NAD+, NMN, SARM1 and neuroprotection. - Cure Parkinson's

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NAD+, NMN, SARM1 and neuroprotection.

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FOR INFORMATIONAL PURPOSES ONLY

………..Wallerian Degeneration…………….

Axons are considered to be a particularly vulnerable component of the nervous system; impairment of a neuron's axon leads to an effective silencing of a neuron's ability to communicate with other cells. 1

The nervous system has therefore evolved plasticity mechanisms for adapting to axonal damage. These include acute mechanisms that promote the degeneration and clearance of damaged axons and, in some cases, the initiation of new axonal growth and synapse formation to rebuild lost connections. 1

One such mechanism, Wallerian Degeneration, is an active programmed process of  degeneration of an axon that is triggered by  nerve damage or insult.  2

Axonal degeneration is observed in a variety of contexts in both the central and peripheral nervous systems. The pathological signaling programs that  regulate the progression of axonal degeneration have  been studied using Wallerian degeneration models. 3

Axons are essential for nervous system function and axonal pathology is a common hallmark of many neurodegenerative diseases. Over a century and a half since the original description of Wallerian axon degeneration, advances over the past five years have heralded the emergence of a comprehensive, mechanistic model of an endogenous axon degenerative process that can be activated by both injury and disease. 4

Wallerian degeneration is a conserved axonal self-destruction program implicated in a number of neurological diseases. It  is driven in part, by  the activation of the NAD+ degrading SARM1 pathway, eventually leading to axonal fragmentation and degeneration. 5

Axon degeneration is an early pathological event in many neurological diseases. 6

Sterile Alpha and Toll Interleukin Receptor Motif-containing protein 1 (SARM1) has been identified as a key driver of axon degeneration and an emerging therapeutic target for diseases that exhibit Wallerian-like degeneration.  These diseases include traumatic brain injury, peripheral neuropathy, and neurodegenerative diseases. 7

Thus genes, like SARM1, that drive the Wallerian degeneration process, are excellent candidates as  therapeutic targets for treatment of conditions that involve  axon degeneration including  Parkinson’s Disease. 8

Another pathway associated with active axon degeneration involves Dual Leucine-zipper Kinase (DLK) [also known as mitogen-activated protein kinase kinase kinase 12 (MAP3K12)] which  is expressed predominately in neuronal cells. DLK and its downstream enzyme, c-Jun N-terminal kinase (JNK), play major roles in neuron apoptosis and degeneration. 9

The following paragraphs  review how these diverse processes are influenced by the therapeutically targetable enzyme SARM1 and how SARM1 catalyzes the breakdown of NAD+, which, when unmitigated, can lead to depletion of this essential metabolite and ultimately axonal degeneration. 1

……… Pro-survival versus axon degeneration…..


Nicotinamide adenine dinucleotide (NAD+) is one of the most abundant metabolites in the human body and is predominantly synthesized through the NAD+ salvage pathway in mammalian cells, where nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme.  10

NAD+ is a critical cofactor in numerous reactions, with its role in energy metabolism (glycolysis, TCA cycle, oxidative phosphorylation, and fatty acid oxidation) being the most well-known. NAD+ also functions as a substrate for certain NAD+-consuming enzymes, including sirtuins, poly-(ADP-ribose) polymerases (Parps), CD38/157, and sterile α and TIR motif-containing protein 1 (SARM1). 10

Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme that mediates various redox reactions. Particularly, mitochondrial NAD plays a critical role in energy production pathways. 11

The balance between axon survival and self-destruction is intimately tied to axonal NAD+ metabolism. These mechanistic insights may enable axon-protective therapies for a variety of human neurodegenerative diseases including peripheral neuropathy, traumatic brain injury and potentially ALS and Parkinson's.  4

Axonal integrity is maintained by the opposing actions of the survival factors NMNAT2 and STMN2 and pro-degenerative molecules DLK and SARM1. 4

During axon degeneration, NAD+ levels are largely controlled  by the  enzyme: SARM1 (sterile alpha and toll interleukin motif containing protein 1).  12

SARM1 activity  decreases the concentration of NAD+ 12

SARM1 promotes neurodegeneration by catalyzing the hydrolysis of NAD+ to form a mixture of ADPR and cADPR. 7

