99 replies to this topic

[abolitionist]

http://www.nootropic...itochondria.htm

"The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), considered as the pathogenic agent of many diseases and of aging. We have investigated the role of Complex I in superoxide radical production and found by combined use of specific inhibitors of Complex I that the one-electron donor in the Complex to oxygen is a redox center located prior to the sites where three different types of coenzyme Q (CoQ) competitors bind, to be identified with an Fe-S cluster, most probably N2, or possibly an ubisemiquinone intermediate insensitive to all the above inhibitors. Short-chain coenzyme Q analogues enhance superoxide formation, presumably by mediating electron transfer from N2 to oxygen. The clinically used CoQ analogue idebenone is particularly effective, raising doubts about its safety as a drug. The mitochondrial theory of aging considers somatic mutations of mitochondrial DNA induced by ROS as the primary cause of energy decline; in rat liver mitochondria, Complex I appears to be most affected by aging and to become strongly rate limiting for electron transfer. Mitochondrial energetics is also deranged in human platelets upon aging, as demonstrated by the decreased Pasteur effect (enhancement of lactate production by respiratory inhibitors). Cells counteract oxidative stress by antioxidants: CoQ is the only lipophilic antioxidant to be biosynthesized. Exogenous CoQ, however, protects cells from oxidative stress by conversion into its reduced antioxidant form by cellular reductases. The plasma membrane oxidoreductase and DT-diaphorase are two such systems: likewise, they are overexpressed under oxidative stress conditions."

[nootropi]

@abolitionist:

I have seen this before. Idebenone has been around for more than 15 years. James South published an article that complied the results of several studies which support the converse of this hypothesis:

http://smart-drugs.n...h-idebenone.htm

[nootropi]

Also see this:

http://www.vrp.com/art/486.asp

[nootropi]

And this:
click here

[nootropi]

And this too
Idebenone has been studied for over 15 years (mostly in Japan); there are clear benefits to the human brain.

These negative effects that are demonstrated in test tubes have not been demonstrated in humans. Animal studies show clear benefits at a 90 mg/day dosage.

With R-Alpha Lipoic acid supplementation, (as LifeMirage astutely suggested) any excess mitochondrial superoxide free radicals would be destroyed. Therefore idebenone users should increase RALA supplementation. If you do not have RALA, then to be safe maybe refrain from using idebenone.

[nootropi]

If I were you I would stop the regular ALA and get the R-ALA. You can get very high quality R-ALA from smi2le for VERY cheap. I recently increased my dose of R-ALA to 450 mg per day, i take 45 mg of idebenone with my breakfast (you need to take it with food; otherwise much is unabsorbed) and 55 mg with my lunch.

Take care,

Adam

[abolitionist]

The studies you are referring to clearly show the Idebenone has great potential as a treatment for certain diseases. However, I'm still not convinced by what I've seen that Idebenone would be a good supplement for long term use aimed at longevity for otherwise healthy people. Do you have any links to studies that are more related to this type of intended usage?

thanks!!

[nootropi]

There are no such studies available for any substance. Usually we have to draw inferences from studies of elderly people experiencing dementia; or recovery rates of rats whose brains are literally fried by scopaline yet administered a nootropic and are able to better withstand amnesiac effects.
As Dave Tolson has elequently stated, people are considered "crazy" for "desiring" to make themselves "smarter." In the United States the Food and Drug Administration (FDA) only approves the use of drugs for "sick" people. Yes, this is true; even if there is a drug that enhances the functionality of parts of your body (ie brain, liver, heart, penis, etc.) it will only be approved for uses pertaining to aiding in restoring what is considered dysfunctional back to its "functional" state.

There are NO studies in which what you call "otherwise healthy people" are administered nootropics and the performance of their executive functioning measured by an index which could be correlated with "higher performance" executive funtioning.

Do a bit of reading at www.pubmed.com; try entering different search terms such as memory, acetylcholine, and the name of a nootropic you are interested in to see what research has been conducted in this field.

