Sustained Release R-Lipoic Acid

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Sustained Release R-Lipoic Acid

AOR CODE: AOR04339

New & Improved Sustained Release R-Lipoic Acid

Continual cellular protection over 8 hours

Fountain of youth antioxidant for longevity

AOR was the first in the world to offer sustained release R-lipoic acid

Use this product for: Weight Management

Details

Lipoic acid is a versatile antioxidant known for its ability to protect the brain and nerve cells from free radicals and heavy metals that promote cognitive and neurodegenerative diseases. Lipoic acid is known as the “captain of the antioxidants” due to its ability to recycle and recharge other antioxidants such as vitamins C and E. Numerous studies have shown that lipoic acid can balance blood sugar and repair damaged nerves in diabetics. Additionally, this powerful anti-aging nutrient has been shown to mimic some of the effects of caloric restriction, the only proven method of extending health span and lifespan. It does so by protecting the mitochondria, the tiny power plants inside of each of the body’s cells, against free radical damage. Due to its action on the mitochondria it can revive damaged cells, especially those found in nerves and in the liver. It is an ideal partner for glutathione, the most powerful antioxidant produced in the body. 

In 2005, AOR introduced the world’s first sustained release pure R-lipoic acid. Unlike most conventional alpha-lipoic acid supplements, AOR’s 95% pure R-lipoic acid delivers the most effective form of this valuable antioxidant without the negative actions of S-lipoic acid. Since lipoic acid has a very short half-life, R SR has been designed to be slowly released into the blood stream over a period of 8 hours. R SR’s new tablet form allows for a better sustained release formula, designed and manufactured by AOR’s research team in our state of the art facility. 

R-Lipoic acid is a powerful, natural and well-rounded antioxidant with many mechanisms of action such as repairing nerves, balancing blood sugar, protecting the brain and increasing energy formation in the mitochondria. The sustained release formula gives you continual antioxidant protection around the clock for many health conditions or for general health and longevity.

Label Info

Discussion

AOR’s Sustained Release R-Lipoic Acid tablets provide only the natural ‘R’ form of this vital antioxidant, unlike most alpha-lipoic acid supplements which also contain the synthetic, inactive ‘S’ form. R-Lipoic Acid is formulated with advanced sustained release technology to provide continuous antioxidant protection.

Product Variation

Product Code NPN Size
AOR04339 80056336 90 TABLETS

Supplements Facts

Serving Size: 1 Tablet Amount
R+(α) Lipoic Acid (sodium salt)* 150 mg

*≥95% R+(α) lipoic acid, contains 15 mg sodium per tablet.

Non-medical ingredients:

sodium stearyl fumarate, xanthan gum.

Guarantees

AOR™ guarantees that all ingredients have been declared on the label. Contains no wheat, gluten, corn, nuts, peanuts, sesame seeds, sulphites, mustard, soy, dairy, eggs, fish, shellfish or any animal byproduct.

Adult Dosage

Take 1 tablet twice daily with/without food, or as directed by a qualified health care practitioner. 

Cautions

Consult a health care practitioner prior to use if you are pregnant or breastfeeding or if you have diabetes. If you experience sweating, paleness, chills, headaches, dizziness and/or confusion, discontinue use and consult a health care practitioner as these may be symptoms of serious low blood sugar.

Source

Pharmaceutical synthesis

Main Application

Network antioxidant

Mitochondrial function

Cognitive support

Neurological function

Anti-aging

Glucose metabolism

Disclaimer

The information and product descriptions appearing on this website are for information purposes only, and are not intended to provide or replace medical advice to individuals from a qualified health care professional. Consult with your physician if you have any health concerns, and before initiating any new diet, exercise, supplement, or other lifestyle changes.

Research

Background

A New & Improved Formula

AOR’s popular, world-first R SR returns in tablet form. This new and improved formula developed by our Research and Development team in our new facility is cleaner and provides solid research data behind its sustained release mechanism.

The Right Form and Lifespan of Lipoic Acid

Alpha lipoic acid (ALA) is an extraordinary antioxidant. Unfortunately, its effectiveness has been limited on two fronts. Firstly, supplemental lipoic acid has been manufactured with the R and S- enantiomers – two molecules with the same chemical formula but with different structures. The R form is naturally occurring and the beneficial effects of alpha lipoic acid come from the R isomer. The S form however is artificial, a byproduct of the manufacturing process and is harmful because it is thought to prevent the utilization of the R enantiomer. This is especially detrimental with ALA because the molecule has a very short half-life in the body, estimated at 22 minutes; the second shortcoming of this molecule.