 SARM1 knockout mice (mice bred to genetically lack the SARM1 gene) show decreased neurodegeneration in animal models of axon degeneration, highlighting the therapeutic potential of targeting this novel NAD+ hydrolase. 12

 Since  genetic  SARM1 knockdown prevents degeneration, it suggests that SARM1 inhibitors will also likely be efficacious in treating  diseases characterized by neurodegeneration. 7

Consistent with this hypothesis is the observation that NAD+ supplementation is axoprotective. 7

 Understanding metabolism of nicotinamide adenine dinucleotide (NAD+) and the functional regulation of Sarm1 has generated great progress in this field.   Described here is our current understanding of the axonal degeneration mechanism, with special reference to the biology related to  Sarm1.  3

 

…………. NAD+ Metabolism……………..

The first step in the synthesis of NAD+ from nicotinic acid amide (or nicotinamide, NAM) NAM is catalyzed by the Nicotinamide phophoribosyltransferase (NAMPT) enzyme. By virtue of this enzymatic reaction, NAM is transformed into nicotinamide mononucleotide (NMN), which is then used by NMNATs to synthesize NAD+ 13

However, Nicotinamide Mono-Nucleotide (NMN) accumulation can activate SARM1, elevating cellular cADPr levels while depleting NAD+, ultimately leading to non-apoptotic cell death. SARM1 is known to be an important contributor in regulating axonal degeneration (discussed below).  13

SARM1 is an inducible NAD+ hydrolase that is the central executioner of pathological axon loss. 14

 Recently, researchers  elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD+ and its precursor, nicotinamide mononucleotide (NMN). 14

 In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to the SARM1 allosteric binding site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD+ ratio and thereby promoting NMN binding to the SARM1 binding site, which in turn  activates the SARM1 NAD+ hydrolase; ultimately depleting NAD+ 14

 Hence, NAD+ metabolites both regulate the activation of SARM1 and, in turn, are regulated by the SARM1 NAD+ hydrolase. 14

 This dual upstream and downstream role for NAD+ metabolites in SARM1 function has hindered mechanistic understanding of axoprotective mechanisms that manipulate the NAD+ metabolome. 14

 Counterintuitively, attempting to salvage neurons by raising neuronal NAD+ levels through raising the NAD+ precursor, NMN, may inadvertently  activate the pro-neurodegenerative (sARM1) pathway in vulnerable axons.

 Less is  known about the second pro-neurodegenerative enzyme  Dual Leucine-zipper Kinase (DLK).

 After axonal insult and injury, Dual Leucine-zipper Kinase (DLK) conveys retrograde pro-degenerative signals to neuronal cell bodies via its downstream target c-Jun N-terminal kinase (JNK). Researchers  recently reported that such signals critically require modification of DLK by the fatty acid palmitate, via a process called palmitoylation. Compounds that inhibit DLK palmitoylation could thus reduce neurodegeneration, but identifying such inhibitors requires a suitable assay.15

 Experimental results seem to suggest an application of this knowledge in patient care.

 Pharmacological strategies that modulate NMN and NAD+ metabolism, namely the inhibition of the NMN-synthesizing enzyme NAMPT, activation of the nicotinic acid riboside (NaR) salvage pathway and inhibition of the NMNAT2-degrading DLK MAPK pathway in an axotomy model in vitro were explored. 5

Results show that NAMPT  inhibition causes a significant  delay of Wallerian axon degeneration. This neuroprotection is related to reduction of NMN by blocking the enzyme responsible for its synthesis (NAMPT) and elevation of NAD+ using the alternative precursor molecule Nicotinamide Riboside (NR). 5

 Other studies show how NR could increase NAD+ levels in cultured mammalian cells, rodent tissues and peripheral blood mononuclear cells in humans after oral administration. The ability of NR to act as a NAD+ precursor in mammalian cells and organisms has since been replicated by multiple independent labs. 13

 Supplementation of NAMPT inhibition with Nicotinamide Riboside has an enhanced effect that does not depend on timing of intervention and leads to robust neural protection. 5

 In humans, NR has been administered to doses up to 2 g/day, without any apparent side effects. 13

 The observed neuroprotection could be further extended by the addition of  DLK inhibition.