I am honestly not trying to be rude with my other statements; I just would appreciate if you learn more about the topic you wish to discuss before making general declarative statements.

[abolitionist]

How about studies in rats, where mitochondrial DNA mutation is measured at death, comparing the results of placebo and Idebenone?

I haven't seen any studies that test the hypothesis that Idebenone may actually cause increased oxidative damage to mtDNA over a period of time, medline or otherwise, have you?

[nootropi]

Idebenone protects hippocampal neurons against amyloid beta-peptide-induced neurotoxicity in rat primary cultures.

Hirai K, Hayako H, Kato K, Miyamoto M.

Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Osaka, Japan.

The application of amyloid beta-peptide (Abeta) 1-40 (10 microM) caused neurodegeneration of hippocampal neuronal cells, as indicated by the release of lactate dehydrogenase (LDH) into the culture medium. Treatment with idebenone (10-1000 nM), a potent antioxidant in mitochondria, protected the hippocampal neurons against the Abeta1-40(10 microM)-induced neurotoxicity. To determine the morphological change in neurons during the Abeta1-40-induced cytotoxicity, the cells were immunostained with anti-MAP2 antibodies. After 4-day exposure to 10 microM Abeta1-40, the number of neurons was reduced, and the surviving neurons had an apparently reduced number of neurites which were shorter than those of control neurons. When idebenone was added to the culture medium with Abeta1-40, the number of surviving neurons was significantly increased, and their neurites were as long as seen in control culture. These results suggest that reactive oxygen species mediate neurotoxicity of Abeta1-40, and idebenone protects neurons against the Abeta1-40-induced neurotoxicity.

Erratum in:

    * Free Radic Biol Med 1998 Oct;25(6):754.


The effect of idebenone, a coenzyme Q analogue, on hydrophobic bile acid toxicity to isolated rat hepatocytes and hepatic mitochondria.

Shivaram KN, Winklhofer-Roob BM, Straka MS, Devereaux MW, Everson G, Mierau GW, Sokol RJ.

Department of Pediatrics, University of Colorado School of Medicine, Denver, USA.

Oxidant stress induced by hydrophobic bile acids has been implicated in the pathogenesis of liver injury in cholestatic liver disorders. We evaluated the effect of idebenone, a coenzyme Q analogue, on taurochenodeoxycholic acid (TCDC)-induced cell injury and oxidant stress in isolated rat hepatocytes and on glycochenodeoxycholic acid (GCDC)-induced generation of hydroperoxides in fresh hepatic mitochondria. Isolated rat hepatocytes in suspension under 9% oxygen atmosphere were preincubated with 0, 50, and 100 micromol/l idebenone for 30 min and then exposed to 1000 micromol/l TCDC for 4 h. LDH release (cell injury) and thiobarbituric acid reactive substances (measure of lipid peroxidation) increased after TCDC exposure but were markedly suppressed by idebenone pretreatment. In a second set of experiments, the addition of 100 micromol/l idebenone up to 3 h after hepatocytes were exposed to 1000 micromol/l TCDC resulted in abrogation of subsequent cell injury and markedly reduced oxidant damage to hepatocytes. Chenodeoxycholic acid concentrations increased to 5.15 nmol/10(6) cells after 2 h and to 7.05 after 4 h of incubation of hepatocytes with 1000 micromol/l TCDC, and did not differ in the presence of idebenone. In freshly isolated rat hepatic mitochondria, when respiration was stimulated by succinate, 10 micromol/l idebenone abrogated the generation of hydroperoxides during a 90-minute exposure to 400 micromol/l GCDC. These data demonstrate that idebenone functions as a potent protective hepatocyte antioxidant during hydrophobic bile acid toxicity, perhaps by reducing generation of oxygen free radicals in mitochondria.

Does this answer your question?

Inhibition of brain mitochondrial swelling by idebenone.

Suno M, Nagaoka A.

Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.

