14 replies to this topic

[k10]

Quote

Neurotox Res. 2011 May 3. [Epub ahead of print]
Idebenone Induces Apoptotic Cell Death in the Human Dopaminergic Neuroblastoma SHSY-5Y Cells.
Tai KK, Pham L, Truong DD.
Source
The  Parkinson's and Movement Disorder Research Laboratory, Long Beach  Memorial Medical Center, 2801 Atlantic Ave., Long Beach, CA, USA,  kktai@yahoo.com.


Abstract
Idebenone  is a coenzyme Q10 analog and an antioxidant that has been used  clinically to treat Friedreich Ataxia. Being an antioxidant, idebenone  could have potential therapeutic potential to treat other  neurodegenerative diseases such as Parkinson's disease in which  oxidative stress plays a role in their pathogenesis. But whether  idebenone can be used to treat Parkinson's disease has not been  evaluated. In this study, we found that exposure of the dopaminergic  neuroblastoma SHSY-5Y cells to 1-10 μM idebenone for 72 h had no effect  on the cell viability revealed by trypan blue exclusion assay and MTT  assay. However, cells exposed to 25 μM or higher concentrations of  idebenone showed extensive trypan blue-positive staining and significant  reduction in cell viability revealed by MTT assay indicating that most  of the cells were no longer viable. Idebenone-induced cell death was  characterized by genomic DNA fragmentation and accumulation of  cytochrome c in the cytosol indicating that the death was apoptotic in  nature. In addition, idebenone induced an increase in the total RNA of  the pro-apoptosis protein BAX, it also increased the caspase-3 activity  in the cell lysates when compared with the untreated control cells or  cells exposed to 10 μM or lower concentrations of idebenone. The  detrimental effect of idebenone was attenuated by glutathione, an  antioxidant, suggesting that oxidative stress contributed to the  idebenone-induced cell death. In conclusion, our results suggest that  antioxidant idebenone induced apoptosis when used in high  concentrations.

PMID:21547417 [PubMed - as supplied by publisher]

This doesn't sound too good to me...

[Ark]

k10, on 22 June 2011 - 09:39 AM, said:

Quote

Neurotox Res. 2011 May 3. [Epub ahead of print]
Idebenone Induces Apoptotic Cell Death in the Human Dopaminergic Neuroblastoma SHSY-5Y Cells.
Tai KK, Pham L, Truong DD.
Source
The  Parkinson's and Movement Disorder Research Laboratory, Long Beach  Memorial Medical Center, 2801 Atlantic Ave., Long Beach, CA, USA,  kktai@yahoo.com.


Abstract
Idebenone  is a coenzyme Q10 analog and an antioxidant that has been used  clinically to treat Friedreich Ataxia. Being an antioxidant, idebenone  could have potential therapeutic potential to treat other  neurodegenerative diseases such as Parkinson's disease in which  oxidative stress plays a role in their pathogenesis. But whether  idebenone can be used to treat Parkinson's disease has not been  evaluated. In this study, we found that exposure of the dopaminergic  neuroblastoma SHSY-5Y cells to 1-10 μM idebenone for 72 h had no effect  on the cell viability revealed by trypan blue exclusion assay and MTT  assay. However, cells exposed to 25 μM or higher concentrations of  idebenone showed extensive trypan blue-positive staining and significant  reduction in cell viability revealed by MTT assay indicating that most  of the cells were no longer viable. Idebenone-induced cell death was  characterized by genomic DNA fragmentation and accumulation of  cytochrome c in the cytosol indicating that the death was apoptotic in  nature. In addition, idebenone induced an increase in the total RNA of  the pro-apoptosis protein BAX, it also increased the caspase-3 activity  in the cell lysates when compared with the untreated control cells or  cells exposed to 10 μM or lower concentrations of idebenone. The  detrimental effect of idebenone was attenuated by glutathione, an  antioxidant, suggesting that oxidative stress contributed to the  idebenone-induced cell death. In conclusion, our results suggest that  antioxidant idebenone induced apoptosis when used in high  concentrations.