 Therefore, DLK inhibitors may potentially be effective in the inhibition of the DLK/JNK pathway to provide greatly needed treatments for many neurological diseases and disorders resulting from neurodegeneration. 9

 Metabolite analyses revealed complex effects indicating that NAMPT and DLK/MAPK inhibition act by reducing NMN levels, ameliorating NAD+ loss and suppressing SARM1 activity. 5

 ……………… NAD, SARM1 and Parkinson’s ……………………..

 NAD regulates energy metabolism, DNA damage repair, gene expression, and stress response. Numerous studies have demonstrated the involvement of NAD metabolism in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and retinal degenerative diseases. 11

  Mitochondrial dysfunction is considered crucial pathogenesis for neurodegenerative diseases such as AD and PD. Maintaining appropriate NAD levels is important for mitochondrial function. Indeed, decreased NAD levels are observed in AD and PD, and supplementation of NAD precursors ameliorates disease phenotypes by activating mitochondrial functions. 11

 

Summary: Targets to impede neurodegeneration. 

 

1.  Maintain adequate levels of neuronal NAD+.

2.  Use Nicotinic Riboside

3.  Avoid NMN

4.  Block NAMPT

a.   Mangostin inhibits NAMPT 16–18

5.  Block SARM1

a.   berberine  inhibits SARM1. 7

6.  Block DLK

a.   palmitoylation inhibitors

  .......... 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.   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).

17.   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).

18.   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).

 

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House2
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Bolt_Upright profile image
Bolt_Upright

Powerful stuff House2! I like that Berberine is good!

Now to the brass tacks. This part got my interest:

"The first step in the synthesis of NAD+ from nicotinic acid amide (or nicotinamide, NAM) NAM is catalyzed by the Nicotinamide phophoribosyltransferase (NAMPT) enzyme. By virtue of this enzymatic reaction, NAM is transformed into nicotinamide mononucleotide (NMN), which is then used by NMNATs to synthesize NAD+ 13

However, Nicotinamide Mono-Nucleotide (NMN) accumulation can activate SARM1, elevating cellular cADPr levels while depleting NAD+, ultimately leading to non-apoptotic cell death. SARM1 is known to be an important contributor in regulating axonal degeneration (discussed below). 13

SARM1 is an inducible NAD+ hydrolase that is the central executioner of pathological axon loss. 14"

Here is my bone to pick: The article says NAM is a bad NAD+ precursor as it creates NMN and NMN can activate SARM1 and SARM1 is bad so use NR.

Fair enough, and GOOD TO KNOW, but! (I have a HS degree): Nicotinic Acid is a NAD+ precursor and does not create NMN. In fact, the NA to NAD process wikipathways.org/index.php/... seems to create "Nicotinic Acid Mononucleotide" on its way to creating NAD.

And this is very cool: Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection 2022 biorxiv.org/content/10.1101...

NA to NAD
House2 profile image
House2 in reply toBolt_Upright

I think in humans, the major pathway is the salvage not the Preiss-Handler pathway.

Bolt_Upright profile image
Bolt_Upright in reply toHouse2

Thanks. I hope you don't mind this discussion. You have raised a VERY important issue and I and We need to get this right.

Everything I find say Preiss-Handler pathway for Nicotinic Acid. Nicotinic Acid seems to be special:

neurohacker.com/how-is-nad-...

"The Salvage Pathway: Introduction

The salvage pathway is used to produce NAD+ from nicotinamide molecules. Whether the source of the nicotinamide is vitamin B3 (as niacinamide), newer nicotinamides (e.g., nicotinamide riboside [NR], nicotinamide mononucleotide [NMN]), or molecules in food that get broken down during digestion into nicotinamide, the salvage pathway turns them into NAD+ in our tissues.

We can make the NAD+ molecule starting from three different pathways. These are (1) synthesizing it from one of the salvage pathway substrates mentioned above (i.e., NAM, NR, NMN), (2) producing it from niacin (nicotinic acid; NA) by the Preiss-Handler pathway, or (3) building the niacinamide molecule from scratch starting from L-tryptophan (Trp) using the de novo synthesis pathway. But, no matter which of these ways is used to make NAD+ the first time, the salvage pathway is the way we remake NAD+ after it gets used for cell signaling purposes (i.e., NAD+ consumption uses)."