The effects of idebenone on the swelling of rat brain mitochondria were studied. When FeCl3 was added to a mitochondrial suspension, a pronounced mitochondrial swelling occurred accompanied by the production of lipid peroxide; the two phenomena were closely correlated (r = 0.96, p less than 0.01). Idebenone inhibited the mitochondrial swelling and lipid peroxidation in a concentration-dependent manner; the concentration giving 50% inhibition was 37 microM for swelling and 53 microM for lipid peroxidation. Metabolites of idebenone also inhibited the lipid peroxidation. These results suggest that idebenone stabilizes the mitochondrial membrane by inhibiting lipid peroxidation in brain mitochondria.

[abolitionist]

Yes, it's apparent that Idebenone functions both as an anti-oxidant in mitochondria (relatively unselectively - http://www.ncbi.nlm...._uids=12923074) and at the same time it's involvement in the respiratory chain causes increased oxidative stress.

Still, I want to see a study where normal mitochondria are treated with Idebenone for a long term study and the results in mtDNA mutation compared to placebo. I prefer to error on the side of caution, especially when I'm thinking about taking something daily for the next 50 years. Believe me, I would love for this stuff to be totally safe and as beneficial as purported to be, and I would love to see Rizzer selling bulk amounts at rock-bottom prices.

Also, I agree that the FDA tries to limit the improvement of mankind, take a look at my webpage;

www.abolitionist-society.com/abolitionism.htm

[abolitionist]

http://www.ncbi.nlm....t_uids=12923074

for some reason, that link didn't get posted correctly

[nootropi]

Okay Sean; I wanted to emphasize that the reason I take idebenone is NOT for its antioxidant properties! The fact that idebenone increases NGF in the human brain is the primary reason I injest it. If it increases mitochondrial ROS, and I can alleviate that by a larger dose of RALA, then that solves the ROS issue, doesen't it?

[nootropi]

Nerve growth factor is important for the growth and maintainance of the cholergenic system..

Right click this link and select "open in new window."

[abolitionist]

Yeah, Idebenone looks to be very useful for quite a number of purposes. The only reason I would be hesitant about using it personally - would be for long-term usage aimed at protecting mtDNA. I would tend to agree with you about simply taking R-ALA to block (possible) increased ROS production.

I'm a young guy (29) looking into starting a long-term anti-aging regimen - hoping that I will be around long-enough to see the biotechnology revolution blossom. Someday, we may yet break free from genetic slavery.

Let's all hope that American politicians don't blow up the world first

[nootropi]

Let's all hope that American politicians don't blow up the world first

Here you go again...did you think before you wrote this?

I would not be afraid of American politicians blowing up the world...American politicians probably will protect the world from being blown up; it is the American political system which is the one I would like others to model; one in which the people are ultimately in control of who leads them; a balance of power in the judiciative, legislative, and executive branches of government, representatives are ELECTED by the people.

What are you saying, you would rather have a communist regime? Or perhaps you would prefer a dictator?


[glasses] [huh]

[fieyaa]

Let's all hope that American politicians don't blow up the world first

Here you go again...did you think before you wrote this?

I would not be afraid of American politicians blowing up the world...American politicians probably will protect the world from being blown up; it is the American political system which is the one I would like others to model; one in which the people are ultimately in control of who leads them; a balance of power in the judiciative, legislative, and executive branches of government, representatives are ELECTED by the people.

What are you saying, you would rather have a communist regime? Or perhaps you would prefer a dictator?


[glasses] [huh]

adamp2p,

I dont know if you have personal beef with abolitionist but your more recent posts (in other topics as well) slamming him make you look really bad and I would suggest taking any conflicts you have with him to PM. I'm more of a lurker on this board but you seem very knowledgable, intelligent and a bright guy so you can see how a situation like this would make me (and others) think differently. I'm not sure if these posts bother anyone else besides myself (not sure if i even care) but please take it to PM. Thanks man

JR

[nootropi]

To be honest with you JR, I could care less of what you think of me, okay? I am not in the business of appearances, so please proceed back to your "lurking" status. If somebody makes a ridiculous comment, I am going to respond accordingly; you are just as free to express your opinion. You do not, however, have the right to silence mine. Good day.

