18 replies to this topic

[Logic]

Novel molecular targets of the neuroprotective/neurorescue multimodal iron chelating drug M30 in the mouse brain.

The Novel multifunctional brain permeable iron, chelator M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In the present study, we demonstrate that systemic chronic administration of M30 resulted in up-regulation of hypoxia-inducible factor (HIF)-1? protein levels in various brain regions (e.g. cortex, striatum, and hippocampus) and spinal cord of adult mice. Real-time RT-PCR revealed that M30 differentially induced HIF-1?-dependent target genes, including vascular endothelial growth factor (VEGF), erythropoietin (EPO), enolase-1, transferrin receptor (TfR), heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), and glucose transporter (GLUT)-1. In addition, mRNA expression levels of the growth factors, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) and three antioxidant enzymes (catalase, superoxide dismutase (SOD)-1, and glutathione peroxidase (GPx)) were up-regulated by M30 treatment in a brain-region-dependent manner. Signal transduction immunoblotting studies revealed that M30 induced a differential enhanced phosphorylation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK)/ERK kinase (MEK), protein kinase B (PKB/Akt), and glycogen synthase kinase-3? (GSK-3?). Together, these results suggest that the multifunctional iron chelator M30 can up-regulate a number of neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain that might function as important therapeutic targets for the drug in the context of neurodegenerative disease therapy.

http://www.ncbi.nlm....pubmed/21570450
 

Neuroprotection by the multitarget iron chelator M30 on age-related alterations in mice.

Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelating compound, M30, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we report that a chronic systemic treatment of aged mice with M30 (1 and 5mg/kg; 4 times weekly for 6 months), had a significant positive impact on neuropsychiatry functions and cognitive age-related impairment. M30 significantly reduced cerebral iron accumulation as demonstrated by Perl's staining, accompanied by a marked decrease in cerebral β-amyloid plaques. In addition, our results demonstrate that M30 caused a significant inhibition of both MAO-A and -B activities in the cerebellum of aged mice, compared with vehicle-treated aged control mice. In summary, the present study indicates that the novel MAO inhibitor/iron chelating drug, M30, acting against multiple brain targets could reverse age-associated memory impairment and provide a potential treatment against the progression of neurodegeneration in ageing.

http://www.ncbi.nlm....rations in mice.
 
Niner had this to say:
"Wow, M30 is a very interesting compound...expect it to take a hell of a long time to see the light of day. I imagine that intrepid experimenters could get a batch whipped up by a Chinese synthesis house without too much trouble."

http://www.longecity...ndpost&p=561890

I agree with him and feel that M30 deserves its own thread?

[Logic]

Sigma-Aldrich has it!

http://www.sigmaaldr...ng=en&region=ZA

[Nattzor]

Sigma-Aldrich has it!

http://www.sigmaaldr...ng=en&region=ZA

 

I don't think you know what Sigma-aldrich is. They have tons of supplier for everything, but they only sell to companies/universities. The prices on those sites are insane.

[Raza]

Interesting. If all of those things are downstream effects of reducing iron accumulation, then perhaps bacopa deserves another look while we wait for this to become available.

[Nattzor]

Interesting. If all of those things are downstream effects of reducing iron accumulation, then perhaps bacopa deserves another look while we wait for this to become available.

 

Hup A also reduces iron levels in the brain.

 

http://www.ncbi.nlm....pubmed/24332448

[Strangelove]

Niner had this to say:
"Wow, M30 is a very interesting compound...expect it to take a hell of a long time to see the light of day. I imagine that intrepid experimenters could get a batch whipped up by a Chinese synthesis house without too much trouble."

 

group buy anyone? This is very interesting, who developed it? My only concern is that could not use it continuously being a chelator?

 

I mean I do not think they have in mind to use it indefinitely only as a relatively short term cure? but maybe we want as its a MAOI A/B 

Edited by Strangelove, 17 June 2014 - 09:26 PM.

[Logic]

Chelators in the Treatment of Iron Accumulation in Parkinson's Disease
http://www.hindawi.c...cb/2012/983245/

"...Hydroxyquinoline is a bidentate chelator containing the 8-hydroxyquinoline (8-HQ) moiety. This structure forms stable 5-membered chelate rings with Fe3+ [95]. 8-HQ, a highly lipophilic complex, readily penetrates cell membranes and the BBB and, therefore, has been used as the base for orally effective chelators, including VK-28, M30, and clioquinol..."

"...Since VK-28 so far meets all the needs of an iron chelator, derivatives of VK-28 have been generated. M30, a potent brain-selective inhibitor of monoamine oxidase-A and -B (MAO-A and MAO-B, resp.) based around the pharmacore of VK-28..."
 