And:

NAD+ biosynthetic pathways (Homo sapiens) wikipathways.org/index.php/...

Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations link.springer.com/article/1...

I really appreciate your sharing this info. It is important stuff.

Little_apple profile image
Little_apple in reply toBolt_Upright

compounds, we confirm NMN is metabolized extracellularly to NR that is then taken up by the cell and converted into NAD+. Our results indicate that mammalian cells require conversion of extracellular NMN to NR for cellular uptake and NAD+ synthesis, explaining the overlapping metabolic effects observed with the two compounds.

nature.com/articles/ncomms1...

SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+, thereby inducing feedforward metabolic catastrophe and axonal demise.

pubmed.ncbi.nlm.nih.gov/336...

😳

SARM1 is a newly discovered NAD+ cleavage enzyme in neurons and possibly other cell types (Conforti et al., 2014, Essuman et al., 2017, Gerdts et al., 2013, Osterloh et al., 2012). It is the first member of a new class of NAD+-consuming enzymes and unique among NADases in that its activity is dependent on SARM1’s Toll/interleukin-1 receptor (TIR) domain. Moreover, it is the first example of a TIR domain, previously demonstrated to function as a protein interaction domain, possessing enzymatic activity. In response to neuronal injury, the catalytic TIR domain of SARM1 initiates a cell destruction program by converting cytoplasmic NAD+ to ADPR, cADPR, and NAM (Essuman et al., 2017). This depletes the cell of NAD+and triggers axonal degeneration, which can be blocked by overexpression of NAMPT or NMNAT and by supplementation with NR (Gerdts et al., 2015). Knockout of SARM1 rescues the neuronal defects and embryonic lethality of NMNAT2-KO mice that are defective in their ability to salvage NAD+ (Gilley et al., 2015), indicating that SARM1 is a consumer of NAD+even during embryonic development. Taken together, these results point to SARM1 as an attractive therapeutic target for the treatment of acute neuronal damage and possibly neurodegenerative diseases.

***SARM1 is a consumer of NAD+ ***

2010). There is some evidence indicating that NMN treatment promotes axon degeneration and that the dependence on NMNAT2 for axon survival is due to its consumption of NMN rather than its NAD synthesis activity (Di Stefano et al., 2015). This is supported by recent in vivo work in zebrafish larvae and mice

sciencedirect.com/science/a...

Bolt_Upright profile image
Bolt_Upright in reply toHouse2

@House2 , I did not realize you wrote the article. Very impressive. I take back my "bone to pick" and replace it with a "quibble".

House2 profile image
House2 in reply toBolt_Upright

I appreciate the feedback, Biochemistry is Not my strength

Little_apple profile image
Little_apple in reply toHouse2

can you please explain (again) why NR is good for boosting NAD but NMN is not? NMN increases SARM1 but NR does not? But both NR and NMN are converted to NAD and NMN is converted to NR before being converted to NAD so how is SARM1 up regulated with one and not the other?

Are you familiar with Dr. David Sinclair from Harvard? He has millions of dollars and his reputation at stake. He is active on Twitter and Instagram. You should present your concerns to him. He is working on getting NMN to be considered as a pharmaceutical with the FDA. This is a business maneuver bc he is invested in the NMN company.

House2 profile image
House2 in reply toLittle_apple

This study is pretty compelling I think...

1. Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):10654-10659.

Pharmacological bypass of NAD(+) salvage pathway protects neurons from

chemotherapy-induced degeneration.

Liu HW(1), Smith CB(1), Schmidt MS(2)

Axon degeneration, a hallmark of chemotherapy-induced peripheral neuropathy

(CIPN), is thought to be caused by a loss of the essential metabolite

nicotinamide adenine dinucleotide (NAD+) via the prodegenerative protein SARM1.

Some studies challenge this notion, however, and suggest that an aberrant

increase in a direct precursor of NAD+, nicotinamide mononucleotide (NMN),

rather than loss of NAD+, is responsible.

