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Tox and Hound – No GABA GABA!

February 11, 2019 by Tox & Hound 1 Comment

http://twitter.com/heshiegreshieby Howard Greller

by the author using the Gabbaland! font

We rarely stop and appreciate the beauty that is reflected in our physiology. It’s not until something goes wrong that we recognize how well things were working. For example, our brains . . .

An analogy I like is that our brains are like a car (I definitely need to upgrade to a newer model . . .) Cars are made to drive and our brains are made to be active. Moving the car is a matter of pushing on the accelerator and taking your foot off the brake. In the brain it is similar. When you want to move your arm you need a group of neurons to be activated (think the accelerator) and a group of neurons in the brain to be inhibited (think the brake). Unlike cars, whose resting state is an idle, our brains are constantly revving their engines. We are more awake than we are asleep (teenagers aside) and neuronal excitation is the norm. This is why most neurons fire in a regular fashion even when you sleep.1 Fortunately for us, the brakes in our brain are also constantly being pressed. Neuronal inhibition exists to temper the excitatory impulses. Without this, we would accelerate out of control (insert car peeling out noise)

https://giphy.com/gifs/crazy-charlie-sheen-TNL3m6AUfEsRa

Excessive endogenous or exogenous neuronal excitation is an important factor in multiple conditions, including psychiatric disease, trauma, ischemia, hypoglycemia, and of course, seizures.1,2 In the healthy state, the way we control this excitation is by carefully reducing the inhibition (taking our foot off the brake) which allows the brain to do its thing (drive). Thus, everything that happens in the brain comes from disinhibition. Homer was right . . .

https://giphy.com/gifs/water-solution-tKGFfFcHjKT9m

Gluta-Yin, GABA-Yang

If we delve a little deeper into this balance between stop and go, we find that the primary neurotransmitters that oversee these stimuli, glutamate for excitation and γ-aminobutyric acid (GABA) for inhibition, are in a beautiful symmetry.

Adapted from wikipedia.org
Adapted from wikipedia.org by the author

Where does our excitation come from? Glutamate doesn’t cross the blood brain barrier under normal conditions, so we can’t just eat it. Well, technically, you can eat it as monosodium glutamate, or MSG, but it still does not cross the BBB. So while many of us get excited by umami, we won’t get the right kind of excitement . . .3–5 Glutamate must be synthesized in the brain. It is further compartmentalized within the astrocytes, which have the ability to produce it from precursors, whereas neurons cannot.6,7 Glutamate is made either from the transamination of α-ketoglutarate (Krebs cycle) or from glutamine by glutaminase in the mitochondria.8 Glutamate is stored in vesicles and released into the synapse by Ca2+ dependent exocytosis. Synaptic glutamate that is taken up by astrocytes undergoes conversion back to glutamine by glutamine synthase. Astrocytes then release glutamine, which is taken up by neurons and reconverted to glutamate. This is known as the glutamate-glutamine cycle.9,10

How about the other side of the equation? All of the GABA (inhibition) we have is directly derived from glutamate (excitation). Glutamate is decarboxylated by glutamic acid decarboxylase (GAD) into GABA. In order for GAD to work, it requires a cofactor, pyridoxal 5’-phosphate (P5P). And how do we get this important cofactor? Well, we take pyridoxine (vitamin B6 from our diet) and we phosphorylate it using pyridoxal phosphokinase (PPK). And when we are done using our inhibition, we recycle GABA back into glutamate (with the required cofactor of B6 again) and the cycle starts again.

by the author

Several drugs target different parts of this cycle. Valproic acid increases GABA production by activating GAD, as well as by preventing GABA breakdown by inhibition of succinic semialdehyde dehydrogenase (SSA dehydrogenase). Gabapentin may also stimulate GAD. Vigabatrin, an anticonvulsant, increases GABA by irreversible inhibition of the enzyme GABA-T, thereby decreasing GABA degradation.11,12

This balance between glutamate excitation and GABA inhibition is essential to maintaining normal function, and the essential cofactor for the maintenance of this balance is pyridoxine (B6)

Pyridoxine Lost

So what happens when this recycling is disrupted? And what can lead to this disruption? Well, there are a number of really interesting toxins that can do this, and not surprisingly, they all result in very similar clinical effects.13

https://giphy.com/gifs/explosion-insane-ron-YH8KjvAYNQjhC

The most commonly encountered, and well known, are the hydrazines. There are many examples of this, including the antituberculosis drug INH (isonicotinylhydrazide), the “funny car” / rocket fuel known as monomethylhydrazine (MMH) and the toxin from Gyrometra mushrooms, gyrometrin (which is hydrolyzed to MMH). The common characteristic that these agents share, is that they diminish, sequester and interfere with the enzymatic processes that are dependent on pyridoxine. They inactivate P5P, inhibit PPK, and complex with and lead to increased urinary excretion of pyridoxine. And additionally, even though P5P is also required to breakdown GABA by GABA-T, it is more “tightly” bound as a cofactor to GABA-T. So even though there is a total loss of P5P, GABA-T is still able to breakdown GABA. Thus, while you are inhibiting production of GABA, you are not inhibiting degradation, making the problem worse. What is the overall clinical effect of this? Obligatory .gif . . .

