Method of action for ketamine neuroprotection

[Sturnam]

Can anyone help explain to me how exactly ketamine is neuroprotective? I see lots of journals citing that it is, but without really explaining the mechanism of action. I know that it's related to the NMDA antagonist properties, but that's about it.

Are these neuroprotective effects specific to certain stressors? A lot of the studies seem to focus on ketamine during an ischemic attack, and I'm wondering if the neuroprotection might also protect against MDMA/methamphetamine/other neurotoxic damage, or if this is a completely different kind of damage.

Also, if anyone has any good articles to recommend, I'd like those as well.

Edit: Actually I just found this.

Although there is still a lack of data on the molecular machinery behind ketamine neuroprotection, some consequences of the prevention of pathological NMDA receptor up-regulation were reported: At brain synapses, postsynaptic density (PSD) proteins bind and cluster NMDA receptors to the cytoskeleton and sets of signaling proteins, such as nitric oxide synthase (59,60), or calcium sensors (61). Increased excitatory NMDA receptor input activates protein kinase C isoforms and tyrosine kinase cascades, which
facilitate assembly of signaling molecules with PSD proteins in the NMDA receptor. This leads to further kinase activation, NMDA receptor phosphorylation, and up-regulation of NMDA currents. In this vicious circle, enhanced downstream signals enhance NMDA receptor function, and finally, induce cell injury (44,59).

In short, basically:

The reduction of harmful interactions of NMDA receptors with cascades that transduce signals to destructive intracellular mechanisms may thus represent one effect underlying ketamine neuroprotection.

Is there anything more to the neuroprotection that anyone knows about? This article also said that ketamine prevented hypoxia, ischemia, chemical and mechanical neuronal damage, but doesn't exactly give a good reference for the chemical/mechanical damage claim. Does anyone have any ideas of how it would prevent chemical or mechanical damage to the neuron?

 

[melange]

I have no idea, but there are more ndma antagonists that are neuroprotective as well

 

[kaskelot]

I have no idea, but there are more ndma antagonists that are neuroprotective as well

Aren't all of them, in low doses and not combined with something that makes lesions probable?

 

[shibireru]

Isn't it simply the case that the neuroprotective effect of NMDA antagonists derives from their ability to prevent binding of glutamate (and other agonists) to the NMDA receptor, which when overstimulated precipitate a toxic degree of influx of calcium cations (these being toxic because they somehow stimulate the release of proteolytic enzymes which can damage the cytoskeleton and so forth)? In other words, they prevent excitotoxicity.

Much more interesting to me is why NMDA antagonists become neurotoxic in higher doses. Is it because they allow for the accumulation of toxic levels of glutamate in the synapse, which binds all at once to the NMDA receptor once the antagonist has disassociated from it?

I would really like to understand the mechanisms behind the genesis of Olney's lesions and I would especially like to know once and for all whether these can arise in humans.

 

[Sturnam]

^ So this would mean that ketamine would be neuroprotective only in stressful situations, where glutamate is release, right? Or is there a very mild background neurotoxicity going on with glutamate that the ketamine would prevent as well?

 

[Jamshyd]

^ That's a given, pretty much.

If something is protective, then what does it protect from?

In the case of NMDA antagonists, that seems to be excitotoxicity and ischemia-related neuronal damage, AFAIK.

 

[Holy_cow]

Isn't it simply the case that the neuroprotective effect of NMDA antagonists derives from their ability to prevent binding of glutamate (and other agonists) to the NMDA receptor

Only the rarely used competitive NMDA antagonists prevent the binding of glutamate to its receptor. The non-competitive NMDA antagonists like ketamine, PCP, DXM etc. bind to a site inside the ion channel and thereby act like a plug that prevents the influx of Ca2+ ions. Non-competitive NMDA antagonists can reach their binding site only when the ion channel is opened by the action of endogenous glutamate.

 

[shibireru]

^ So this would mean that ketamine would be neuroprotective only in stressful situations, where glutamate is release, right? Or is there a very mild background neurotoxicity going on with glutamate that the ketamine would prevent as well?

Most likely the former.