In support of this idea, blocking NMN accumulation in neurons by expressing

a bacterial NMN deamidase protected axons from degeneration. We hypothesized

that protection could similarly be achieved by reducing NMN production

pharmacologically.

To achieve this, we took advantage of an alternative pathway for NAD+

generation that goes through the intermediate nicotinic acid mononucleotide (NAMN)

rather than NMN.

We discovered that nicotinic acid riboside (NAR), a precursor of NAMN,

administered in combination with FK866, an inhibitor of the enzyme nicotinamide phosphoribosyltransferase (NAAMPT)that produces NMN, protected dorsal

root ganglion (DRG) axons against vincristine-induced degeneration as well as

NMN deamidase.

>>>Introducing a different bacterial enzyme that converts NAMN to NMN

reversed this protection.<<<

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.

{blocking NMN while increasing NAD+ via NR confers neuroprotection}

Little_apple profile image
Little_apple in reply toBolt_Upright

Bolt, House, can you please confirm that our current takeaway based on info we have resentments shared is that NMN increases SARM1 but Nicotinic acid mononucleotide, and NR do not. ??

And Nicotinic acid mononucleotide is the same or different than Nicotinic acid? Same, correct?

I’ve asked Dr. Brad Stanfield bc he bravely disputes Dr. Sinclair. Dr. Stanfields response was that he highly doubts that NMN increases SARM1. I’ve responded that I’m not hypothesizing this but sharing what substantial literature on this states. Im hoping to eventually get answers from Dr. Sinclair on this.

Im so grateful House that you have shined a light on this.

Bolt_Upright profile image
Bolt_Upright in reply toLittle_apple

What I read is that "Nicotinic acid mononucleotide" is NAM and NAM converts to NMN, so my takeaway was both NAM and NMN were less than optimal. Does that sound right to you @house2 ?

Little_apple profile image
Little_apple in reply toBolt_Upright

But…

Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection

biorxiv.org/content/10.1101...

Did you see this

nad.com/news/small-molecule...

Bolt_Upright profile image
Bolt_Upright in reply toLittle_apple

In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to this allosteric site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD+ ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the SARM1 NAD+ hydrolase.

Little_apple profile image
Little_apple in reply toBolt_Upright

thank you! Imperative distinction!

I’m a bit petrified and paranoid now. NR good, Niacin good, NMN not good bc

“with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD+ ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the SARM1 NAD+ hydrolase”

This has been extremely important to learn! But, my anxiety is through the roof now and, as is evident I’m sure, my OCD is kicked in to high gear. Which is why I leave and come back, leave and come back. Balance is hard for me. I think Azilect is maybe making my OCD worse. I’ve got the same “gift” as you Bolt, I’m sure of it. Plus the OCD and anxiety etc etc etc etc etc!

I must go cold Turkey on HU again to refocus on work. OCD is challenging.

Bolt_Upright profile image
Bolt_Upright in reply toLittle_apple

Try not to get too worried. I doubt you have done any damage. It is just time to change horses.

Bolt_Upright profile image
Bolt_Upright in reply toLittle_apple

That second link is about something called "DSRM-3716".

Little_apple profile image
Little_apple in reply toBolt_Upright

it’s a SARM1 inhibitor being researched. Other than Berberine, are there good supplemental options for inhibiting SARM1? Melatonin I think.

House2 profile image
House2 in reply toHouse2

In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to the SARM1 allosteric binding site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD+ ratio and thereby promoting NMN binding to the SARM1 binding site, which in turn activates the SARM1 NAD+ hydrolase; ultimately depleting NAD+ 14

Little_apple profile image
Little_apple in reply toHouse2

“In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to the SARM1 allosteric binding site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD+ ratio and thereby promoting NMN binding to the SARM1 binding site, which in turn activates the SARM1 NAD+ hydrolase; ultimately depleting NAD+ 14”

Restating for emphasis and so I can find it later. I will use this info when writing to doctors promoting NMN as “safe,” doctors who I felt compelled by to take NMN.

Little_apple profile image
Little_apple in reply toHouse2

NMN reduces methylation so it’s recommended to take TMG / Betaine when taking NMN. That , I don’t think, is relevant to the subject of SARM1, or is it ?