NB: DEFERIPRON: same paper; in Phase II trials?

"...Iron chelators, therefore, may be required to remove iron in a highly selective manner whilst stabilising iron levels elsewhere even within the same cell. Initial clinical trials [65] demonstrate that doses of deferiprone are well tolerated over the long term (6 months) with no stated propagation of a challenge to systemic iron homeostasis. The early successes of these patient studies demonstrate that this issue may not be as pertinent in PD as in FA. Furthermore, deferiprone itself has been shown to be highly selective when used at low concentrations in FA patients—relocating iron from areas of accumulation in the brain to ferritin, thereby preventing deprivation in other tissues..."

[tunt01]

Cilantro can chelate mercury.  I'm not sure if it can chelate iron or other heavy metals (it would be nice if someone researched this).  

[Logic]

Thx for the Hup A and Bacopa leads in this nootropic dominated sub-forum; keep em coming!

It would be great if there was a group buy for M30 or Deferipron (see previous post) which has had more testing.

[Flex]

From what I´ve read, is that Iron reacts with Dopamine and causing oxidative stress

http://pubs.acs.org/....1021/cn400105d

 

But interresting is, that seemingly increased Iron blood levels perhaps decrease brain iron content:

 

Increased Blood Iron Levels Linked to Reduced Parkinson’s Disease Risk

...This is not the first time that the relationship between iron levels and Parkinson’s disease has been investigated.  In past studies, researchers had noticed significant quantities of iron in the brains of people with PD. This study is different in that it look at levels of iron in the blood. Previous studies of blood iron showed conflicting results, but the majority of studies including this one, suggest that low iron levels in blood are associated with PD.

Right now, it is not clear how iron levels in the blood influence the iron levels in the brain in PD. Therefore, the potential development of new dietary and pharmaceutical treatments might treat PD by increasing blood iron, by decreasing stored iron in the brain or by using both strategies...

http://www.pdf.org/e...e/pr_1376577203

 

So as Logic said, maybe chelating the whole body iron "could" according from what I´ve understand,not be benefical.

Edited by Flex, 20 June 2014 - 02:14 PM.

[Dazzcat]

Very interesting molecule, thanks for sharing Logic.

 

The iron chelating effect sounds like a worth while approach to reducing long term iron neurotoxicity, I wonder if it also has affinity for aluminum? However, a real concern for me is the irreversible MAOI A & B properties, this may cause some serious side effects. I gather M30 would suit those who benefit from MAOI activity and can justify any side effects. This then raises a question, is there any significant iron chelation at sub MAOI doses?

[Logic]

Very interesting molecule, thanks for sharing Logic.
 
The iron chelating effect sounds like a worth while approach to reducing long term iron neurotoxicity, I wonder if it also has affinity for aluminum? However, a real concern for me is the irreversible MAOI A & B properties, this may cause some serious side effects. I gather M30 would suit those who benefit from MAOI activity and can justify any side effects. This then raises a question, is there any significant iron chelation at sub MAOI doses?

 
Check out Deferipron in post # 7, as well as the info on the non MOAI substances M30 is derived from.

"...Iron chelators, therefore, may be required to remove iron in a highly selective manner whilst stabilising iron levels elsewhere even within the same cell...deferiprone itself has been shown to be highly selective...relocating iron from areas of accumulation in the brain to ferritin, thereby preventing deprivation in other tissues..."

So basically M30 caught my eye 1st, but there is lots of info to digest in the supplied links.

 

I wonder though whether M30 might be the ideal substance to take when stopping/ed smoking?

Edited by Logic, 21 June 2014 - 05:53 PM.

[ceridwen]

I would definitely be interested in a group buy. While I'm waiting should I take Bacopa and Huperzine A? I have just noticed that the veins in  my hands are very swollen. I used to have really smooth hands. I've been suffering from Alzheimers since October. I used to have really smooth young looking hands. It looks as if they veins are really swollen makes my hands look much older. Thought you might be interested. I did notice that Bacopa and Huperzine A did make a difference when I took them before. I think I remember reading something about Mosaic Downs people aging over night hair going grey and so on. This seems to have just happened to my hands weird. Also I didn't go through the MCI stage before getting Alzheimers. Had a memory problem all my life though perhaps that was the MCI stage? I had felt reluctant to take Huperzine A and Bacopa together because I read that Bacopa can affect the heart when taken with something else and worried that if I take Huperzine A might inhibit any natural Acetycholine that I still have. Perhaps the time for worrying about that has past.Could we have a group buy of Bexarotene too please.