PMID:21547417 [PubMed - as supplied by publisher]

This doesn't sound too good to me...

What about the fact that it's great for stimulating nerve growth factor.

[agwoodliffe]

Thanks for posting this. In regards to supplementation, perhaps we should stick to ordinary Coenzyme-Q10 (with/without a bioavailability enhancer), and leave Idebenone to be used only for its approved medical conditions, under the supervision of a doctor.

[Mortuorum]

k10, on 22 June 2011 - 09:39 AM, said:

Quote

Neurotox Res. 2011 May 3. [Epub ahead of print]
Idebenone Induces Apoptotic Cell Death in the Human Dopaminergic Neuroblastoma SHSY-5Y Cells.
Tai KK, Pham L, Truong DD.
Source
The  Parkinson's and Movement Disorder Research Laboratory, Long Beach  Memorial Medical Center, 2801 Atlantic Ave., Long Beach, CA, USA,  kktai@yahoo.com.


Abstract
Idebenone  is a coenzyme Q10 analog and an antioxidant that has been used  clinically to treat Friedreich Ataxia. Being an antioxidant, idebenone  could have potential therapeutic potential to treat other  neurodegenerative diseases such as Parkinson's disease in which  oxidative stress plays a role in their pathogenesis. But whether  idebenone can be used to treat Parkinson's disease has not been  evaluated. In this study, we found that exposure of the dopaminergic  neuroblastoma SHSY-5Y cells to 1-10 μM idebenone for 72 h had no effect  on the cell viability revealed by trypan blue exclusion assay and MTT  assay. However, cells exposed to 25 μM or higher concentrations of  idebenone showed extensive trypan blue-positive staining and significant  reduction in cell viability revealed by MTT assay indicating that most  of the cells were no longer viable. Idebenone-induced cell death was  characterized by genomic DNA fragmentation and accumulation of  cytochrome c in the cytosol indicating that the death was apoptotic in  nature. In addition, idebenone induced an increase in the total RNA of  the pro-apoptosis protein BAX, it also increased the caspase-3 activity  in the cell lysates when compared with the untreated control cells or  cells exposed to 10 μM or lower concentrations of idebenone. The  detrimental effect of idebenone was attenuated by glutathione, an  antioxidant, suggesting that oxidative stress contributed to the  idebenone-induced cell death. In conclusion, our results suggest that  antioxidant idebenone induced apoptosis when used in high  concentrations.

PMID:21547417 [PubMed - as supplied by publisher]

This doesn't sound too good to me...

Do you have the entire paper? Clearly it is cause for serious concern. However, the study does seem to be in vitro and this can evolve in ways quite distinct from and even contrary to in vivo metabolism. Obviously, more research needs to be done. There has been some dissenting research on Idebenone in the past generating superoxide radical formation, though those studies, as well, were largely in vitro ones and scant indeed proportionate to all of the positive studies done on it. Also, the "possible" superoxide radical formation could easily be circumvented by other supplementation and even quality dietary intake most of us here do or should be engaged within anyway. The implications of this study seem a bit more alarming to me, though. But, more research, in vivo, is required, obviously.    

Considering how long this substance has been around and in usage, not to mention the wealth of research data and studies conducted, you'd imagine results such as these would have arisen long ago, especially when its main officiated applications were treatment of neurological maladies....?

Unfortunately, CoQ10/Ubiquinol is not really an adequate "substitute" for those who've been deriving beneficial resultant effects from it. Idebenone imparts singular mitochondria protective (though now maybe not!...haha...), powerful radical scavenging and protection under duress of acute hypoxia scenarios, metabolic and particularly cerebral energy metabolism/neurological and cognitive enhancing qualities unique to itself. CoQ10 also has intrinsic problems of its own as a supplement, too. So, bad day for fans of it, like myself!

Edited by Mortuorum, 22 June 2011 - 05:52 PM.

[Mortuorum]

Also, this study does indicate that attenuation of these deleterious in vitro effects of Idebenone upon the cells was achieved through Glutathione application. So, it is possible it is another case of necessitating other free radical scavenging antioxidants are taken concomitantly. This requires more study research, preferably in vivo.

