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Friday, 9 December 2016

Glutamate Inhibitors to Treat Some Autism and ADHD




 A festive queue at the pharmacy for Glutamate Inhibitors


We have now established that much autism and indeed other disorders, from Down Syndrome to Schizophrenia, features a degree of excitatory/inhibitory (E/I) imbalance.

It is very likely that there are multiple underlying causes for this and so there may be multiple treatments.  We can even potentially use a treatment for one cause (ALS) to improve outcomes in others.  So we can (partially) solve a problem without fully understanding its origin, as frequently is the case in biology.

An E/I imbalance might cause anxiety in the adult with Asperger (treatable with Baclofen), contribute to MR/ID in the child with Down Syndrome and contribute to seizures and cognitive loss in someone with severe autism.

Very interestingly in the comments to a previous post, Agnieszka has pointed out why common penicillin type antibiotics (beta-lactams) improve many people’s autism.  This is very common observation and our other guest blogger Seth Bittker found the same in his son. Nat’s guest speaker at her autism conference also found this in his son.

The Glutamate Transporter 1 (GLT-1) is a protein that in humans is encoded by the SLC1A2 gene.   It is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. Glutamate is an excitatory neurotransmitter, so it encourages neurons to fire.

By upregulating the GLT1 transporter you increase the inactivation of glutamate and so shift the Excitatory/Inhibitory balance towards inhibitory.

Agnieszka highlighted this paper from Johns Hopkins:-




Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many beta-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. beta-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the beta-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.



It actually gets more interesting and relevant to treatment.

Mutations in SLC1A2 which decrease expression of the GLT-1 protein are associated with amyotrophic lateral sclerosis (ALS). 

The drug riluzole approved for the treatment of ALS upregulates GLT-1.

This would suggest that Agnieszka, Seth and John Rodakis might want to pay a visit to the pharmacy and pick up some riluzole.  It is certainly worth investigating.

I did check and there is even a trial on Riluzole in autism and evidence of existing off-label use.  They have not of course made Agnieszka’s connection; they seem to be just trying it because nothing else seems to help. That really is trial and error and makes this blog look positively scientific by comparison.
Drug: Riluzole

50mg once daily (QD) for 12 weeks for participants 6-11 years old; 50mg twice daily (BID) for 12 weeks for participants 12-17 years old





A reformulation of riluzole that originated at Yale University and is known by the code name BHV-0223 is under development for the treatment of generalized anxiety disorder and mood disorders  by Biohaven Pharmaceuticals.

  
Anyway, are there any other ways to inhibit Glutamate?

Yes, our reader Valentine just stumbled on one, tizanidine, but there are at least two others. 


α2 adrenergic agonists

Three other known inhibitors of glutamate happen to be α2 adrenergic agonists

·        Clonidine

·        Guanfacine

·        Tizanidine


All three of the above are already used in ADHD and sometimes in autism, but not to reduce glutamate.

I wrote a post about Clonidine use in autism a long time ago.



Guanfacine is an ADHD drug known to inhibit glutamate release.



At five sites, children with ASD and moderate to severe hyperactivity were either given guanfacine or a placebo tablet for eight weeks, in a randomized and double-blind clinical trial. The research team collected information from parents and measured each child’s overall response. After eight weeks of treatment, extended release guanfacine was superior to placebo for decreasing hyperactivity and impulsiveness.


Our reader Valentina seems to have stumbled upon tizanidine, but finds it helpful for her son. Tizanidine is a α2 adrenergic agonists but also inhibits glutamate.  It is one of the drugs used off-label by Dr Chez in ADHD and autism




CONCLUSION:


The overall safety of tizanidine in the pediatric group appeared good; however, the adverse event profile differed from that in adults. This difference most likely reflects the off-label use of tizanidine as adjunctive treatment for attention disorders and autism. The frequency and nature of adverse events in adults were consistent with the tizanidine prescribing information as reported for its approved indication, i.e. management of spasticity.



Conclusion

Ideally you would have a comparison of the four drugs:


·        Riluzole

·        Tizanidine

·        Clonidine

·        Guanfacine


We know clonidine is not an autism wonder drug, but then what is?

I think Riluzole is likely to be a good one, but very likely what works best will vary from person to person.

Perhaps a positive response to beta-lactam (penicillin) antibiotics is a biomarker for people who will respond to Riluzole? It should be.







23 comments:

  1. Peter, you made me laugh with this photo, I am going to ask Baclofen to Santa for Christmas!
    Valentina

    ReplyDelete
  2. Hi Valentina,
    If you still don't have access to Baclofen, where I live it's OTC and last time I checked 10mg/50 tabs cost something less than 4 euros.
    You could send me your e-mail for details.

