Saturday, 27 May 2017

GABA and Remyelination-Its Confusing I know but no cause for concern

Yesterday I caused a bit of concern by a post on myelination as a GABA (inhibitory nerve transmitter) blocker stimulated developmental myelination, so people were worried about their GABA receptor stimulating drugs. Would they block repair? Answer is I do not definitively know but suspect not.

In contrast there could be implications that stimulation of GABA could save nerves. Again we don't have the data.

I will try explain a bit, but it is very, very complicated.

First things first, the report of GABAergic control of myelination is based on developmental myelination (myelinating nerves from the first time), and as the docs from Cambridge/Edinburgh have shown remyelination may not be the same process as developmental myelination.

Next it is far more complex than just GABA. What else has to be stimulated?

We have already been told that the oligodendrocyte precursor cells get stimulated by glutamate (excitatory nerve transmitter). This transmits their function via activity on glutamate receptors. Here there are lots of types, over twenty receptor genes.  There are three main ionotrophic (opens channels for electrically charged (ion) sodium calcium or potassium) subtypes AMPA, Kainate and NMDA binding subtypes

Myelination first acts via the AMPA sensitive variants, then their influence stops whilst the NMDA-sensitive subtypes come into play. This process will be influenced by the GABA receptors. This stimulates developmental maturation of the oligodendrocyte precursor cell and myelination of un-myelinated nerves. During this process the glutamate receptors and ion channels get down regulated. It is not the odd one, but loads of them.
Here are the potassium channelsN) or should I say some as I got bored and stopped at about M  ie. KCNM) but could have gone on eg  KCNN etc

Next there are more than one type of GABA receptor. There are two main types. One is GABA A and the other is GABAB. GABA A is an ionotrophic (via chloride) channel that can be stimulated by different types of drug as it has multiple sites and there are multiple genes making a multi-component receptor.

GABA B is a metabotrophic receptor which G protein coupled receptor that is linked signalling to control calcium channel activity and can signal via potassium channels.

Baclofen is the main GABA B receptor stimulator, used for spasticity. GABApentin, Pregabalin look like GABA but do not bind to the GABA receptors, although they may influence GABA production they act via ion channels to be ant-convulsants and pain controllers. The story about GABA and oligodendrocytes involved GABA A receptors, so the story is not about these drugs

Indeed in the experimental study they blocked the GABA response with a drug called Gabazine (SR-95531). It is used in scientific research and has no role in medicine, as it would be expected to produce convulsions. 

Any drug used in humans would never block the GABA A receptor to the extent used in the experiments so a block would never happen in humans. Experimental studies often use crazy doses of drugs to show a theorhectic possibility or define a mechanism. But they have no translational value. 

If the authors had read the ARRIVE guidelines about reporting experimental studies, they could have talked about the translatable aspects and if they had used clinical concentrations of GABA A blocking drugs, I bet they would have shown nothing...Nothing does not make for a good publication. But until this expriment is done, no cause for concern.

The importance of this post was to show that oligodendrocytes have ionotrophic function and they have loads of ion channels including loads of potassium channels.

#PatientSpeak: I have primary progressive MS ..........

I am preparing myself to let my patients with PPMS down. Are you? #PatientSpeak, #MSBlog #Ocrelizumab

I saw one of my patients the other day who has PPMS. His disability is worsening and clearly wants something done about it. He was very excited about the news that the FDA had licensed ocrelizumab for PPMS and wanted to know when ocrelizumab would be available under the NHS. I explained to him that ocrelizumab had yet to be licensed by the EMA and as the EMA tends to be more conservative than the FDA it wasn't certain by any means that it would be licensed in Europe for PPMS.  Even if ocrelizumab is licensed for PPMS, I suspect the EMA won't give it as broad a label as the FDA has done and may limit it to a particular population of pwPPMS. If this happens I informed this patient he may fall outside of the licensed indication, for example his PPMS may not be active enough. 

In addition, if and when the EMA licenses ocrelizumab for PPMS then NICE has to green-light it for use in the NHS. The latter may be a problem, particularly if ocrelizumab is priced to be cost-effective for RRMS. At the RRMS price NICE will need to compare it to best supportive care (no DMT) for PPMS and it is unlikely to be cost-effective using this comparator. I have been arguing for sometime now that this may be the time for Pharma to explore differential pricing and charge the NHS less when ocrelizumab is prescribed for PPMS. 

When I told this patient about the various hurdles that will need to be overcome for me to prescribe ocrelizumab for him he was very disappointed, so I asked him to put something down in words to start a conversation with other pwPPMS who live in Europe. 

Please note that Mark has given me permission to publish his name. In fact Mark sits on the Barts-MS Advisory Group and wrote a blog post on this in December 2015

A patient-with-PPMS's Perspective on Ocrelizumab

"Some 4 months after I was diagnosed with PPMS in May 2008, I remember speaking to a man who had had MS for a number of years and he said that I would be one of the lucky ones – there would be treatment for PPMS in the next ten years or so. I have always remembered this but of course with less and less conviction as the years have gone by. Now I think I will be just another of the countless unlucky ones, there will be no treatment for me.