by the author

Therapeutically, benzodiazepines are not going to work, no matter how much you give (it makes me so sad to type that . . .) This is because benzos are indirect GABA agonists; they work by enhancing the effect of GABA. But to do anything they need GABA. Thus, the first therapy needed to restore GABA in the brain is the cofactor, pyridoxine (B6), to make GABA. For a seizing INH overdose you are supposed to give the same dose of pyridoxine as the ingested dose of INH. But since you almost never know how much someone took, the recommended empiric dose of pyridoxine is 5 grams IV (you will need to call the pharmacy and tell them your order is indeed correct, or you’ll face delays in therapy as they argue for 50 mg instead without knowing the case specifics). Once you’ve done that, then you can utilize benzos to your heart’s content. You can also use direct GABA channel agonists (such as barbiturates) if you didn’t have such large doses of pyridoxine.

Other toxins that disrupt the balance

https://commons.m.wikimedia.org/wiki/File:Seeds_of_Ginkgo_biloba.jpg

There are a few other toxins that result in a disruption of our balance between glutamate and GABA. Large ingestions of Ginkgo biloba seeds have resulted in recurrent seizures. Ginkgo species contain 4-methyoxypyridoxine, which acts as a competitive antagonist of P5P, and in a similar fashion to the hydrazines, inhibits GAD and impairs GABA synthesis.14,15

The mushroom toxins ibotenic acid and muscimol are in a structurally similar dichotomy as glutamate and GABA. Ibotenic acid, a direct glutamate agonist, is decarboxylated to muscimol just like glutamate is to GABA. Muscimol binds to the GABA binding site on the GABA-A complex, mimicking the action of GABA. Ibotenic acid works as a glutamate agonist, working in similar locations centrally. Interestingly, eating one of these mushrooms results in variable toxicity. This is because each mushroom will contain different concentrations of each compound depending on a number of factors, and the impact on a human is similarly variable. It seems that in adults, inhibitory manifestations predominate, whereas in children it is more excitation.16 Management is supportive, with benzodiazepines for manifestations of excitation.

https://commons.wikimedia.org/wiki/File:Possum_cyanide_warning.JPG
https://commons.wikimedia.org/wiki/File:Possum_cyanide_warning.JPG

Cyanide inhibits numerous enzymes besides cytochrome oxidase (learn a whole lot more about cyanide in this Fellow Friday post by Steve Curry). An additional enzyme that it inhibits is GAD and this inhibition occurs in a pyridoxine-independent fashion, as if cyanide wasn’t bad enough. This is one putative mechanism for why you can see seizures with cyanide poisoning.17

Domoic acid is the bioaccumulated toxin that is responsible for amnestic shellfish poisoning. It is produced by the diatom N. pungens. In 1987, there was an outbreak of amnestic shellfish poisoning from domoic acid contaminated mussels in Canada. Patients exhibited a wide variety of symptoms including nausea, vomiting, and diarrhea. Patients also developed neurologic symptoms such as seizures, anterograde amnesia, and motor and sensory neuropathies. Post-mortem pathology of four of the patients showed necrosis in hippocampal and amygdala neurons, similar to administration of another glutamate analog, kainic acid.18,19 Domoic acid toxicity in birds is thought to have explained their attack on the city of Capitola, CA in 1961, likely inspiring Hitchcock’s The Birds.20

https://giphy.com/gifs/the-birds-rod-taylor-tippi-hedren-bTixcIRW1bWqk

Domoic acid has structural similarity to glutamate which is thought to explain the excessive excitation and resultant neuronal damage.21 Domoic acid has diverse, complex mechanisms of toxicity that include inhibition of glutamate reuptake by astrocytes decreasing neuronal concentrations and thus diminishing the conversion to GABA. Additionally, to tie everything together, domoic acid inhibits GAD further exacerbating the problem.21,22

So let’s remember to keep our cars fueled with the kind of things necessary to keep the balance of excitation and inhibition intact. Eating foods rich in pyridoxine, and avoiding your aunts (in)famous ginkgo muscaria mussels. It has always amazed me that the difference between excitation and inhibition (decarboxylation) is a simple CO2 molecule. We neuronally dance the razors edge, figuratively one breath away from seizing.

Amanita Muscaria by Igor Yemelianov

mussels by chuttersnap

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Hogberg H, Bal-Price A. Domoic Acid-Induced Neurotoxicity Is Mainly Mediated by the AMPA/KA Receptor: Comparison between Immature and Mature Primary Cultures of Neurons and Glial Cells from Rat Cerebellum. J Toxicol. 2011;2011:543512. [PubMed]
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Filed Under: The Tox and The Hound Tagged With: amantia muscaria, cyanide, domoic acid, GABA, ginkgo biloba, glutamate, ibotenic acid, INH, muscimol, pyridoxine, seizures

Comments

  1. Taylor Sanders says

    March 2, 2019 at 09:14

    awesome. thank you

    Reply

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