From Fatigue to saving nerves

F

Nerves can be activating or deliver inhibitory signals. The ones that excite often produce a molecule called gluatamate and the inhibitory one is called GABA. When you get spasticity, it can result from a change in the balance excitation and inhibition. You can try to block the excitation or augment the inhibition. For example which is what baclofen does. It increases the inhibition. You can image the presence of glutamate and GABA using magnetic resonance spectroscopy. In this study they found inbalances in the glutamate and GABA.

What can we do about this inbalance we can block the excitation but this can be sedating or one can augment the inhibition but this is also sedating. Also if you really block the excitatory glutamate receptors and you would do doolally. There are few thrapeutic drugs that hit this target and are very week inhibitors. If you are interested you can have a look at Memantine for Multiple Sclerosis: A Systematic Review and Meta-Analysis of Randomized Trials.Turalde CWR, Espiritu AI, Anlacan VMM.Front Neurol. 2021 Feb 15;11:574748

These glutamate work by allowing movement of calcium ions into the cell and as such they are called ionotrophic and the calcium ions help create the electrical activity that gets the nerves firing..

Altered in vivo brain GABA and glutamate levels are associated with multiple sclerosis central fatigue.Arm J, Oeltzschner G, Al-Iedani O, Lea R, Lechner-Scott J, Ramadan S.Eur J Radiol. 2021 Feb 24;137:109610. doi: 10.1016/j.ejrad.2021.109610. Online ahead of print.

Purpose: Fatigue is a common symptom in patients with multiple sclerosis (MS) with unknown pathophysiology. Dysfunction of the GABAergic/glutamatergic pathways involving inhibitory and excitatory neurotransmitters such as γ-aminobutyric acid (GABA) and glutamine + glutamate pool (Glx) have been implicated in several neurological disorders. This study is aimed to evaluate the potential role of GABA and Glx in the origin of central fatigue in relapse remitting MS (RRMS) patients.

Methods: 24 RRMS patients and 16 age- and sex-matched healthy controls (HC) were scanned using Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) with a 3 T system to quantify GABA+ and Glx from prefrontal (PFC) and sensorimotor (SMC) cortices. Self-reported fatigue status was measured on all participants using the Modified Fatigue Impact Scale (MFIS).

Results: RRMS patients had higher fatigue scores relative to HC (p ≤ 0.05). Compared to HC, Glx levels in RRMS patients were significantly decreased in SMC (p = 0.04). Significant correlations were found between fatigue scores and GABA+ (r = -0.531, p = 0.008) and Glx (r = 0.511, p = 0.018) in PFC. Physical fatigue was negatively correlated with GABA+ in SMC and PFC (r = -0.428 and -0.472 respectively, p ≤ 0.04) and positively with PFC Glx (r = 0.480, p = 0.028).

Conclusion: The associations between fatigue and GABA + and Glx suggest that there might be dysregulation of GABAergic/glutamatergic neurotransmission in the pathophysiological mechanism of central fatigue in MS.

So you may be interested the next paper. As not all glutamate receptors involve movement of ions there others that are called metabotropic gluatmate receptors there are alot of them. One is involved in have the natural cannabis work. Too much glutamate signalling may cause nerve damage. So this paper points out one possible new target

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with continuous neuronal loss. Treatment of clinical progression remains challenging due to lack of insights into inflammation-induced neurodegenerative pathways. Here, we show that an imbalance in the neuronal receptor interactome is driving glutamate excitotoxicity in neurons of MS patients and identify the MS risk–associated metabotropic glutamate receptor 8 (GRM8) as a decisive modulator. Mechanistically, GRM8 activation counteracted neuronal cAMP accumulation, thereby directly desensitizing the inositol 1,4,5-trisphosphate receptor (IP3R). This profoundly limited glutamate-induced calcium release from the endoplasmic reticulum and subsequent cell death. Notably, we found Grm8-deficient neurons to be more prone to glutamate excitotoxicity, whereas pharmacological activation of GRM8 augmented neuroprotection in mouse and human neurons as well as in a preclinical mouse model of MS. Thus, we demonstrate that GRM8 conveys neuronal resilience to CNS inflammation and is a promising neuroprotective target with broad therapeutic implicatio

