression is not stopped in people taking baclofen. What is your experience?

However remember the treatment pyramid and you want to layer neuroprotection on top of effective immunomodulation.

27 comments:

  1. MD, why do you spoil everything? I saw the title of this paper and the names of the researchers and felt positive. Then your note decimated any hope I had. Were you bullied at school? Surely we can have one research paper where you can say "great research, didn't spot this in EAE, should make a real difference to people with MS". You should head off to the Notting Hill carnival, come back and stroke your mice, and add a positive not to the next research paper.

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    1. Bullied at school....No.

      I am not sure why you are so negative and downbeat.

      The plus point is that people who have been taking baclofen for their spasticity have probably unknowingly been protecting their nerves (although this has yet to be prooved)...so you have access to a neuroprotective without having to wait for 10 years....surely this is very positive news?

      P.S. We spot things in EAE because we do stuff years before things advance in the clinic and we read and assimilate too.

      P.S. It may be a bad habit to simply associate names with happy....as your bubble will get burst.:-(

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    2. M.D. knows all the flaws with other peoples studies, but he has no clue about the causes of M.S. it's a safe position to be in.

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    3. we are talking clues to the cause of neurodegeneration...we have plenty of ideas and some have already shown merit

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  2. Gabapentin and Baclofen, the big question would be the dosage, the person would like the Zombies Walking Dead ... I at least felt like a zombie when used Gabapentin, at least helped them sleep fast ...

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    1. This is the potential problem of boosting inhibition....the zombie effect also know as the ragdoll effect. However, I believe we have a solution..just need to do the experiments to prove it.

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    2. But I felt that Gabapentin had some effect on the rapid improvement in my running since I had lost my leg strength esquerdac I used Gabapentin after the pulse surge that made me discover the EM in two weeks or so of physical therapy, Rebif, Vitamin D and Gabapentin I had regained strength and was walking normally. But I was still at the time the body tingles with the Gabapentin really helped a lot in this regard. My neuro even wanted me to have pursued with Gabapentin, only the tingling gone and I really felt very dizzy, and I've only took 01 tablet a day ... Will VSN16R of Canbex would have the same neuroprotective effect? I confess that when I read about on the VSN16R I was very interested because I keep playing sports, bodybuilding to be exact, and some sensations spastic sometimes appear ...

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    3. VSN16R is being developed as a symptomatic therapy e.g the use of baclofen and GABApentin is symptomatic treatment so any neuroprotective effect is hypothetical

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  3. I have foot drop and took baclofen night and day and Gabapentin night and day. I saw a FES consultant who weaned me off baclofen and stopped daytime Gabapentin. The only noticeable difference, I am more aware of where I am placing the foot with foot drop

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  4. This gets an "extremely helpful" vote from me; I'm always happy to hear of researchers applying their intelligence to the development of neuroprotectives.

    Baclofen's potential side effects don't sound too great though. "Side effects affect about 45% of people taking baclofen. These include drowsiness, fatigue, dizziness and difficulty sleeping. If the dose is too high, muscle tone can be reduced too much leading to weakness. Abrupt discontinuation may result in severe withdrawal symptoms, which include hallucinations and seizures, so discontinuation of treatment requires the gradual reduction of the daily dose." (http://www.mstrust.org.uk/atoz/baclofen.jsp)

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    1. Yep so we need to develop something that avoids these effects

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  5. I hate baclofen. Horrible drug. I will rather tolerate spasticity.

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    1. That is why we are trying to develop an alternative that lacks the side effect potential of baclofen

      We are recruiting now

      CoI. founders of canbex

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  6. Gabapentin aso appeared on the list of potentially remyelinating compounds in one of the published screens (I think oxcarbazapine was the min hit in that study)

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  7. Could this be why anxiety has been implicated in Ms?
    Along with EBV/ocd link

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  8. Would this also suggest pregabalin as a gaba agonist could possibly be neuroprotective

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  9. MD,

    This is an excellent exciting post; a quick Google returns that baclofen is in the same class as zolpidem. Is it possible that zolpidem might also be effective?

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  10. What study are you recruiting to? It would be great if a de-dopified Baclofen was found to be neuroprotective :-)

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    1. We have to prove that this approach is neuroprotective but this is the obvious approach to try to monitor

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    2. the study we are recruiting to is symptom control...hope to post clinical trials gov soon

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  11. Very happy to read this post as I take pregabalin 300mg and baclofen 60mg daily. Pregabalin at best takes the edge off horrible central pain, baclofen (to be honest) does very little for neck/upper back spasms/stiffness so am currently reducing dose to try without it. At least I might have been unknowingly neuroprotecting for the last 3 years!

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  12. When someone cannot sleep anymore from damage CNS includes spinal cord, GABA receptor and transmitterx SCN (Supra Chiasmatic Nucleus). Do you think death is the best solution than suffer and dying by never sleep anymore causing the deteroitation of the immune system that causing the unhealed damage to the organs and infections and the growth of the candidas? 3 month already not able to sleep (this is not insomnia, this is disability cause they are terminated). Wishing for euthanesia.

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    1. Re: "Wishing for euthanasia."

      Can I suggest you see your neurologist or specialist nurse there is a lot that can be done for insomnia.

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    2. Even though disturbed sleep and vivid dreams are frequently reported as a side effect (which does go away after a few weeks) I found the opposite happened for me with LDN. Within a week of starting LDN my very disturbed sleep patterns and insomnia and the 2am "wide awake and can't get back to sleep" bouts went away and have stayed away. I didn't get any of the other "miracles" that some others claim with LDN, but the good sleep I have had since starting on it has made a world of difference, so I have kept taking it despite the cost.

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