The solution is, in theory, simple.  For ALA to be considered a viable treatment for diabetes, the molecule must confer protection for longer than the 22-minute half-life currently limiting its effectiveness. Sustained release ALA formulations allow for constant improvements in insulin sensitivity and the results obtained in human trials done with sustained release R( )-lipoic acid are impressive.

Absorption

ALA is absorbed in the small intestine, carried to the liver via the portal circulation and distributed throughout the body by the systemic circulation. ALA is a small molecule that is readily assimilated in a non-saturable fashion in doses of 50 to 600 mg. It is naturally present in food although in very small quantities. Supplemental ALA reaches doses that are hundreds of times higher than what is found in food. ALA was thought to be a vitamin in humans and animals but it has since been shown that it is endogenously produced. The R form of ALA is more active and more absorbable. ALA can cross the blood brain barrier and, after its absorption, it is found intramitochondrially as well as intra and extra cellularly. It therefore prevents oxidative damage both inside and outside our cells and mitochondria throughout the body. The antioxidant effect associated with Lipoic Acid may confer protection in cases of diabetes, diabetic neuropathy, mitochondrial dysfunction, liver disease, lactic acidosis and could even help control the replication of the human immunodeficiency virus.

One of the Five Networking Antioxidants

Alpha lipoic acid and DHLA form a redox couple capable of recycling antioxidants and are involved in cellular energy production. Incredibly, the antioxidant potential of ALA extends to both the reduced and oxidized form of the molecule. Supplementation with Alpha Lipoic acid decreases plasma protein carbonyls, markers of oxidative stress. The molecule recycles important antioxidants such as vitamin C, vitamin E, glutathione and ubiquinone.

Anti-Aging Antioxidant in the Mitochondria

There is evidence that lipoic acid is an anti-aging agent. The key to the anti-aging effect of ALA lies in its ability to protect the mitochondria from oxidative stress. It has been demonstrated that as we age, our mitochondria slowly become less and less efficient at producing energy. This loss of efficiency results in an increased production and release of free radicals, which injure the cell and the mitochondria, leading to a harmful and destructive cycle.

The Aging Brain

There is much interest in the role of mitochondrial dysfunction in Alzheimer’s disease. People with Alzheimer’s have been often found to have abundant mitochondrial dysfunction in the brain. Since lipoic acid is a mitochondrial antioxidant, the role of lipoic acid in helping Alzheimer’s disease is a currently a hot topic of research. Animal studies indicate that ALA may be of benefit for the management and care of Parkinson’s, Alzheimer’s, Huntington’s, and amyotrophic lateral sclerosis.

High Blood Sugar and its Neural Complications

Alpha lipoic acid is indicated for the treatment of any condition where elevated blood glucose levels and free radicals are involved in the disease process. Both of those mechanisms cause problems in several degenerative processes and are both thought to impact the aging process significantly. Alpha lipoic acid can be used to prevent cataract formation, because it can inhibit the enzyme aldose reductase involved in the formation of lens opacities. Supplementation with this antioxidant also improved biochemical parameters in patients suffering from glaucoma and lead to improvements in visual function.

The area that has been studied most intensely when it comes to the use of lipoic acid is its utilization for diabetic patients. Supplementation improves insulin sensitivity, cellular glucose uptake, prevents diabetic complications, prevents protein glycation, reduces plasma free fatty acids, stimulates glycolysis and inhibits aldose reductase. Incredibly, ALA can treat diabetes once it has developed, prevents the progression of complications related to diabetes and alleviates complications if they are already present.  Lipoic acid is a promising treatment for diabetes and its related complications such as diabetic neuropathy, a treatment for which lipoic acid is approved in Germany.

Help Warding Off the Effects of High Blood Sugar Early

In healthy people, the benefits are not to be overlooked either. Free radicals, which are quenched by (R )-lipoic acid, are well known for their injurious effect on health. They damage body structures, oxidize lipids, injure blood vessels, can lead to DNA mutations, contribute to inflammation and are thought to play a key role in degenerative disorders. On a different front, elevations in blood glucose levels damage proteins and lipids. Indeed, sugars and their intermediates will attach to amino acid residues and lipids leading to the formation of advanced glycation end products and advanced lipoxidation end products. As we age, insulin sensitivity decreases which contributes to increases in blood glucose levels, which accelerates the glycation/lipoxidation process. This leads to the loss of function in cellular structures and speeds up the aging process. Alpha lipoic acid offsets this course by increasing insulin sensitivity, which enhances glucose uptake by cells and decreases blood sugar levels.