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9 comments

  • Hope this wel come to therapeutic use in the not to far future. About spasticity; Baclofen, Botox, CBD oil did nothing. Crazy enough THC oil works amazing. It works almost as good as Fampridine, which gave me insomnia, THC does the opposite

    So i am now searching for good cannabis oil as this contains all the cannabinoids, see how that goes. Time to ask my doctor for drugs i guess

    • THC blocks calcium entry into nerve making it less excitable and also affects potassium channels making it less excitable

  • Could melatonin or 5-HTP supplementation help with this. I know there’s a study into melatonin supplementation in MS. It will be interesting to see the results.

    Good sleep obviously is important but a lot of things can effect your sleep cycle. The beneficial hormones released by your body naturally during sleep are more neuro protective than any drug.

    • Make sure you have a cup of cocoa before bed and wake up refreshed….maybe ProfG or NDG will report on this Coe S, Cossington J, Collett J, et al.
      A randomised double-blind placebo-controlled feasibility trial of flavonoid-rich cocoa for fatigue in people with relapsing and remitting multiple sclerosis.
      Journal of Neurology, Neurosurgery and Psychiatry 2019 Mar 4. [Epub ahead of print].

  • Hello,

    I take Fampridine, one 10mg pill twice a day, and some nights I find it very hard to fall asleep even though I am very tired. An added problem is that sometimes I suffer from restless legs. This could easily be interpreted as spasms.

    A large slug of rum does resolve the problem but this is not a long term solution. Increasing my Gabapentin intake at night from 60 mg to 90 or 120 mg seems to allow me to fall asleep much more easily, touch wood.

    Does the gabapentin inhibit the fampridine?

  • Thanks MD for a great article and nice to see spasticity taking a prominent role on the blog, even for a short time. This is the one MS symptom that has utterly restricted my life – all the others I can cope with, adjust to accommodate, or take meds for. This has been the force contributing to me going from EDSS 0 to 6 and controlling my quality of life, but it seems to be a rather neglected area of MS research. Everything I have tried to conquer spasticity has been a bad experience. Baclofen take large doses and cause brain fog and other ‘orrible side effects of which long term muscle loss is a problem. The heart is a muscle and its rather important, but its also affected by baclofen. Gabapentin in combination with somethign else is good causes intense dizziness. Sativex (medicinal cannabis, THC) affects how I think and gives regular stomach problems, and gave me permanent munchies (!) – while this is undoubtedly great for some people, its wasn’t for me. I also smelt of pot at work and this was commented on lots, and colleagues noted I had slowed down mentally. Tizanidine does some good but is not enough alone, and also means regular blood tests for known side effects. Botox is a pain to get, takes time to work, and for me hit optimum levels for a very short time period so was not worth the effort – I hear better success stories from others though. Combinations of Tizanidine and Baclofen, or Baclofen and Gabapentin as as good as its got for me, but long term its been a constant downhill trajectory. So, finding a new treatment that targets gluatamate and GABA responses and levels could be a breakthrough many of us with spasticity have been looking forwards to. If there are trials, I’d sign up like a shot.

    As calcium seems to be an important factor here, would ramping up calcium levels with mineral supplements have any effect at all – probably can’t do any harm.

    • Dietry calcium is not going to make a difference, it is a cellular thing and too much calcium is not good for a cell as it makes it commit suicide. Make sure you get enough, but dont go mad on it.

      “Everything I have tried to conquer spasticity has been a bad experience”
      Know the experience having spent 14 years of my life on it for the trial to fail, but we have now made more CNS penetrant variants and more powerful versions of the anti-spastic drug. Hate to say COVID may have killed this……terrible experience

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