When you read studies about the neuroprotective effects of NMDA antagonists or group II metabotropic glutamate receptor agonists, you'll always find that the researchers have previously or subsequently administered a high dose of some excitotoxic substance. We're evidently supposed to ooh and ahh at these results that show that the toxicity produced by a substance can be counteracted with a substance with a mechanism of action antithetical to that of the toxic one. Well, blow me down! I would never have guessed. Thanks Mr. smart researcher man.

Glutamatergic excitotoxicity generally doesn't manifest to any significant degree under normal conditions. It occurs in cases of severe insult to the homeostasis of the brain - such as occurs in ischaemia, reperfusion, concussion, Alzheimer's disease, etc...

But if you're worried about it, you could try to keep your calcium intake low and magnesium intake high, and use melatonin. A better bet would be to use a variety of antioxidants: Alpha lipoic acid, R+ lipoic acid, vitamin C, n-acetyl-cysteine, superoxide dismutase, vinpocetine (not in and of itself an anti-oxidant, I don't believe, but it has been shown that chronic use brings the brain to such a condition that upon ischaemic insult, far less damage occurs than would otherwise), etc...

 

[shibireru]

Only the rarely used competitive NMDA antagonists prevent the binding of glutamate to its receptor. The non-competitive NMDA antagonists like ketamine, PCP, DXM etc. bind to a site inside the ion channel and thereby act like a plug that prevents the influx of Ca2+ ions. Non-competitive NMDA antagonists can reach their binding site only when the ion channel is opened by the action of endogenous glutamate.

Oh, right. Thanks for the refresher.

 

[theWorldWithin]

To put it much more simply for common drug addicts such as myself to understand: excitotoxicity occurs when NMDA receptors become overactive in certain extreme conditions. They become so active that the excess heat generated literally'fries' the neuron. Ketamine is neuroprotective because it too overexcites the NMDA receptors to such an extreme degree that they totally shut off and quit functioning at a full anesthetic dose. The flip side of this is that sub anesthetic doses will simply over excite the neuron and probably cause excitotoxicity! This happens severely at recreational K hole doses.

Please someone correct me if I am wrong about this mechanism, bear in mind this is an extreme simplification for the rest of us to grasp.

 

[Holy_cow]

To put it much more simply for common drug addicts such as myself to understand: excitotoxicity occurs when NMDA receptors become overactive in certain extreme conditions. They become so active that the excess heat generated literally'fries' the neuron. Ketamine is neuroprotective because it too overexcites the NMDA receptors to such an extreme degree that they totally shut off and quit functioning at a full anesthetic dose. The flip side of this is that sub anesthetic doses will simply over excite the neuron and probably cause excitotoxicity! This happens severely at recreational K hole doses.

This is complete nonsense.

 

[Jamshyd]

^ And...?

*sigh*.

 

[Sturnam]

Thanks for the answers everyone. I know the general mechanism of action for ketamine neuroprotection, I was just confused about a few things, and don't really know what I was thinking at the time.

TWW, ketamine is neuroprotective because it stops the NMDA receptor from being activated. This means that when there is excess glutamate around, it won't be able to bind to the NMDA receptors and cause excitotoxicity. Now, this is only at low doses. At high doses (not sure where 'high' is for ketamine though) the NMDA antagonist causes exictotoxicity.

 

[Holy_cow]

TWW, ketamine is neuroprotective because it stops the NMDA receptor from being activated. This means that when there is excess glutamate around, it won't be able to bind to the NMDA receptors and cause excitotoxicity. Now, this is only at low doses. At high doses (not sure where 'high' is for ketamine though) the NMDA antagonist causes exictotoxicity.

Again, complete nonsense.

 

[Jamshyd]

^ Can you please enlighten those poor misguided ignorami of what is NOT nonsense, instead of wasting space with your pompous criticism, your highness?

 

[Jamshyd]

Sturnam: The Glutamate will still bind to its site, but it will have no effect w.r.t. the NMDA receptor since the channel is blocked anyway.

That said, I know nothing of Ketamine "causing" excitotoxicity at high doses...