[devinthayer]

So... don't use it in high concentrations...  

25uM is 8.45 milligrams per liter (338.439*25*10^-6 = 8.45).  If the average person has 6 liters of blood, then that's 50.7mg a person can take up a vein.  Given that most are oral doses, the percentage in the bloodstream is considerably less at any given point in time, plus there is all that room to spread out once it exits the blood stream.

Edited by devinthayer, 22 June 2011 - 07:26 PM.

[Mortuorum]

devinthayer, on 22 June 2011 - 07:07 PM, said:

So... don't use it in high concentrations...

This is a common theme I find.  What makes something nootropic as opposed to plain psychotropic is that the beneficial dose is non-toxic, usually 1/3 or less of toxic dose.

25uM per cell seems a little high, don't you think?  That's 3.022*10^16 molecules of Idebenone per cell... that's 8.45 micrograms per cell.  I'm not sure what the average human cell weighs, but the SHSY-5Y cells can be so small, they are mistaken for contaminates.

Do you have the link to the full study?

Ideally need complete paper, more numbers and data to "crunch" to get an idea how high concentrations were and then theoretically transpose them upon an in vivo oral dose administered to a human model.

Again, "in vitro" versus "in vivo" are often two different animals in terms of metabolism, effects.....

Study is very new, doubt we can find it for 'free', maybe someone with paid account somewhere can help us......?

Edited by Mortuorum, 22 June 2011 - 07:34 PM.

[devinthayer]

Mortuorum, on 22 June 2011 - 07:22 PM, said:

devinthayer, on 22 June 2011 - 07:07 PM, said:

So... don't use it in high concentrations...

This is a common theme I find.  What makes something nootropic as opposed to plain psychotropic is that the beneficial dose is non-toxic, usually 1/3 or less of toxic dose.

25uM per cell seems a little high, don't you think?  That's 3.022*10^16 molecules of Idebenone per cell... that's 8.45 micrograms per cell.  I'm not sure what the average human cell weighs, but the SHSY-5Y cells can be so small, they are mistaken for contaminates.

Do you have the link to the full study?

Need more numbers and data to "crunch" to get an idea how high concentrations were and theoretically transpose upon a human model intake dose. I have no idea how to figure this out based upon what is presented summarily here. Again, "in vitro" versus "in vivo" are often too different animals, too.....

Study is very new, doubt we can find it for 'free', maybe someone with paid account somewhere can help us......?

Sorry, I just updated my response.  I forgot that uM mean micromoles in a solution of one Liter.  That's 338g (using molecular weight) of Idebenone in a liter.

[pycnogenol]

Mortuorum, on 22 June 2011 - 07:22 PM, said:

Ideally need complete paper, more numbers and data to "crunch" to get an idea how high concentrations were and then theoretically transpose them upon an in vivo oral dose administered to a human model.

Contact them at kktai@yahoo.com and see if they will give you the complete paper.

[niner]

Quote

Eur J Clin Pharmacol. 2009 May;65(5):493-501. Epub 2009 Jan 6.
Pharmacokinetics and metabolism of idebenone in healthy male subjects.
Bodmer M, Vankan P, Dreier M, Kutz KW, Drewe J.

Department of Clinical Pharmacology, University Hospital Basel, Basel, Switzerland.

PURPOSE:

Idebenone is a synthetic analogue of ubiquinone that may be beneficial in the treatment of Friedreich's ataxia. Since in previous pharmacokinetic trials only lower doses were studied, it was the aim of this study to evaluate the pharmacokinetics of idebenone in higher doses of up to 2,250 mg/day.
METHODS:

In this open, randomized trial, 25 healthy male subjects received first either a single oral dose of 150 mg or 750 mg of idebenone, then the same dose given at 8-h intervals for 14 days.
RESULTS:

Idebenone and its metabolites appeared in the plasma quickly. Over 99% of parent idebenone was metabolized, indicating a high first-pass effect. C(max) and AUC(0-t) values for parent idebenone and its metabolites increased in a dose-proportional manner. There was virtually no accumulation of parent drug or metabolites following multiple dosing.
CONCLUSIONS:

Idebenone exhibited dose-dependent pharmacokinetics in daily doses up to 2,250 mg. In 6/14 subjects, adverse events of mild to moderate severity were observed.

