[Shai Hulud]

Dear all,

I just registered and hope you guys can help me with your knowledge.

I'm interested in the drug phenelzine (Nardil).
There are now studies showing it's usefulness in traumatic brain injury, mitochondrial functional preservation and several other diseases/problems, which all seem related to it's ability to scavenge several radical molecules (aldehydes etc.)
This opens several questions to me:
1) Does it's reactivity also mean it will readily react with some proteins etc., just like the compounds it will react with for positive effects (as explained above)?
2) What will happen with these adducts (ie hydrazones). Will they be further metabolized and become radicals again so the positive effects are more in splitting up the radical load so the body is better able to handle it or will they mainly be discreted?
3) Related to this: The drug has a biological half-life (as stated in wikipedia) of 11.6 hours.
However, if it does indeed react and under the condition these adducts won't be degraded again to phenelzine (or another hydrazine): Will this influence it's half-life related to load of reactive molecules in the body?
4) Has the scavenger-property meaning in a "normal" therapeutic setting (chronic use as antidepressant / anti-anxiety drug, lower dosage)?
5) Last one needs some further explanation: The drug (and it's metabolite PEH) also reacts with Pyridoxal phosphate, which plays a role in side and therapeutic effects (the latter one through blockage of PLP-dependent enzymes). This
(http://www.sciencedirect.com/science/article/pii/0041008X60900077?via%3Dihub) older study has shown pyridoxine pretreatment to be protective against toxicity of a very high dose of phenelzine in mice, while pyridoxal enhanced the same. Phenelzine and pyridoxal (phosphate) form adducts and inhibit pyridoxal kinase, probably resulting in the toxicity if enough enzymes are inhibited (or through resulting inhibition of other processes).
What I know is: Pyridoxal kinase binds to PLP dependent enzymes to give them the needed co-factor. Is someone able explain  to me how pyridoxine would block the inhibition from happening?

I hope everything is understandable, English isn't my first language.

[Shai Hulud]

Is this to specific? Wrong sub forum maybe?

[Borek]

Too specific most likely.

[Shai Hulud]

Ok, so any ideas where to look to get a little closer to understanding these things?

Like what to search or what would be especially important areas of chemistry/biology to look into?

[Yggdrasil]

I'm interested in the drug phenelzine (Nardil).
There are now studies showing it's usefulness in traumatic brain injury, mitochondrial functional preservation and several other diseases/problems, which all seem related to it's ability to scavenge several radical molecules (aldehydes etc.)

Aldehydes are not radicals, so I'm not sure what you're saying here.  Phenelzine is thought to act as a monoamine oxidase inhibitor (MAOI).  Monoamine oxidases are a family of enzymes involved in a number of biological processes including the metabolism of neurotransmitters (which is why many MAOIs are used as antidepressants).  Phenelzine does contain a hydrazine functional group, which can react with groups like aldehydes and is important to its function as an MAOI.  However, aldehydes are fairly rare in biology due to their reactivity (though, as you point out they do occasionally exist as in the case of pyridoxal phosphate). I did not find many recent papers discussing radical scavenging as a mechanism of action of phenelzine after a quick search.

[Shai Hulud]

Thanks for the answer! These are some studies:

https://www.ncbi.nlm.nih.gov/pubmed/23321786
http://uknowledge.uky.edu/neurobio_etds/12/
http://online.liebertpub.com/doi/abs/10.1089/neu.2016.4624?journalCode=neu
https://link.springer.com/article/10.1023/A:1026119708124