10 replies to this topic

[lynx]

http://groups-beta.g...a0983b4e6cff1c9

Kidney Int. 2005 Apr;67(4):1371-80. Related Articles, Links 


Mechanisms of antioxidant and pro-oxidant effects of alpha-lipoic acid in the diabetic and nondiabetic kidney.

Bhatti F, Mankhey RW, Asico L, Quinn MT, Welch WJ, Maric C.

Department of Medicine, Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, DC.

Mechanisms of antioxidant and pro-oxidant effects of alpha-lipoic acid in the diabetic and nondiabetic kidney. Background.alpha-Lipoic acid is a potent antioxidant that improves renal function in diabetes by lowering glycemia, however, the mechanisms by which alpha-lipoic acid exerts its antioxidant effects are not completely understood. Methods. Metabolic parameters, renal function, and morphology, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subunit expression were analyzed in nondiabetic and streptozotocin-induced diabetic rats fed normal rat chow (control) with or without alpha-lipoic acid (30 mg/kg body weight) for 12 weeks. Results. Blood glucose was increased with diabetes (nondiabetic + control 89 +/- 3 mg/dL and diabetic + control 336 +/- 28 mg/dL) and was similar with alpha-lipoic acid treatment (diabetic +alpha-lipoic acid 351 +/- 14 mg/dL). In contrast, alpha-lipoic acid attenuated albuminuria (nondiabetic + control 8.9 +/- 1.3 mg/day; diabetic + control 28.1 +/- 4.6 mg/day; and diabetic +alpha-lipoic acid 17.8 +/- 1.2 mg/day) associated with diabetes. Similarly, alpha-lipoic acid attenuated glomerulosclerosis (nondiabetic + control 0.22 +/- 0.01; diabetic + control 0.55 +/- 0.04; diabetic +alpha-lipoic acid 0.36 +/- 0.03), tubulointerstitial fibrosis (nondiabetic + control 0.42 +/- 0.18; diabetic + control 1.52 +/- 0.05; diabetic +alpha-lipoic acid 1.10 +/- 0.05), superoxide anion (O(.-) (2)) generation (nondiabetic +control 15.8 +/- 1.7; diabetic +control 87.1 +/- 3.5; diabetic +alpha-lipoic acid 25.5 +/- 3.3 RLU/mg protein), and urine 8-isoprostane (8-iso) excretion (nondiabetic + control 7.4 +/- 1.4; diabetic + control 26.0 +/- 4.5; diabetic +alpha-lipoic acid 19.6 +/- 5.6 ng/day) associated with diabetes. alpha-Lipoic acid also reduced kidney expression of NADPH oxidase subunits p22phox and p47phox. Surprisingly, alpha-lipoic acid appears to cause pro-oxidant effects in nondiabetic animals, resulting in increased albuminuria (nondiabetic +alpha-lipoic acid 14.2 +/- 1.2 mg/day), increase in plasma creatinine levels (nondiabetic + control 59 +/- 6; diabetic + control 68 +/- 6; nondiabetic +alpha-lipoic acid 86 +/- 9; diabetic +alpha-lipoic acid 69 +/- 7 mumol/L), exacerbated glomerulosclerosis and tubulointerstitial fibrosis, increased O(.-) (2) generation, up-regulated p22phox and p47phox expression and increased 8-iso excretion. Conclusion. We conclude that alpha-lipoic acid improves albuminuria and pathology in diabetes by reducing oxidative stress, while in healthy animals, alpha-lipoic acid may act as a pro-oxidant, contributing to renal dysfunction.

PMID: 15780089 [PubMed - in process]

[johnmk]

What can we conclude from this? Don't take ALA unless you feel you're exposing yourself to oxidative stress? Would my amphetamine & ALCAR cause me enough oxidate stress such that ALA might be helpful? Sorry for asking so many questions, you guys are a treasure trove of knowledge.

[shapeshifter]

I wonder what the outcome would be if they had used R-Lipoic Acid instead of Lipoic Acid...

[johnmk]

Or perhaps K-R-ALA?

[LifeMirage]

No one takes a single antioxidant because many even the famed DHLA (1.) can pro-oxidant effects, most people take many antioxidants to regenerate each other (2.).