So when Ocrelizumab was announced as a possible treatment for PPMS I was overjoyed and thought, you know, maybe he was indeed correct. However, as ever with this disease any joy is always mixed with disappointment and so it was when I discovered that I was too old to be considered for the trial – I was 57. This was a bitter disappointment as I do not consider myself to be old, let alone too old. Indeed I have taken part in 3 trials since being diagnosed, I am generally fit, look after myself, lost weight, go to the physio twice weekly and maintain a good positive outlook. I do “my bit” but, there you are, I am too old.

Following the Ocrelizumab trials I like others with PPMS are very keen for the drug to licensed as currently it is our only hope. I understand that whilst it is not particularly effective where MS has taken a hold - eg on the lower limbs, it is effective on the upper limbs. For this reason alone it should be prescribed as our upper limbs must be saved they act as our legs by allowing us to use a stick and maintain some independence by using mobility scooters and other aids. Once our arms are as stiff as our legs we are effectively quadriplegic - if that can be avoided or at least delayed then surely we should have the drug. After all if there was a cancer treatment that whist not effective on the primary tumour but reduced or delayed the spread of secondary tumours, I am sure that would be licensed."

Mark Harrington, May 2017, London

Friday, 26 May 2017

#BrainHealth: a brain health guide for nurses

CMSC launch of our #BrainHealth guide for MS nurse specialists. #CMSC2017 

The main focus of the CMSC meeting is CME (continuing medical education) for allied medical professionals in particular MS clinical nurse specialists. For this reason we have used this meeting to launch our Brain Health guide for MS specialist nurses, or nurse practitioners as they are frequently referred to in the US. Please download the guide, read it and use it in your clinical practice. 

Jodi Haartsen
MS Brain Health Champion & MS Nurse Practitioner extraordinaire, 

on our Brain Health stand at the CMSC in New Orleans.

CoI: multiple

First case of PML on Ocrelizumab reported

We have been saying one of the important considerations when starting treatment is how do you switch off your drug, we reported rebound after fingolimod and this is a well known problem with Natalizumab. PML is the other major problem with natalizumab.

The first case of PML on ocrelizumab has been reported. Again one suspects that subclinical PML due to natalizumab was the problem. According to Media the case occurred in a JC virus-positive pwMS who had stopped taking natalizumab in February after being on the drug for three years, and switched to ocrelizumab with a first dose given in April. Ocrelizumab is not licenced within Europe but it was apparently used in Germany where the case occurred.

ProfG will no doubt get the details, but perhaps not the news you want when going to the regulators to get approval for use in Europe.

GABA controls oligodendrocytes

Hamilton NB, Clarke LE, Arancibia-Carcamo IL, Kougioumtzidou E, Matthey M, Káradóttir R, Whiteley L, Bergersen LH, Richardson WD, Attwell D. Endogenous GABA controls oligodendrocyte lineage cell number, myelination, and CNS internode length. Glia. 2017;65(2):309-321

Adjusting the thickness and internodal length of the myelin sheath is a mechanism for tuning the conduction velocity of axons to match computational needs. Interactions between oligodendrocyte precursor cells (OPCs) and developing axons regulate the formation of myelin around axons. We now show, using organotypic cerebral cortex slices from mice expressing eGFP in Sox10-positive oligodendrocytes, that endogenously released GABA, acting on GABAA receptors, greatly reduces the number of oligodendrocyte lineage cells. The decrease in oligodendrocyte number correlates with a reduction in the amount of myelination but also an increase in internode length, a parameter previously thought to be set by the axon diameter or to be a property intrinsic to oligodendrocytes. Importantly, while TTX block of neuronal activity had no effect on oligodendrocyte lineage cell number when applied alone, it was able to completely abolish the effect of blocking GABAA receptors, suggesting that control of myelination by endogenous GABA may require a permissive factor to be released from axons. In contrast, block of AMPA/KA receptors had no effect on oligodendrocyte lineage cell number or myelination. These results imply that, during development, GABA can act as a local environmental cue to control myelination and thus influence the conduction velocity of action potentials within the CNS.

GABA is the major inhibitory neurotransmitter and blocks signals from excitatory nerves such as glutamate. A few years ago, it was found that oligodendrocyte precursors have glutamate receptors and when these get stimulated it probably acts as a signal to the oligodendrocyte precursor cells to change into an oligodendrocyte and to start myelination. The glutamate is essentially a calcium channel making the inside of the  cell more electrically positive. however blocking this made no infuence on cell numbers. However, if you stimulate with GABA A which is a chloride channel meaning the inside becomes more electrically negative you get less oligos and less myelination. Is there any evidence that benzodiazepines block or stimulate myelination ?  Don't think so, but have people looked ?.