 

Research

An Antioxidant fo Macular Degeneration

Age-related macular degeneration (AMD) is thought to be related to oxidative stress. One double-blind, placebo-controlled study found that R-alpha lipoic acid supplementation increased levels of superoxide dismutase (SOD), the main antioxidant in the mitochondria, in subjects with early and intermediate dry AMD. Therefore, it is thought that lipoic acid could help prevent the progression of AMD.

Support for Diabetics on Many Levels

Several recent studies have administered alpha lipoic acid to either type 1 or type 2 diabetic subjects. The longest duration was 6 months with the highest dose at 1200mg/day. The results showed some reduced platelet activity (since platelet activity is typically elevated in diabetes), slightly reduced oxidative stress, increased antioxidant levels (glutathione peroxidase), dose-dependent reduced HbA1c, lower fasting blood glucose, post-prandial blood glucose and insulin resistance, and possibly reduced lipid peroxidation.

Supplementation with a sustained release alpha lipoic acid supplement resulted in sustained decreases in blood glucose that averaged 184mg/dl or just over a 46% decrease.

Diabetic Neuropathy

Another study administered a combination of superoxide dismutase (SOD) with 600mg of alpha-lipoic acid to diabetes mellitus patients with diabetic neuropathy for 4 months. These patients had deficits in both sensory and motor nerve function. The treatment improved both perceived pain and sensory nerve conduction, showing that SOD and ALA might be a feasible treatment for diabetic neuropathy.

A second study examining ALA for diabetic neuropathy administered a high dose of 1800mg (600mg 3x/daily) or a placebo to diabetic patients for 12 weeks. After only 2 weeks, symptoms improved significantly including pain, numbness and burning sensations. These symptoms continued to improve until the end of treatment along with HbA1c. Interestingly, nerve conduction velocity did not improve in this study.

A Meta-analysis reviewed all the clinical trials undertaken for the treatment of diabetic neuropathy with alpha lipoic acid. 1258 diabetic patients were included in the analysis, the largest study population ever used to evaluate the effectiveness of a particular treatment for diabetic neuropathy. The conclusions favored the use of lipoic acid in this population. The analysis revealed that the molecule is an effective treatment for neuropathies and that oral supplementation for 4-7 months reduces neuropathic deficits and improves cardiac neuropathy. It was also clear that Alpha lipoic acid is a well-tolerated and safe treatment.

Other Diabetic Complications

In diabetic rats, alpha lipoic acid reduces growth retardation and congenital anomalies in fetuses, supporting the theory that reactive oxygen species are linked to embryonic malformations. Animal studies have shown that in a high fructose diet, lipoic acid helps maintain the function of the antioxidant system and lowers lipid peroxidation and insulin resistance.

Inflammation

How does lipoic acid help reduce inflammation? Alpha lipoic acid is thought to reduce oxidation and inflammation by mediating the cyclic AMP/ protein kinase A cascade. ALA has been shown to suppress NK cell (natural killer cell) activation and cytotoxicity and reduce IL-6, IL-17 and T-cell activation. When 1200mg of ALA were given to MS (multiple sclerosis) patients, cAMP did indeed increase.

Boosts Glutathione

Studies in older rats have shown that glutathione levels drop significantly with age. Glutathione is a powerful free radical scavenger and the major antioxidant species found in cells. Drops in glutathione levels in older rats reached 58% in the heart and 66% in the brain in comparison to younger counterparts. Lipoic acid supplementation increased glutathione levels in the aging brain.

Mitochondrial Dysfunction & Parkinson’s Disease

One very interesting cell culture study found that R-lipoic acid prevented GSH (glutathione) loss and subsequently prevented impaired function of mitochondrial complex I, which usually go hand in hand. This is relevant because oxidative stress is thought to play a role in Parkinson’s disease. Oxidative stress is aggravated with decreased levels of glutathione, which can result in mitochondrial dysfunction and therefore cellular dysfunction and cell death in the neurons in the substantia nigra, the area most affected in Parkinson’s disease.

Liver Protection

In another experiment, liver cells isolated from young and older rats were used to see the effectiveness of alpha lipoic acid at preventing liver injury. Total glutathione cellular levels were 37.7% lower in older rats. (R )-lipoic acid significantly protected the hepatocytes against Butylhydroperoxide (an oxidative stress inducing agent) both in vitro and in vivo. The results suggest that ALA is indicated in liver conditions where oxidative stress confers pathology such as alcoholic liver disease and viral hepatitis. ALA was also shown to protect against cadmium-induced hepatotoxicity in animals.

