L-Phenylalanine for DRA neuroprotection?

[SquidInSunglasses]

Per this paper, the activation of microglia plays a role in dopamine-related neurotoxicity (the paper is specifically about meth, but the mechanisms involved should be general), and this activation can be inhibited by NMDA antagonists, which in turn prevents neurotoxic effects from occuring. However, since DXM is also a serotonin reuptake inhibitor, it is a risk if taken in combination with SSRIs or MDMA, due to the increased risk of serotonin syndrome (the combination with SSRIs is currently a concern, but MDMA would be a concern in the future). My question is, given that L-phenylalanine is easily available and acts as an NMDA antagonist at the glycine site, would it be usable as a neuroprotective agent?

 

[aced126]

It could be neuroprotective in the mechanism you described, as well as serving as a replenishment for dopamine (it is only 3 metabolic steps away from DA). It's also a substrate at LAAT for transport across the blood-brain barrier. However though I have no quantitative calculations to back this up, there could be a possibility of phenylketunoria due to excess L-phe within the brain.

 

[SquidInSunglasses]

It could be neuroprotective in the mechanism you described, as well as serving as a replenishment for dopamine (it is only 3 metabolic steps away from DA). It's also a substrate at LAAT for transport across the blood-brain barrier. However though I have no quantitative calculations to back this up, there could be a possibility of phenylketunoria due to excess L-phe within the brain.

That's definitely a concern, agreed. Do you have any idea what the effects of PKU on adults are? Wikipedia only mentions its effects on developing children, not what the impact of excess phenylalanine on adults would be.

 

[sekio]

I dont think you can induce PKU in a healthy person just by feeding them L-PA... regulatory stuff in your body prevents it from oversaturating the brain

for that reason I doubt taking oral L-PA will boost brain concentrations as much as youd hope

 

[serotonin2A]

I dont think you can induce PKU in a healthy person just by feeding them L-PA... regulatory stuff in your body prevents it from oversaturating the brain

for that reason I doubt taking oral L-PA will boost brain concentrations as much as youd hope

Exactly! Phenylalanine levels in the brain are regulated. Plus, high levels of phenylalanine are neurotoxic. The concentration of L-phenylalanine required to block the glycine co-agonist site falls within the brain concentration range seen in PKU patients.

 

[SquidInSunglasses]

Exactly! Phenylalanine levels in the brain are regulated. Plus, high levels of phenylalanine are neurotoxic. The concentration of L-phenylalanine required to block the glycine co-agonist site falls within the brain concentration range seen in PKU patients.

Back to the drawing board then. Would it still be worth taking some L-PA afterwards to help replenish dopamine levels, or should I just leave it alone entirely?

What would be a cleaner/non-serotoninergic NMDA antagonist for my purposes? Would something like ketamine need to be at dissociation-producing doses to have an effect, or would you be able to use a sub-threshold amount and still get the protective effect without interfering with the stimulant high?

 

[serotonin2A]

What would be a cleaner/non-serotoninergic NMDA antagonist for my purposes? Would something like ketamine need to be at dissociation-producing doses to have an effect, or would you be able to use a sub-threshold amount and still get the protective effect without interfering with the stimulant high?

I don't think anyone can answer those questions with any degree of confidence. There is a consensus that METH is neurotoxic, but dosages and use patterns vary so widely that there is probably no advice that is relevant to everyone. Further, most of what is known about the neuroprotective effects of NMDA blockade against METH toxicity is derived from animal models, meaning that we have no clue if the protective effect occurs in humans, and we certainly don't know the necessary level of blockade that would be required. People had high hopes that NMDA receptor antagonists could be used clinically to treat hypoxia and stroke, based on animal models, and that wasn't very successful. The situation with METH toxicity may or may not be the similar.