Edited: fixed incorrect spelling "rediculous" to "ridiculous."

Edited by adamp2p, 03 June 2004 - 07:23 PM.

[fieyaa]

To be honest with you JR, I could care less of what you think of me, okay? I am not in the business of appearances, so please proceed back to your "lurking" status. If somebody makes a rediculous comment, I am going to respond accordingly; you are just as free to express your opinion. You do not, however, have the right to silence mine. Good day.

It's spelled ridiculous not rediculous...

[nootropi]

Okay, I will go fix this now. Thanks for the pull up.

[abolitionist]

adamp2p, that is me expressing my frustration with the current administration, don't take it too seriously (note the winking smiley)

Even if you don't agree with someone, you can still show respect for them. IMO, people are more likely to listen to your point of view if you treat them with respect.

[nootropi]

Well I wasn't the one taking this so seriously.



This is an internet forum, okay? This is not a coffee house nor bar; there are no formal nor informal rules for interaction.
With regards to your political views:
I just think you should be a bit more clear when expressing your view of armegeddon, okay?

[abolitionist]

sorry adamp2p, my 10-point plan for armegeddon is top-secret, only George Jr. and I know about it.... [wis]

[AORsupport]

Okay Sean; I wanted to emphasize that the reason I take idebenone is NOT for its antioxidant properties!  The fact that idebenone increases NGF in the human brain is the primary reason I injest it.

Can you provide a citation to a study showing that idebenone increases NGF in the human brain?

  If it increases mitochondrial ROS, and I can alleviate that by a larger dose of RALA, then that solves the ROS issue, doesen't it?

It may or may not. We do not know that R-LA will successfully combat idebenone-induced mitochondrial ROS production, as we still don't know the exact mechanism of action of R-LA's effects in this regard. If (as I expect) it is a secondary result to alterations in the NADH:NAD ratio, then I would certainly anticipate such an effect, but even then we would not know the magnitude of the effect, the appropriate relative dose, etc without actual data to hand on the subject.

I originally offered up the suggestion that R-LA might offer such protection, but I cannot agree that it is prudent for a healthy life extensionist to take idebenone and simply assume that any increase in mitochondrial ROS is thereby nullified in our present state of knowledge.

In the absence of new evidence on the issue at hand (mitochondial ROS generation), I do not intend to continue going 'round on this issue.

AOR

Edited by AORsupport, 07 June 2004 - 07:15 PM.

[nootropi]

Fair enough.

[nootropi]

sorry adamp2p, my 10-point plan for armegeddon is top-secret, only George Jr. and I know about it....

LOL

[nootropi]

Free Radic Biol Med. 2003 Dec 1;35(11):1500-14.  Related Articles, Links
   
Cytosolic and mitochondrial ROS in staurosporine-induced retinal cell apoptosis.

Gil J, Almeida S, Oliveira CR, Rego AC.

Institute of Biochemistry, Faculty of Medicine, University of Coimbra and Center for Neuroscience and Cell Biology of Coimbra, Coimbra, Portugal.

In this study, we investigated the involvement of reactive oxygen species (ROS) and calcium in staurosporine (STS)-induced apoptosis in cultured retinal neurons, under conditions of maintained membrane integrity. The antioxidants idebenone (IDB), glutathione-ethylester (GSH/EE), trolox, and Mn(III)tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) significantly reduced STS-induced caspase-3-like activity and intracellular ROS generation. Endogenous sources of ROS production were investigated by testing the effect of the following inhibitors: 7-nitroindazole (7-NI), a specific inhibitor of the neuronal isoform of nitric oxide synthase (nNOS); arachidonyl trifluoromethyl ketone (AACOCF(3)), a phospholipase A(2) (PLA(2)) inhibitor; allopurinol, a xanthine oxidase inhibitor; and the mitochondrial inhibitors rotenone and oligomycin. All these compounds decreased caspase-3-like activity and ROS generation, showing that both mitochondrial and cytosolic sources of ROS are implicated in this mechanism. STS induced a significant increase in intracellular calcium concentration ([Ca(2+)](i)), which was partially prevented in the presence of IDB and GSH/EE, indicating its dependence on ROS generation. These two antioxidants and the inhibitors allopurinol and 7-NI also reduced the number of TdT-mediated dUTP nick-end labeling-positive cells. Thus, endogenous ROS generation and the rise in intracellular calcium are important inter-players in STS-triggered apoptosis. Furthermore, the antioxidants may help to prolong retinal cell survival upon apoptotic cell death.