1. [Free Radic Res. 1994 Feb;20(2):119-33.
Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation.

Scott BC, Aruoma OI, Evans PJ, O'Neill C, Van der Vliet A, Cross CE, Tritschler H, Halliwell B. Neurodegenerative Diseases Research Centre, Kings College, University of London, UK.

A detailed evaluation of the antioxidant and pro-oxidant properties of lipoic acid (LA) and dihydrolipoic acid (DHLA) was performed. Both compounds are powerful scavengers of hypochlorous acid, able to protect alpha 1-antiproteinase against inactivation by HOCl. LA was a powerful scavenger of hydroxyl radicals (OH.) and could inhibit both iron-dependent OH. generation and peroxidation of ox-brain phospholipid liposomes in the presence of FeCl3-ascorbate, presumably by binding iron ions and rendering them redox-inactive. By contrast, DHLA accelerated iron-dependent OH. generation and lipid peroxidation, probably by reducing Fe3+ to Fe2+. LA inhibited this pro-oxidant action of DHLA. However, DHLA did not accelerate DNA degradation by a ferric bleomycin complex and slightly inhibited peroxidation of arachidonic acid by the myoglobin-H2O2 system. Under certain circumstances, DHLA accelerated the loss of activity of alpha-antiproteinase exposed to ionizing radiation under a N2O/O2 atmosphere and also the loss of creatine kinase activity in human plasma exposed to gas-phase cigarette smoke. Neither LA nor DHLA reacted with superoxide radical (O.2-) or H2O2 at significant rates, but both were good scavengers of trichloromethylperoxyl radical (CCl3O2.). We conclude that LA and DHLA have powerful antioxidant properties. However, DHLA can also exert pro-oxidant properties, both by its iron ion-reducing ability and probably by its ability to generate reactive sulphur-containing radicals that can damage certain proteins, such as alpha 1-antiproteinase and creatine kinase.]


2. [Gen Pharmacol. 1997 Sep;29(3):315-31.
The pharmacology of the antioxidant lipoic acid.

Biewenga GP, Haenen GR, Bast A. Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, Department of Pharmacochemistry, The Netherlands.

1. Lipoic acid is an example of an existing drug whose therapeutic effect has been related to its antioxidant activity. 2. Antioxidant activity is a relative concept: it depends on the kind of oxidative stress and the kind of oxidizable substrate (e.g., DNA, lipid, protein). 3. In vitro, the final antioxidant activity of lipoic acid is determined by its concentration and by its antioxidant properties. Four antioxidant properties of lipoic acid have been studied: its metal chelating capacity, its ability to scavenge reactive oxygen species (ROS), its ability to regenerate endogenous antioxidants and its ability to repair oxidative damage. 4. Dihydrolipoic acid (DHLA), formed by reduction of lipoic acid, has more antioxidant properties than does lipoic acid. Both DHLA and lipoic acid have metal-chelating capacity and scavenge ROS, whereas only DHLA is able to regenerate endogenous antioxidants and to repair oxidative damage. 5. As a metal chelator, lipoic acid was shown to provide antioxidant activity by chelating Fe2+ and Cu2+; DHLA can do so by chelating Cd2+. 6. As scavengers of ROS, lipoic acid and DHLA display antioxidant activity in most experiments, whereas, in particular cases, pro-oxidant activity has been observed. However, lipoic acid can act as an antioxidant against the pro-oxidant activity produced by DHLA. 7. DHLA has the capacity to regenerate the endogenous antioxidants vitamin E, vitamin C and glutathione. 8. DHLA can provide peptide methionine sulfoxide reductase with reducing equivalents. This enhances the repair of oxidatively damaged proteins such as alpha-1 antiprotease. 9. Through the lipoamide dehydrogenase-dependent reduction of lipoic acid, the cell can draw on its NADH pool for antioxidant activity additionally to its NADPH pool, which is usually consumed during oxidative stress. 10. Within drug-related antioxidant pharmacology, lipoic acid is a model compound that enhances understanding of the mode of action of antioxidants in drug therapy.]

[scottl]

Hi LifeMirage,

Care to make any comment on R-ALA vs K-R-ALA?