 

Market Trends

Lipoic acid is a popular antioxidant and is also known for its anti-glycemic effects. However, most lipoic acid supplements are “racemic” mixtures of 50% R( ) and 50% S(-) lipoic acid. The R( ) form is naturally-occurring in the body whereas the S(-) form is a synthetic byproduct that is formed during the process of making lipoic acid. The S(-) form can actually antagonize or inhibit the activity of the R( ) form, and even cause adverse effects. It’s therefore very important to be sure that you are getting pure or almost pure R-lipoic acid rather than regular alpha-lipoic acid.

AOR Advantage

In 1999, AOR was the first in the world to offer pure R( ) lipoic acid, based on the most current research. 2005 marked another world-first, R( ) lipoic acid in a sustained release formula to overcome the challenges associated with its short half-life in order to benefit the most from this tremendous nutrient over a longer period of time.

References

Al Ghafli MH, Padmanabhan R, Kataya HH, Berg B. Effects of alpha-lipoic acid supplementation on maternal diabetes-induced growth retardation and congenital anomalies in rat fetuses. Mol Cell Biochem. 2004 Jun;261(1-2):123-35.

Bustamante J, Lodge JK, Marcocci L, Tritschler HJ, Packer L, Rihn BH. Alpha-lipoic acid in liver metabolism and disease. Free Radic Biol Med. 1998 Apr;24(6):1023-39. Review.

Hagen TM, Vinarsky V, Wehr CM, Ames BN. (R)-alpha-lipoic acid reverses the age-associated increase in susceptibility of hepatocytes to tert-butylhydroperoxide both in vitro and in vivo. Antioxid Redox Signal. 2000 Fall;2(3):473-83.

Hagen TM, Ingersoll RT, Lykkesfeldt J, Liu J, Wehr CM, Vinarsky V, Bartholomew JC, Ames AB. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J. 1999 Feb;13(2):411-8.

Hendler SS, Rorvik D (2001). Physicians’ Desk Reference for Nutritional Supplements. New Jersey: Thompson PDR

Huerta AE, Navas-Carretero S, Prieto-Hontoria PL, Martínez JA, Moreno-Aliaga MJ. Effects of α-lipoic acid and eicosapentaenoic acid in overweight and obese women during weight loss. Obesity (Silver Spring). 2014 Dec 31. 

Jellin JM, Gregory P, Batz F, Hitchens K, et al. Pharmacist’s Letter/ Prescriber’s Letter Natural Medicines Comprehensive Database. 3rd ed. Stockton, CA: Therapeutic Research Faculty; 2000

McNeilly AM, Davison GW, Murphy MH, Nadeem N, Trinick T, Duly E, Novials A, McEneny J. Effect of α-lipoic acid and exercise training on cardiovascular disease risk in obesity with impaired glucose tolerance. Lipids Health Dis. 2011 Nov 22;10:217.

Packer L, Kraemer K, Rimbach G. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition. 2001 Oct;17(10):888-95. Review. 

Suh JH, Wang H, Liu RM, Liu J, Hagen TM. (R)-alpha-lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: evidence for increased cysteine requirement for GSH synthesis. Arch Biochem Biophys. 2004 Mar 1;423(1):126-35.

Suh JH, Shigeno ET, Morrow JD, Cox B, Rocha AE, Frei B, Hagen TM. Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid. FASEB J. 2001 Mar;15(3):700-6.

 

Abstract

Effects of α-lipoic acid and eicosapentaenoic acid in overweight and obese women during weight loss.

Obesity (Silver Spring). 2014 Dec 31.

Huerta AE, Navas-Carretero S, Prieto-Hontoria PL, Martínez JA, Moreno-Aliaga MJ.

OBJECTIVE: To evaluate the potential body weight-lowering effects of dietary supplementation with eicosapentaenoic acid (EPA) and α-lipoic acid separately or combined in healthy overweight/obese women following a hypocaloric diet.

METHODS: This is a short-term double-blind placebo-controlled study with parallel design that lasted 10 weeks. Of the randomized participants, 97 women received the allocated treatment [Control, EPA (1.3 g/d), α-lipoic acid (0.3 g/d), and EPA   α-lipoic acid (1.3 g/d   0.3 g/d)], and 77 volunteers completed the study. All groups followed an energy-restricted diet of 30% less than total energy expenditure. Body weight, anthropometric measurements, body composition, resting energy expenditure, blood pressure, serum glucose, and insulin and lipid profile, as well as leptin and ghrelin levels, were assessed at baseline and after nutritional intervention.