[nootropi]

The Coenzyme Q10 analog decylubiquinone inhibits the redox-activated mitochondrial permeability transition: role of mitcohondrial [correction mitochondrial] complex III.

Armstrong JS, Whiteman M, Rose P, Jones DP.

Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore.

The mitochondrial permeability transition (MPT) is a key event in apoptotic and necrotic cell death and is controlled by the cellular redox state. To further investigate the mechanism(s) involved in regulation of the MPT, we used diethylmaleate to deplete GSH in HL60 cells and increase mitochondrial reactive oxygen species (ROS) production. The site of mitochondrial ROS production was determined to be mitochondrial respiratory complex III (cytochrome bc1), because 1). stigmatellin, a Qo site inhibitor, blocked ROS production and prevented the MPT and cell death and 2). cytochrome bc1 activity was abolished in cells protected from the redox-dependent MPT by stigmatellin. We next investigated the effect of pretreating cells with coenzyme Q10 analogs decylubiquinone (dUb) and ubiquinone 0 (Ub0) on the redox-dependent MPT. Pretreatment of HL60 cells with dUb blocked ROS production induced by GSH depletion and prevented activation of the MPT and cell death, whereas Ub0 did not. Since we also found that dUb did not inhibit cytochrome bc1 activity, the mechanism of protection against redox-dependent MPT by dUb may depend on its ability to scavenge ROS generated by cytochrome bc1. These results indicate that dUb, like the clinically used ubiquinone analog idebenone,may serve as a candidate antioxidant compound for the development of pharmacological agents to treat diseases where there is an oxidative stress component.

[nootropi]

Although this may have been posted already, I would like to highlight the fact that there seems to be an inconsistency with the results of this study with the general consensus throughout the medical community that idebenone is a free radical scavenger rather than a creator. Idebenone is characterized as an antioxidant; as it has proven to be particularly effective in aiding those afflicted with mitochondrial functionality defects.

Exp Biol Med (Maywood). 2003 May;228(5):506-13.  Related Articles, Links
   
Mitochondrial production of oxygen radical species and the role of Coenzyme Q as an antioxidant.

    Genova ML, Pich MM, Biondi A, Bernacchia A, Falasca A, Bovina C, Formiggini G, Castelli GP, Lenaz G.

    Dipartimento di Biochimica "G Moruzzi", University of Bologna, 40126 Bologna, Italy.

    The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), which is considered as the pathogenic agent of many diseases and of aging. We have investigated the role of complex I in superoxide radical production and found by the combined use of specific inhibitors of complex I that the one-electron donor to oxygen in the complex is a redox center located prior to the sites where three different types of Coenzyme Q (CoQ) competitors bind, to be identified with an Fe-S cluster, most probably N2, or possibly an ubisemiquinone intermediate insensitive to all the above inhibitors. Short-chain Coenzyme Q analogs enhance superoxide formation, presumably by mediating electron transfer from N2 to oxygen. The clinically used CoQ analog, idebenone, is particularly effective, raising doubts on its safety as a drug. Cells counteract oxidative stress by antioxidants. CoQ is the only lipophilic antioxidant to be biosynthesized. Exogenous CoQ, however, protects cells from oxidative stress by conversion into its reduced antioxidant form by cellular reductases. The plasma membrane oxidoreductase and DT-diaphorase are two such systems, likewise, they are overexpressed under oxidative stress conditions.