PMID: 19125241

The dose makes the poison, and 25 uM in vitro is a far cry from what is actually happening in the body.  If 99% of it is getting nuked in first pass, it's going to be pretty tough to reach anything close to 25 uM.

[devinthayer]

niner, on 23 June 2011 - 12:43 AM, said:

Quote

Eur J Clin Pharmacol. 2009 May;65(5):493-501. Epub 2009 Jan 6.
Pharmacokinetics and metabolism of idebenone in healthy male subjects.
Bodmer M, Vankan P, Dreier M, Kutz KW, Drewe J.

Department of Clinical Pharmacology, University Hospital Basel, Basel, Switzerland.

PURPOSE:

Idebenone is a synthetic analogue of ubiquinone that may be beneficial in the treatment of Friedreich's ataxia. Since in previous pharmacokinetic trials only lower doses were studied, it was the aim of this study to evaluate the pharmacokinetics of idebenone in higher doses of up to 2,250 mg/day.
METHODS:

In this open, randomized trial, 25 healthy male subjects received first either a single oral dose of 150 mg or 750 mg of idebenone, then the same dose given at 8-h intervals for 14 days.
RESULTS:

Idebenone and its metabolites appeared in the plasma quickly. Over 99% of parent idebenone was metabolized, indicating a high first-pass effect. C(max) and AUC(0-t) values for parent idebenone and its metabolites increased in a dose-proportional manner. There was virtually no accumulation of parent drug or metabolites following multiple dosing.
CONCLUSIONS:

Idebenone exhibited dose-dependent pharmacokinetics in daily doses up to 2,250 mg. In 6/14 subjects, adverse events of mild to moderate severity were observed.

PMID: 19125241

The dose makes the poison, and 25 uM in vitro is a far cry from what is actually happening in the body.  If 99% of it is getting nuked in first pass, it's going to be pretty tough to reach anything close to 25 uM.

If 99% is being chopped up and shipped off, it sounds more like a nutrient than a poison.

[Sophomoric]

I've seen a study which indicates that idebenone acts as a mitochondrial pro-oxidant. I'm surprised however that this study hasn't been mentioned on the board:

http://www.ncbi.nlm....pubmed/15374477

Suggesting that in certain specific areas idebenone increases the enzyme superoxide dismutase.

[devinthayer]

Sophomoric, on 19 July 2011 - 07:46 PM, said:

I've seen a study which indicates that idebenone acts as a mitochondrial pro-oxidant. I'm surprised however that this study hasn't been mentioned on the board:

http://www.ncbi.nlm....pubmed/15374477

Suggesting that in certain specific areas idebenone increases the enzyme superoxide dismutase.

50mg/kg is a LOT of idebenone.  That's 1800mg (using this allometric scaling calculator: http://home.fuse.net.../allometry.html).  I think 50mg is a preferred nootropic dose, perhaps 180mg in some stores.

Edited by devinthayer, 19 July 2011 - 09:19 PM.

[rasgyle]

Uh, I apologize for the zombie rez here, but I got here from a Google search and I thought this should be dealt with.

Induction of cytochrome c and manipulating death ligands in cancerous cells are two theorized chemotherapeutic pathways.

That's a neuroblastoma you're talking about. Apoptosis in a tumor. Unless someone here likes tumors, that's a thing that should strike you as good, not bad.

[neuropill]

I've taken it in the past with NARALA and did not feel any concerns about it's pro-oxidant effects were any different any well any other antixoidant or ALC. Looks like Canada approved it as a drug awhile ago as Catena.

http://www.santhera....d=58&vid=&lang=

"Nerve and muscle cells, including heart muscle cells, are particularly energy-demanding and are, therefore, more prone to rapid cell damage or death due to mitochondrial dysfunction. Through preserving mitochondrial function and protecting cells from oxidative stress, it is believed that Catena® can prevent cell damage and increase the production of energy..."