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    Replies
    1. Hi Petra, thanks so much,how lucky you are! For now, Tizanidine controls his anxiety very well and sleep improved a lot, it was a grat discovery added to Bacilor. But Baclofen is something I always wanted to try for my son. The great problem I see, is the entrance of medications to the country.
      Valentina

      Delete
    2. Valentina, Where do you live where Baclofen is otc? Is there a good pharmacy that you would recommend there? Thanks, MH

      Delete
  3. Hi Valentina,
    You are welcome.
    Since your child responds to antispasmodics, I wanted to ask if you have ever used camomile tea.
    Bisabodol and flavonoids have demonstrated this effect in animal studies. Flavonoids and cumarins are considered smooth muscle relaxants and can have anxiolytic effect, according to Wikipedia.
    There are some drug interactions and when camomile is taken in combination with some drugs there may be exacerbation of effects.
    Baclofen gives some benefit to my son for a few days but then there comes a loop.
    I am having a trial with camomile and thought I should let you and everyone here know.

    ReplyDelete
    Replies
    1. Petra, Camomile is very interesting, I have used it for my son but not in a regular basis, I will try it again, it is very recommended for its anxiolytic effect. Besides, I saw a study of Jhon Hopkins University about the fungicidal and bactericidal properties of bisabodol.Let me know about your trial.
      Valentina

      Delete
  4. Peter, I think camomile exacerbates Low dose clonazepam, so I quitted for a while.
    With Bumetanide he seems ok. As long as we don't have behavioural arousal with this combination, do you think that it might be a problem elsewhere if camomile exacerbates Bumetanide effect?

    ReplyDelete
    Replies
    1. Petra, chamomile is known to interact with sedatives, blood thinners, antiplatelet drugs, aspirin, and NSAID painkillers.

      Delete
  5. Hi Valentina and all,
    From the very short term chamomile trial, I've concluded that it can be a potent anti-inflammatory drug as I noticed my son acting physically healthy. It can also help with involuntary movements.
    On the other hand, probably due to its binding to Gaba like a benzo, in my son's case, it created more E/I imbalance and didn't help with anxiety.
    I had never expected that an innocent cup of chamomile could create behavioural arousal.

    ReplyDelete
    Replies
    1. Petra, I am very happy that chamomile has worked for your son. May be it also helps with anxiety, I think involuntary movements have a lot to do with it.
      Valentina

      Delete
  6. NAC has also been found to upregulate GLT-1

    ReplyDelete
    Replies
    1. Thanks Lucia, yet another good reason to try NAC, if you have autism.

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  7. My son is getting better at ceftin ( cephalosporin) antibiotic. Good sleep, good learning and nice boy.

    ReplyDelete
    Replies
    1. That is great. How long have you used ceftin? How long do you plan to continue?

      Delete
    2. Peter would clarithromycin be in this family as well.

      Delete
    3. To affect GLT-1 with an antibiotics it has to be in the beta-lactam class of antibiotics, which includes penicillins, cephalosporins, monobactams, and carbapenems.

      Clarithromycin is a macrolide antibiotic, so apparently not a beta lactam.

      http://www.emedexpert.com/lists/antibiotics.shtml

      Delete
  8. The first time I gave it 7 days. The doctor said bronchitis. I saw Wow. And it wasn't bronchitis, I think. Later, I twice gave ceftin. 14 and 28 days. And every time son had improved. I'd like to try now Ceftriaxone. I think beta-lactam antibiotics help GLT-1 transporter.

    http://onlinelibrary.wiley.com/doi/10.1111/jnc.13200/full

    ReplyDelete
    Replies
    1. You can achieve the same effect on GLT-1 using riluzole or bromocriptine. Riluzole looks better and is available as a generic.

      Delete
    2. Could you tell us if your son kept the gains how much did you dose how old is your son.

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    3. Hi
      What is the dose of certain? What exactly is the wow factor? Behavior, speech? After stopping ceftin the effect is still there? What he learned is still there? Thank you.

      Delete
  9. In my country, riluzole is not registered. :(

    ReplyDelete
  10. Write about the first time the antibiotic.
    The effect remained after cancellation, but something was missing. My son couldn't sleep from 16 months to 42 months. I could spend hours sleep. On the antibiotic he immediately began to sleep well. Fell asleep at 9pm and slept until 7am. He was no longer ADHD. Began to say the word "no" . Praised by teachers in the classroom. After discontinuation of the antibiotic, he again became ADHD. A good night's sleep forever. Verbal skills slow, but improving. Sorry if I wrote bad, English is not my native language.

    ReplyDelete
    Replies
    1. You might want to consider guanfacine in the above post, which was shown effective in autism with ADHD. The effect may be similar to the beta lactam.

      Delete

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