Neuroprotection Cheat Sheet

[House2]

Summary: Targets to impede neurodegeneration. 

1.  Maintain adequate levels of neuronal NAD+.

2.  Use Nicotinic Riboside 5  13

3.  Avoid MNM  13

4.  Block NAMPT

a.   Melatonin inhibits NAMPT 16 17

b.  Mangostin inhibits NAMPT 18–20

5.  Block SARM1

a.   berberine  inhibits SARM1. 7

6.  Block DLK

a.   palmitoylation inhibitors (none identified)

b.  block  JNK downstream of DLK. 9

c.   Melatonin down regulates JNK  21 22

 

 ///// References

 1.      Waller, T. J. & Collins, C. A. Multifaceted roles of SARM1 in axon degeneration and signaling. Front. Cell. Neurosci. 16, 958900 (2022).

2.      Wallerian Degeneration. Physiopedia physio-pedia.com/Wallerian_....

3.      Funakoshi, M. & Araki, T. Mechanism of initiation and regulation of axonal degeneration with special reference to NMNATs and Sarm1. Neurosci. Res. S0168-0102(21)00223–6 (2021) doi:10.1016/j.neures.2021.11.002.

4.      Figley, M. D. & DiAntonio, A. The SARM1 axon degeneration pathway: control of the NAD+ metabolome regulates axon survival in health and disease. Curr. Opin. Neurobiol. 63, 59–66 (2020).

5.      Alexandris, A. S. et al. Protective effects of NAMPT or MAPK inhibitors and NaR on Wallerian degeneration of mammalian axons. Neurobiol. Dis. 171, 105808 (2022).

6.      Bratkowski, M. et al. Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease. Neuron 110, 3711-3726.e16 (2022).

7.      Loring, H. S., Parelkar, S. S., Mondal, S. & Thompson, P. R. Identification of the first noncompetitive SARM1 inhibitors. Bioorg. Med. Chem. 28, 115644 (2020).

8.      Peters, O. M. et al. Genetic diversity of axon degenerative mechanisms in models of Parkinson’s disease. Neurobiol. Dis. 155, 105368 (2021).

9.      Abdel-Magid, A. F. Dual Leucine Zipper Kinase Inhibitors: Potential Treatments for Neurodegenerative Diseases. ACS Med. Chem. Lett. 6, 11–12 (2014).

10.   Lundt, S. & Ding, S. NAD+ Metabolism and Diseases with Motor Dysfunction. Genes 12, 1776 (2021).

11.   Hikosaka, K., Yaku, K., Okabe, K. & Nakagawa, T. Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases. Nutr. Neurosci. 24, 371–383 (2021).

12.   Icso, J. D. & Thompson, P. R. The chemical biology of NAD+ regulation in axon degeneration. Curr. Opin. Chem. Biol. 69, 102176 (2022).

13.   Cercillieux, A., Ciarlo, E. & Canto, C. Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations. Cell. Mol. Life Sci. 79, 463 (2022).

14.   Sasaki, Y. et al. Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection. Exp. Neurol. 345, 113842 (2021).

15.   Martin, D. D. O. et al. Identification of Novel Inhibitors of DLK Palmitoylation and Signaling by High Content Screening. Sci. Rep. 9, 3632 (2019).

16.   Guo, J. Y. et al. Melatonin inhibits Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes to attenuate osteoarthritis. Oncotarget 8, 55967–55983 (2017).

17.   Huang, Y. et al. Nicotinamide Phosphoribosyl Transferase Controls NLRP3 Inflammasome Activity Through MAPK and NF-κB Signaling in Nucleus Pulposus Cells, as Suppressed by Melatonin. Inflammation 43, 796–809 (2020).

18.   Ding, Y.-Y. et al. α-Mangostin reduced the viability of A594 cells in vitro by provoking ROS production through downregulation of NAMPT/NAD. Cell Stress Chaperones 25, 163–172 (2020).

19.   Hu, Y.-H. et al. α-Mangostin Alleviated Inflammation in Rats With Adjuvant-Induced Arthritis by Disrupting Adipocytes-Mediated Metabolism-Immune Feedback. Front. Pharmacol. 12, 692806 (2021).

20.   Tao, M. et al. α-Mangostin Alleviated Lipopolysaccharide Induced Acute Lung Injury in Rats by Suppressing NAMPT/NAD Controlled Inflammatory Reactions. Evid.-Based Complement. Altern. Med. ECAM 2018, 5470187 (2018).

21.   Nopparat, C., Porter, J. E., Ebadi, M. & Govitrapong, P. The mechanism for the neuroprotective effect of melatonin against methamphetamine-induced autophagy. J. Pineal Res. 49, 382–389 (2010).

22.   Lu, K.-H. et al. Melatonin attenuates osteosarcoma cell invasion by suppression of C-C motif chemokine ligand 24 through inhibition of the c-Jun N-terminal kinase pathway. J. Pineal Res. 65, e12507 (2018).