[Nattzor]

I would definitely be interested in a group buy. While I'm waiting should I take Bacopa and Huperzine A? I have just noticed that the veins in  my hands are very swollen. I used to have really smooth hands. I've been suffering from Alzheimers since October. I used to have really smooth young looking hands. It looks as if they veins are really swollen makes my hands look much older. Thought you might be interested. I did notice that Bacopa and Huperzine A did make a difference when I took them before. I think I remember reading something about Mosaic Downs people aging over night hair going grey and so on. This seems to have just happened to my hands weird. Also I didn't go through the MCI stage before getting Alzheimers. Had a memory problem all my life though perhaps that was the MCI stage? I had felt reluctant to take Huperzine A and Bacopa together because I read that Bacopa can affect the heart when taken with something else and worried that if I take Huperzine A might inhibit any natural Acetycholine that I still have. Perhaps the time for worrying about that has past.Could we have a group buy of Bexarotene too please.

 

 

If you have AD I'd recommend you to look into MB, it slows down progression by a lot. Also check out J147 (there's a seller for that soon, check the Isoxazole-9 + neurogenesis thread to see which company it is). NSI-189 could be worth too.

 

Holw old are you btw?

[ceridwen]

55

[ceridwen]

I tried to order today 2nd time of trying but I don't have a P.O. number and it was essential. HOw frustrating working against you getting well to live in a world which is actively working against you getting well

[Logic]

Ceridwen

 

There is a specific type of Alzheimer's which can basically be thought of as Diabetes of the brain. In this case EV Coconut Oil works as the brain is able to use the MCTs in it as fuel, rather than the glucose as is the norm.

 

Nattzor's advice on MB is also good, but look at taking it with Niacin as explained in Turnbuckle's profile page.  Note that Ascorbic Acid (Vit C) turns MB clear which makes it a lot less messy and may even improve its effectiveness. 

 

An easy and cheap way to drop excess iron is to donate blood.

 

I am sure that if you start a thread looking for someone with the required credentials to help you buy these research chems/chelators ; someone will.

[Logic]

"...Another mechanistic effect of M30 and structurally related chelators is induction of hypoxia-inducible factor-1α (HIF-1α), possibly through enhanced phosphorylation of the p42/44 mitogen-activated protein kinase (MAPK)/ER kinase (MEK) and protein kinase C (PKC) signaling pathways (Avramovich-Tirosh et al., 2010). As a transcriptional activator, HIF-1α is known to regulate a range of neuroprotective signaling pathways and treatment with M30 was shown to increase the gene expression of erythropoietin (EPO), vascular endothelial growth factor (VEGF), enolase 1 and inducible nitric oxide synthase (iNOS) in NSC-34 cells (Kupershmidt et al., 2009), and rat primary embryonic cortical neurons (Avramovich-Tirosh et al., 2010). In vivo mice studies with M30 showed upregulation of HIF-1α protein in brain (cortex, hippocampus, and striatum) and spinal cord when given over 30days. Enhanced HIF-1α levels coincided with increased gene expression of EPO, VEGF, iNOS, glucose transporter 1 (GLUT-1), and heme oxygenase-1 (HO-1) in one or more brain regions but only VEGF showed upregulation in the spinal cord. Additionally, M30 in vivo also increased mRNA expression of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) as well as the antioxidant enzymes catalase, SOD-1, and glutathione peroxidase (GPx) in spinal cord and some brain regions (Kupershmidt et al., 2011).

The induction of VEGF by M30 is particularly interesting in light of the many studies demonstrating a neuroprotective role of VEGF in ALS (for review see Llado et al., 2013). Indeed, genetic studies link polymorphisms in the VEGF gene to the development of sALS (Lambrechts et al., 2003; Lysogorskaia et al., 2012) and VEGF therapy has been shown to prevent motor neuron degeneration and increase survival in mutant SOD-1 mice (Storkebaum et al., 2005; Wang et al., 2007). On the basis of these and other observations, VEGF is a suggested therapeutic intervention for ALS. Besides M30, other Fe chelators including desferrioxamine (DFO; the standard clinically used Fe chelator for Fe overload) have also been shown to induce VEGF expression in non-ALS models (Beerepoot et al., 1996)..."


http://www.ncbi.nlm....les/PMC4107949/

[mag1]

"We think it important to emphasize that the most effective clinical treatment yet devised for moderate- to late-stage AD patients was

the implementation of the first generation anti-oxidant and trivalent iron/aluminum chelator desferrioxamine to attempt to remove

aluminum from the brains of AD patients...

 

Second generation aluminum chelators such as Feralex-G,..."

 

 

Aluminum and its potential contribution to Alzheimer's disease (AD) Front Aging Neurosci. 2014; 6: 62.