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.

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