 

[FractalDancer]

To put it much more simply for common drug addicts such as myself to understand: excitotoxicity occurs when NMDA receptors become overactive in certain extreme conditions. They become so active that the excess heat generated literally'fries' the neuron. Ketamine is neuroprotective because it too overexcites the NMDA receptors to such an extreme degree that they totally shut off and quit functioning at a full anesthetic dose. The flip side of this is that sub anesthetic doses will simply over excite the neuron and probably cause excitotoxicity! This happens severely at recreational K hole doses.

Please someone correct me if I am wrong about this mechanism, bear in mind this is an extreme simplification for the rest of us to grasp.

There is no heat frying neurons... excitotoxicity from excess glutamate occurs as a previous poster said - by increasing influx of Ca2+ ions into the neuron. NMDA receptor antagonists by their nature do no excite the neuron - being an antagonist they block it (ketamine blocks in the channel pore altho some other NMDAR antagonists block elsewhere) preventing excitation.

The NMDAR antagonist MK-801 is known to be neurotoxic, and ketamine can be with repeated high dose administration but i'm pretty sure this is via another mechanism - not excitotoxicity. According to our old friend Olney... they cause neurotoxic vacuoles...

 

[theWorldWithin]

Like I said this was an extreme oversimplification for average people to get a grasp on the concept. I believe heat does play a role in excitotoxicity but I may be mistaken.

What I do know for certain is that you have your dosage response completely reversed. At full anesthetic doses K shuts down the NMDA receptor blocking toxicity and thus becoming neuroprotective. At sub anesthetic doses it is most definitely toxic, possibly in a variety of manners.

 

[leungkachong]

The evidence places the role of nitric oxide synthase (NOS... both the neuronal and endothelial isoforms...) at the centre of all the neurotoxicty (and protection). Simply:

You get oxygen starved --> you get the flood of glutamate as a result --> High levels of glutamate use the Ca++. adenylyl cyclase and protein kinase C (path too complicated for here) --> Causes high levels of NOS activity --> NO (from NOS and L-Arg) and superoxide (from oxygen-starving) form **peroxynitrate** --> necrotic cell death followed by apoptosis in surrounding area.

Simple as can be... when you block the glutamate-mediated increase in nNOS (little n is neuronal isoform) using your non-competitve antagonist (Ketamine), you only get the relatively mild damage of hydroxyls and superoxides... rather than *dum dum dummmm* PEROXYNITRITE.

Yes, this increase in free radicals, or increase in NO (if separate) usually wouldn't be a that huge problem... But when you get NO + O2- (superoxide), an equilibrium forms ONOO- (peroxynitrite, which also goes on to form nitrogen dioxide and carbonate radicals). ONOO- is an EXTREMELY powerful oxidant, and is the 'big contender' for excitotoxic damage during ischaemia, anemia, etc.

The typical way of studiyng this is to use mid-cerebral-artery-occulusion to wreak havoc. The resultant damaged area is divided into core (acute death) and penumbra (signalled death in days to come). Both the necrotic and apoptotic areas appear to have a large degree of the activity occur via NOS activity. When we used NO donors to study it, results were confusing. But now we have knockouts. nNOS knockout causes a smaller core... and eNOS knockout increases the size of the penumbra. So increased NOS activity in endothelial tissue post-stroke is actually helpful to reduce apoptosis (due to increased bloodflow w/ less superoxide)... but when you've got a SHITLOAD of free radicals from an oxygen debt, nitric oxide is gonn skullf#ck you via peroxynitrite.

This is actually the first topic I worked on formally (other than giving pigs heart attacks to test CPR-enhancing toys)... our model was haemodilutional however (switch half of the blood w/ pentastarch).


So yes... shibireru, Jamshyd, and all of you are right about Glutamate... but you're still a few steps away from the actual biochemically causative step. I hope that this clears this stuff up... if this isn't clear enough, just ask. This stuff isn't VERY new (5 years-ish), but it doesn't seem to be making it's way into the textbooks yet.

 

[DHYANA]

holy shit at giving pigs heart attacks. How did you do that btw?