Bolt_Upright profile image
Bolt_Upright

Important takeaways:

NAM may not be a good NAD precursor as it creates NMN and NMN activates SARM1 and SARM1 is known to be an important contributor in regulating axonal degeneration.

Berberine inhibits SARM1.

House2 profile image
House2 in reply toBolt_Upright

Mangosteen blocks NAMPT

Little_apple profile image
Little_apple in reply toHouse2

Yes, it does but it has detrimental affects. Correct me if I’m not getting it

— Data showed that α-mangostin decreased mitochondrial membrane integrity and inhibited NAMPT signaling, thus depleting NAD production, upregulating ROS ...

sciencedirect.com/science/a...

House2 profile image
House2 in reply toLittle_apple

melatonin blocks NAMPT also

park_bear profile image
park_bear

Your own work? Very impressive.

House2 profile image
House2 in reply topark_bear

Yes my work, which is why it needs scrutiny!

Bolt_Upright profile image
Bolt_Upright

This is interesting. Looks like you can't avoid NAM totally:

"No matter how NAD+ is made the first time, after NAD+ is consumed in NAD+-dependent signaling reactions, NAM will be generated. Because of this, if a precursor is capable of increasing NAD+, it can also increase NAM. Put another way, NAM levels increase in our bodies no matter which niacin equivalent we start from in a supplement. What’s often overlooked with the newer niacin equivalents (NR, NMN) is that these newer niacins increase NAM in tissues and require it to be salvaged, as does everything with niacin equivalent activity."

neurohacker.com/how-is-nad-...

Bolt_Upright profile image
Bolt_Upright

More related material: (maybe take B12 and Folates)

"Methylation support is especially important when higher doses of NAM, NR, and NMN are given, but is also important if NA or Trp are used, because anything that builds more NAD+ can increase demands on methylation. Free NAM can be excreted unmetabolized if methylation capacities are exceeded. Moderate doses that are several-fold higher than the daily value for vitamin B3 are below the threshold where free NAM appears in the urine based on research in this area, but still increase methylation demands much more than a daily value amount (i.e., a low dose).(124–128)

Rather than giving high doses of a single NAD+ salvage precursor (which will substantially increase methylated NAM metabolites), we think a better long-term strategy is to give more modest doses of NAD+ precursors, while also supplying extra methylation support. Methylation can be supported with folates (5-MTFR, folinic acid) and vitamin B12 (cobalamins such as methylcobalamin or adenosylcobalamin). "

House2 profile image
House2 in reply toBolt_Upright

Interesting, I take about 1/3 of the typical NR dose.

Little_apple profile image
Little_apple in reply toBolt_Upright

TMG / Betaine supports methylation and is recommended when taking NMN. Dr. David Sinclair has mentioned taking it and talks up NMN

Bolt_Upright profile image
Bolt_Upright in reply toLittle_apple

Thanks for sharing. I have a big bag full of Betaine :)

Bolt_Upright profile image
Bolt_Upright in reply toLittle_apple

Comprehensive paper: Betaine in Inflammation: Mechanistic Aspects and Applications 2018 ncbi.nlm.nih.gov/pmc/articl...

Thankyou House2 for the research and write up. I'm trying to distill the essential actionable takeaways for those of us trying to come up with a PD treatment protocol.

I think my take aways are

- stop taking NMN (which I've been on for a year)

- start taking NR (question, how much?)

- start taking berberine

Am I understanding your writing correctly?

Thankyou,

Francis aka FightTheGoodFight

Little_apple profile image
Little_apple in reply toFightTheGoodFight

I’ve been taking it for about a year as well. Have you noticed affects from it?

FightTheGoodFight profile image
FightTheGoodFight in reply toLittle_apple

Little_apple - I was trying to mimic David Sinclairs longevity stack, which I did for about a year. It's hard to say if it made a compelling difference; I certainly felt good, but that could be diet, sauna , exercise, other supplements, etc. Then in October I got a PD diagnosis, and have been focused on addressing that over any other concern.

Little_apple profile image
Little_apple

Metro Biotech is conducting in human NMN trials. Dr. David Sinclair was an early investor in this company.

metrobiotech.com/

Dr. Sinclairs instagram
House2 profile image
House2 in reply toLittle_apple

This study is pretty compelling I think...

1. Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):10654-10659.

Pharmacological bypass of NAD(+) salvage pathway protects neurons from

chemotherapy-induced degeneration.

Liu HW(1), Smith CB(1), Schmidt MS(2)

Axon degeneration, a hallmark of chemotherapy-induced peripheral neuropathy

(CIPN), is thought to be caused by a loss of the essential metabolite

nicotinamide adenine dinucleotide (NAD+) via the prodegenerative protein SARM1.

Some studies challenge this notion, however, and suggest that an aberrant

increase in a direct precursor of NAD+, nicotinamide mononucleotide (NMN),

rather than loss of NAD+, is responsible.

In support of this idea, blocking NMN accumulation in neurons by expressing

a bacterial NMN deamidase protected axons from degeneration. We hypothesized

that protection could similarly be achieved by reducing NMN production

pharmacologically.

To achieve this, we took advantage of an alternative pathway for NAD+

generation that goes through the intermediate nicotinic acid mononucleotide (NAMN)

rather than NMN.

We discovered that nicotinic acid riboside (NAR), a precursor of NAMN,

administered in combination with FK866, an inhibitor of the enzyme nicotinamide phosphoribosyltransferase (NAAMPT)that produces NMN, protected dorsal

root ganglion (DRG) axons against vincristine-induced degeneration as well as

NMN deamidase.

>>>Introducing a different bacterial enzyme that converts NAMN to NMN

reversed this protection.<<<

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.

{blocking NMN while increasing NAD+ via NR confers neuroprotection}

Little_apple profile image
Little_apple in reply toHouse2

I am immensely grateful to you House2 and I am horrified that I have been taking NMN. Recently my neuropathy has worsened and I naively did not associate it with my PD. I’ve written to Do Not Age, the company from whom I purchase NMN and I think I will write to Dr. Sinclair as well.

Little_apple profile image
Little_apple

ASO therapy reduced SARM1

Antisense Oligonucleotide Therapy for Neurodevelopmental Disorders

karger.com/Article/FullText...

Gioc profile image
Gioc

great work , House2 , thanks

. In my opinion to benefit from the increase in NAD+, the gradual increase in NAD is the point! This will avoid all harmful imbalances between the various products and by-products. We need to give the body time to balance the reactions and for this I believe that a supplementation with very gradual increases with nicotic acid also called vitamins B3 N A supported by all the other vitamins and minerals is the best solution. Simplifying and in short.

SilentEchoes profile image
SilentEchoes

I really appreciate this thoughtful, supportive, respectful and collaborative discussion. This is how we move the needle closer to a cure for all of us.

It also highlights how we could unintentionally harm ourselves with supplementation. Probably my biggest concern. Life is fragile.

The discussion touched briefly on methylation. I would like to talk more about methylation and sulfation pathway support. Many (most?) ppl with nerve and neurological injury have MTHFR genetic mutations that I believe makes us less resilient to toxic insults. And I would like to know more about the relationship with NAD+.

Currently in hospital so not able to contribute much. The upside is I got my insurance to pay for a round of ketamine. IFYKYK.

Bolt_Upright profile image
Bolt_Upright in reply toSilentEchoes

All I know is what I posted earlier in this thread: NA taxes the methylation (system?) and "Methylation can be supported with folates (5-MTFR, folinic acid) and vitamin B12 (cobalamins such as methylcobalamin or adenosylcobalamin)". And per Little_apple Betaine also supports methylation.

Little_apple profile image
Little_apple in reply toSilentEchoes

There is a genetic test for MTHFR variations. But there’s also a cheaper and more accurate way to test for whether MTHFR variations are causing disease. We simply check the levels of homocysteine in the blood. If levels are high, we can react appropriately. If homocysteine levels are normal — even if there is an MTHFR variation — then nothing needs to be done clinically.In other words, the homocysteine levels determine our actions, not the MTHFR test results.

health.clevelandclinic.org/...

For those with MTHFR, avoiding folic acid is important. Supplementing with folate may not be sufficient. 5mthf might be a better route

thorne.com/products/dp/5-mt...