 

[Larochka]

Hi, dear House2! Just got the final results EMG, CSF, contrast MRI Cervical, Thorax, Brain … NOTHING!!! suggests I have any autoimmune disorder via CNS… he did the full spectrum antibodies test as well, including GAD65; GABA - A… nothing indicates “Stiff Person Syndrome”, and yet, spams non stop…. Beyond me, he wants me to go back to my Orthopedic doc, who initially referred to this Neurologist….

I’m so lost;(

I take NAD+ True Niagen, as well Melatonin & Berberine from dr Mercola … and multiple other supplements, stoped B6 all together … AIP life style for many years, all organic of cause, supplements including, yet, can’t walk, labrum tear, dislocated pelvis due to all those contractions, inadequate physical therapy, tore me apart - bedridden now

[House2 in reply to Larochka]

Try binaural beats

healthunlocked.com/cure-par...

[Larochka in reply to House2]

will do, thank you so much !!

[House2 in reply to Larochka]

I take this for spasms

vitanica.com/online-store/g...

[Larochka in reply to House2]

good read … drjockers.com/gaba/

[Little_apple in reply to House2]

GABA decreases dopamine from what I’ve read

[Larochka]

excellent ! Was just about to oder 2bt 60count, when I saw B6 in the formulae, B6 toxicity I might have talking… I’m debating, a bit confused, since I thought one of the issuer spams related B6 toxicity in my case, what do you think, dear House2?

[House2 in reply to Larochka]

Was that you who had findings in your pons/brainstem?

[Larochka in reply to House2]

initial MRI 3 weeks ago showed hot cross signal in pons, now yesterday MRI shows the signal close to pons area, but not close enough to be worry, according to my Neurologist, as well as the CSF antibody, inflammatory makers, spinal fluid test - all negative … not even sure what all that means, to be honest, since my spams so sever, especially after trying C/L one day … beyond me

[Sydney75 in reply to Larochka]

Pharmagaba design for health has no B6

[Larochka in reply to Sydney75]

thank you Sydney75 so much ! I already found one at dr Jockers store, would appreciate your opinion about this product in particular store.drjockers.com/product...

[Gcf51]

Nothing said about Niacin or Niacin time release to increase NAD???

Is it a yea or nay???

[House2 in reply to Gcf51]

I think niacin gets converted to NMN, which in PD is not a good idea.

[Little_apple in reply to House2]

 inside cells, NR gets converted to NMN via enzymes called 'NRKs. ' Once NMN has been synthesized, the molecules enter the 'nicotinamide core recycling pathway. ' In the 'nicotinamide core recycling pathway,' the enzyme, NMNAT, converts NMN to NAD+.

I don’t recall the source but I had that quote in my notes.

although the issue of SARM is a serious one, increasing NAD is of so much importance that although a moderate and cautious approach is needed, supplementing with NAD precursors should still be considered.

Or, what about intravenous NAD? icryo.com/nad-iv-therapy/

[Gcf51 in reply to House2]

I admit this is way over my head. I used this diagram to explain why you should not take Nicotinamide, but according to this diagram Nicotinic Riboside (NR) gets converted to NMN.

Why you should not take Nicotinamide

[House2 in reply to Gcf51]

Results Phase 1 study

cell.com/cell-metabolism/fu...

[House2 in reply to Gcf51]

Collectively, our data indicate that maintaining NAD+ is not sufficient to protect DRG neurons from vincristine-induced axon degeneration, and elevating NMN, by itself, is not sufficient to cause degeneration. Nonetheless, the combination of FK866 and NAR, which bypasses NMN formation, may provide a therapeutic strategy for neuroprotection.

pubmed.ncbi.nlm.nih.gov/302...

[Little_apple in reply to Gcf51]

NR does get converted to NMN (is my understanding too)

[House2 in reply to Little_apple]

Even if you block NAMPT?

[Gcf51 in reply to Gcf51]

So the first diagram is wrong, where does Nicotinic Riboside (NR) enter the cycle.

This diagram shows a second path for NR to get to NMN.

2nd NAD

[House2 in reply to Gcf51]

"the scientists at Disarm Therapeutics and Evotec showed that NMN and NAD+ compete for a single binding site on SARM1.

When NMN is bound to SARM1, the enzyme is activated. However, when NAD+ is bound to SARM1, the enzyme is inhibited."

[Gcf51 in reply to House2]

Not trying to make a dead horse run:

I wish I could follow tech/medical jargon in my head. I need Pictures to try to understand. I can find/see 2 paths for NR to get to NMN and none for NR to get NAD+ without being processed into NMN before hand.

[Boscoejean]

so what does the NMN do that is bad?

[House2 in reply to Boscoejean]

healthunlocked.com/cure-par...

[Gcf51 in reply to House2]

Is there something simpler? That link just flew over my head.

[House2 in reply to Boscoejean]

the scientists at Disarm Therapeutics and Evotec showed that NMN and NAD+ compete for a single binding site on SARM1.

When NMN is bound to SARM1, the enzyme is activated. However, when NAD+ is bound to SARM1, the enzyme is inhibited."

[PDWarrior1900]

good post, thanks!