[wannafulfill]

No one takes a single antioxidant because many even the famed DHLA (1.) can pro-oxidant effects, most people take many antioxidants to regenerate each other (2.).

I didn't know this, thanks Lifemirage. I read this study and was mildly concerned. The only anti-oxidant I currently take is a 500 mg dose of KRALA 2x day before meals. Do you think I should add other anti-oxidants or change the way/amount of KRALA I take? I have been considering adding something more anyway. What would be good additions? Thank-you very much!

[wannafulfill]

bump

[lemon]

wannafufill,


Lipoic acid is known to regenerate vitamin C and E so a high potency multivitamin with C and full spectrum E would be a good idea.

[shapeshifter]

To be more precise:
R-Lipoic acid, Q10, Vitamin E complex (all tocopherols and tocotrienols), Vitamin C and glutathione. You can boost your glutathione level by taking N-Acetyl Cysteine.

Just read this article on antioxidants network: http://www.aor.ca/pr...2&exec_sum=summ

[watch]

Conclusion. We conclude that alpha-lipoic acid improves albuminuria and pathology in diabetes by reducing oxidative stress, while in healthy animals, alpha-lipoic acid may act as a pro-oxidant, contributing to renal dysfunction.

PMID: 15780089 [PubMed - in process]

I found this study where alpha-lipoic acid was actually given to people with renal dysfunction, I guess it is safe to take it then?

J Clin Pharmacol. 2005 Mar;45(3):313-28.
Pharmacokinetics of alpha-lipoic Acid in subjects with severe kidney damage
and end-stage renal disease.
Teichert J, Tuemmers T, Achenbach H, Preiss C, Hermann R, Ruus P, Preiss R.
University of Leipzig, Institute of Clinical Pharmacology, Hartelstr. 16-18,
04107 Leipzig, Germany.


In an open-label, parallel-group study involving 16 patients (8 with
severely reduced renal function, 8 with end-stage renal disease needing
hemodialysis), the effect of renal function on the pharmacokinetics,
metabolism, and safety and of alpha-lipoic acid (thioctic acid) was
evaluated by comparing the pharmacokinetic parameters with those of a
reference group of 8 healthy subjects. Alpha-lipoic acid 600 mg was
administered orally once daily for 4 days, and the pharmacokinetic
parameters were measured on days 1 and 4. The mean percentage of the
administered dose excreted in urine as parent compound was 0.2 and 0.05 in
healthy subjects and subjects with severely reduced renal function,
respectively. Assuming a bioavailability of 30%, this represents 0.67% and
0.17% of the bioavailable amount of alpha-lipoic acid, respectively. The
percentage of total urinary recovered amounts of alpha-lipoic acid and 5 of
its metabolites was 12.0 on both days. The respective values for patients
with severe kidney damage were 5.2% (day 1) and 6.4% (day 4). The total
percentage of the administered dose removed by hemodialysis was 4.0 in
patients with end-stage renal disease. Renal clearance of alpha-lipoic acid
and its major metabolites, 6,8-bismethylthio-octanoic acid,
4,6-bismethylthio-hexanoic acid and 2,4-bismethylthio-butanoic acid, were
significantly decreased in subjects with kidney damage compared to the
reference group. Apparent total clearance of alpha-lipoic acid was poorly
correlated with creatinine clearance. There is strong evidence that
alpha-lipoic acid is mainly excreted by nonrenal mechanism or further
degraded to smaller units in the catabolic process. The significantly
increased area under the curve values of 4,6-bismethylthio-hexanoic acid and
half-lives of 2,4-bismethylthio-butanoic acid on both days in patients with
severely reduced function and end-stage renal disease were not considered to
be clinically relevant. Although trough levels of both metabolites tend to
increase slightly in these subjects, no accumulation effects were detected.
We conclude that the pharmacokinetics of alpha-lipoic acid are not
influenced by creatinine clearance and are unaffected in subjects with
severely reduced kidney function or end-stage renal disease. Hemodialysis
did not significantly contribute to the clearance of alpha-lipoic acid.
Hence, dose adjustment of alpha-lipoic acid is not necessary in patients
with renal dysfunction