Because MTHFR reduces methylation, B3 and its various forms should be used with caution bc it reduces methylation. (NAD precursors like NMN, reduce methylation)

!!!??? NAD levels are lower with aging and low in PWP. But increasing NAD via NMN has the terrible downside of increasing SARM1 (as explained by House) and niacin / B3 in its various forms reduces methylation which is already lacking in people with the MTHFR mutation so how then are we to increase NAD levels to a healthy amount? Would intravenous NAD accomplish this?

The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease

sciencedirect.com/science/a...

INCREASING NAD LEVELS IS CLEARLY BENEFICIAL TO PWP BUT HOW DO WE DO THIS WITHOUT COMPROMISING METHYLATION AND INCREASING SARM1? IS INTRAVENOUS NAD A WAY TO ACCOMPLISH THIS?

Little_apple profile image
Little_apple

SARM1 inhibitor

nad.com/news/small-molecule...

DSRM-3716 is a Potent Blocker of SARM1

SilentEchoes profile image
SilentEchoes in reply toLittle_apple

Great find! "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."

Little_apple profile image
Little_apple in reply toSilentEchoes

Yep, so, if one was to increase NAD by means other than NMN, the increased NAD would inhibit SARM1 unless of course we have yet to find contrary information.

Little_apple profile image
Little_apple

SARM1 inhibitor

cell.com/cell-reports/pdfEx...

Bolt_Upright profile image
Bolt_Upright

So... I looked at Identification of the First Noncompetitive SARM1 Inhibitors ncbi.nlm.nih.gov/pmc/articl... and it is not "Berberine" that is a SARM1 inhibitor, but it is "Berberine Chloride". Berberine Chloride is about impossible to get hold of and does not look edible.

SilentEchoes profile image
SilentEchoes

NAD+ shots

Little_apple profile image
Little_apple in reply toSilentEchoes

or IV

icryo.com/nad-iv-therapy/?g...

House2 profile image
House2 in reply toLittle_apple

Have you considered getting NFL and neuron specific enolase blood tests to assess/monitor your state of neurodegeneration (as well as the effectiveness of your supplement routine )?

Little_apple profile image
Little_apple in reply toHouse2

Maybe. If many of us did this it could be informative. If I were to, what is the best starting point?

Have you gotten genetic testing?

I’m considering this:

youtu.be/VDMaYdVi_kg

House2 profile image
House2 in reply toLittle_apple

Doesn’t MJF have a genetic testing program?

SilentEchoes profile image
SilentEchoes in reply toLittle_apple

I did Dante Labs it's 30x (diagnostic grade) WGS. Cost has come down a lot, $199 US and they service Europe. us.dantelabs.com/

I had specific genetic testing done at the university, I have PARK9 missense mutation (ATP13A2 risk factor also linked to ALS). I ended up testing my family and running us through Prometheus prometheus.io/docs/introduc...

I couldn't find out what level of sequencing StrateGene performs. Do they give you access to the raw data to upload into other programs?

Another place to get personal genomic health data is Sequencing.com sequencing.com/

SE

Little_apple profile image
Little_apple in reply toSilentEchoes

seekinghealth.com/products/...

StrateGene is from Dr. Ben Lynch. 120 page report. Explained in video above

SilentEchoes profile image
SilentEchoes in reply toLittle_apple

Yes, very expensive about $1500 through functional med. doc. Needs to be infused slowly over several hours.

SilentEchoes profile image
SilentEchoes in reply toLittle_apple

I should have been more clear - IV infusion over several hours.

Little_apple profile image
Little_apple

House, I just got off the phone with the founder of the company Do Not Age. (DoNotAge.org) It is the company from which I have bought a lot of NMN. Initially we corresponded via email. Then he asked for my phone number. He has asked me to email my research. All research on this I have done thanks to your research and really, I’ve only validated what you have said. Therefore, I’m writing to ask, please can you help me with formulating questions for this company? There are researchers and doctors on their advisory board. He said something to the effect, “discuss this with my board.”

I would have preferred to message this privately but that feature appears to be changed.

House2 profile image
House2 in reply toLittle_apple

Feel free to copy my posts, they are referenced.

Little_apple profile image
Little_apple in reply toHouse2

Thank you. I will.

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