Mitochondrial and bioenergetic dysfunction in trauma-induced painful peripheral neuropathy

[pattismith]

2015 Sep

Background
Mitochondrial dysfunction is observed in various neuropathic pain phenotypes, such as chemotherapy induced neuropathy, diabetic neuropathy, HIV-associated neuropathy, and in Charcot-Marie-Tooth neuropathy. To investigate whether mitochondrial dysfunction is present in trauma-induced painful mononeuropathy, a time-course of mitochondrial function and bioenergetics was characterized in the mouse partial sciatic nerve ligation model.

Results
Traumatic nerve injury induces increased metabolic indices of the nerve, resulting in increased oxygen consumption and increased glycolysis. Increased metabolic needs of the nerve are concomitant with bioenergetic and mitochondrial dysfunction. Mitochondrial dysfunction is characterized by reduced ATP synthase activity, reduced electron transport chain activity, and increased futile proton cycling. Bioenergetic dysfunction is characterized by reduced glycolytic reserve, reduced glycolytic capacity, and increased non-glycolytic acidification.

Conclusion
Traumatic peripheral nerve injury induces persistent mitochondrial and bioenergetic dysfunction which implies that pharmacological agents which seek to normalize mitochondrial and bioenergetic dysfunction could be expected to be beneficial for pain treatment. Increases in both glycolytic acidification and non-glycolytic acidification suggest that pH sensitive drugs which preferentially act on acidic tissue will have the ability to preferential act on injured nerves without affecting healthy tissues.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574230/

 

[rodgergrummidge]

2015 Sep

Conclusion
Traumatic peripheral nerve injury induces persistent mitochondrial and bioenergetic dysfunction which implies that pharmacological agents which seek to normalize mitochondrial and bioenergetic dysfunction could be expected to be beneficial for pain treatment. Increases in both glycolytic acidification and non-glycolytic acidification suggest that pH sensitive drugs which preferentially act on acidic tissue will have the ability to preferential act on injured nerves without affecting healthy tissues.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574230/

@pattismith thanks for the post. The results of these studies show that damaging nerve cells (which are 'terminally differentiated' and dont have the capacity to divide, multiply and regenerate) results in a decreased capacity to generate energy (ATP) via i) oxidative phosphorylation in the mitochondria and ii) glyclolysis in the cytoplasm.

Overall, the investigators arrive at a fairly obvious conclusion: That damaging a cell decreases its ability to generate energy. Such findings are entirely expected and neither novel nor significant. It is likely that these reasons contributed to the findings being published in a low-ranking journal.

Rodger that.......

 

[pattismith]

@pattismith thanks for the post. The results of these studies show that damaging nerve cells (which are 'terminally differentiated' and dont have the capacity to divide, multiply and regenerate) results in a decreased capacity to generate energy (ATP) via i) oxidative phosphorylation in the mitochondria and ii) glyclolysis in the cytoplasm.

Overall, the investigators arrive at a fairly obvious conclusion: That damaging a cell decreases its ability to generate energy. Such findings are entirely expected and neither novel nor significant. It is likely that these reasons contributed to the findings being published in a low-ranking journal.

Rodger that.......

What interested me in this article was the chronic pain associated with mitochondria dysfunction.
(this concern CFS/ME, fibromyalgia, possibly mitoDiseases)

Here it is a post injury dysfunction, but there are many articles about chronic neurologic pains associated with mitochondria dysfunction without any physical injury).

What is important is that research seems to focus more and more on the mitochondria function in order to improve chronic pains, which is a great new!

Here are the last papers I read on that topic that seems promising (finger crossed that they were published in high ranking journals):

PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease

http://www.sciencedirect.com/science/article/pii/S0891584916303112

Combination Drug Therapy of Pioglitazone (selective agonist of PPAR) and D-cycloserine (NMDA partial agonist) Attenuates Chronic Orofacial Neuropathic Pain and Anxiety by Improving Mitochondrial Function Following Trigeminal Nerve Injury.

http://journals.lww.com/clinicalpai...n_Drug_Therapy_of_Pioglitazone_and.99030.aspx

D-cycloserin, a NMDA-agonist may be a treatment option for anti-NMDAR encephalitis

http://nnjournal.net/article/view/1543

(some of the CFS/ME patients may have these antibodies, which is why I added this interesting case report)

@Shawn

Also a paper about the small therapeutic windows to treat anxiety disorders with DCS:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006201/

These drugs are not perfect for the moment, so let's hope they will find ones with similar target and less side effects...

 

[rodgergrummidge]

Fascinating @pattismith , thanks for the refs. I didnt realize that there were FDA approved PPAR agonists. I'll definitely have a read.

"There's a little place a place called space,
It's a pretty little place it's across the track"

 

[pattismith]

@Pyrrhus , did you experiment with PPAR gamma agonists to rescue nerve damages?

PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease

...

Losartan has shown partial PPAR gamma agonist properties and neuroprotective effect.

Here a June2020 study about it

Losartan attenuates neuroinflammation and neuropathic pain in paclitaxel‐induced peripheral neuropathy

 

[Pyrrhus]

@Pyrrhus , did you experiment with PPAR gamma agonists to rescue nerve damages?

No I haven't, but I have had good results from B vitamins, especially B12, and from cysteine to boost glutathione. All of which support the mitochondria.

I know that there are also peripheral neuropathy protocols that combine acetyl-L-carnitine (ALCAR) with alpha-lipoic acid (ALA) in order to support the mitochondria. This seemed to work when I tried it, but the ALCAR eventually led to disturbed sleep, so I stopped it.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790425/

 

[pogoman]

Losartan has shown partial PPAR gamma agonist properties and neuroprotective effect.

Here a June2020 study about it

[URL='https://onlinelibrary.wiley.com/doi/full/10.1111/jcmm.15427'][SIZE=7]Losartan attenuates neuroinflammation and neuropathic pain in paclitaxel‐induced peripheral neuropathy[/SIZE][/URL][/QUOTE]

Who knew? lol
Been on Losartan for a few years now, if its something that helps neuropathy I guess I will stay on it even if BP drops on the TRT I started this month.

No I haven't, but I have had good results from B vitamins, especially B12, and from cysteine to boost glutathione. All of which support the mitochondria.

I know that there are also peripheral neuropathy protocols that combine acetyl-L-carnitine (ALCAR) with alpha-lipoic acid (ALA) in order to support the mitochondria. This seemed to work when I tried it, but the ALCAR eventually led to disturbed sleep, so I stopped it.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790425/

Have you tried the mito coctail or variants of such?
B2, coq10 and L-carnatine as the core ingredients.
Having done challenge tests to see what happens if I stop them, B2 helps with neuro pain.

 

[sunshine44]

No I haven't, but I have had good results from B vitamins, especially B12, and from cysteine to boost glutathione. All of which support the mitochondria.

I know that there are also peripheral neuropathy protocols that combine acetyl-L-carnitine (ALCAR) with alpha-lipoic acid (ALA) in order to support the mitochondria. This seemed to work when I tried it, but the ALCAR eventually led to disturbed sleep, so I stopped it.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790425/

Interesting. I’ve not heard of this for neuropathy which I have significant issues with. My Healy scans keep bringing it l- carnitine) up though that my body wants it. I see the kidneys and liver make it but they can be compromised in significant autoimmune states, which I certainly deal with. thanks for sharing.