RESULTS: Body weight loss was significantly higher (P < 0.05) in those groups supplemented with α-lipoic acid. EPA supplementation significantly attenuated (P < 0.001) the decrease in leptin levels that occurs during weight loss. Body weight loss improved lipid and glucose metabolism parameters but without significant differences between groups.

CONCLUSIONS: The intervention suggests that α-lipoic acid supplementation alone or in combination with EPA may help to promote body weight loss in healthy overweight/obese women following energy-restricted diets.

 

Effect of (R)-α-lipoic acid supplementation on serum lipids and antioxidative ability in patients with age-related macular degeneration.

Ann Nutr Metab. 2012;60(4):293-7.

Sun YD, Dong YD, Fan R, Zhai LL, Bai YL, Jia LH.

BACKGROUND/AIMS: Supplementation with antioxidants is of special interest in preventing or delaying the development and progression of age-related macular degeneration (AMD). This investigation aimed to assess the effect of α- lipoic acid (LA) on serum lipids, serum malondialdehyde (MDA) and superoxide dismutase (SOD) in patients with AMD.

METHODS: A total of 62 patients (50-75 years old) with early and intermediate dry form of AMD were randomly assigned to two groups, i.e. LA administration (n = 32) and placebo (n = 30). The levels of serum lipids and MDA and SOD activity were measured before and after LA and placebo intervention.

RESULTS: Compared with the parameters at baseline, serum total cholesterol (CHO), triglyceride and high- and low-density lipoprotein CHO (HDL and LDL) levels were not significantly different after LA and placebo intervention. There was a slight but statistically nonsignificant decrease in serum MDA levels and a statistically significant increase in serum SOD activity after LA intervention. There were no statistically significant differences in serum MDA levels or SOD activity after placebo intervention.

CONCLUSION: The apparent increase in SOD activity caused by LA supplementation indicates that LA may have a possible preventive effect in the development of AMD through an antioxidant mechanism.

 

Glycemic and oxidative status of patients with type 2 diabetes mellitus following oral administration of alpha-lipoic acid: a randomized double-blinded placebo-controlled study.

Asia Pac J Clin Nutr. 2012;21(1):12-21.

Porasuphatana S, Suddee S, Nartnampong A, Konsil J, Harnwong B, Santaweesuk A.

 Despite well-controlled blood glucose levels, diabetic complications still inevitably take place via several mechanisms including excessive generation of free radicals in patients who suffer from diabetes mellitus (DM). A randomized double-blind placebo-controlled clinical trial to investigate the effectiveness of oral supplementation of DL-alpha-lipoic acid (ALA) on glycemic and oxidative status in DM patients was conducted. Thirty eight outpatients with type 2 DM were recruited and randomly assigned to either placebo or treatment in various doses of ALA (300, 600, 900, and 1200 mg/day) for 6 months. Following the treatment, all subjects were evaluated for glucose status and oxidative biomarkers. Results showed that fasting blood glucose, HbA1c trended to decrease in a dose-dependent manner. Increase of urinary PGF2α-Isoprostanes (F2α-IsoP) was noted in placebo but not ALA-treated groups, indicating possible suppressing action of ALA on lipid peroxidation in DM subjects. 8-Hydroxy-2′-deoxyguanosine (8-OHdG) levels, however, were similar in both placebo and ALA groups as well as urinary microalbumin and serum creatinine. Safety evaluation was monitored and treatment was found to be well tolerated despite some minor side effects. Results from this study reflected the benefits of ALA in glucose status with slight efficiency on oxidative stress-related deterioration in DM patients.

 

Combination of alpha lipoic acid and superoxide dismutase leads to physiological and symptomatic improvements in diabetic neuropathy.

Drugs R D. 2012 Mar 1;12(1):29-34.

Bertolotto F, Massone A.

 BACKGROUND AND OBJECTIVE: The management of diabetic neuropathy is still a challenge for physicians. The aim of this study was to assess the efficacy of a new combination of alpha lipoic acid and superoxide dismutase for the treatment of diabetic neuropathy.

METHODS: The setting of this study was ambulatory (outpatient) care. A prospective, non-randomized, open-label study was conducted in 50 patients with diabetes mellitus and with a deficit in both motor and sensory nerve conduction. Treatment was with a new combination of alpha lipoic acid and superoxide dismutase (ALA600SOD®) for 4 months. Electroneurographic parameters and perceived pain were assessed at baseline and after treatment.

RESULTS: After 4 months of treatment, patients significantly (p

CONCLUSION: The combination of two powerful antioxidant agents leads to improvement in both subjective and objective parameters in patients with diabetic neuropathy. New profitable directions for investigations are opened for a non-invasive treatment of diabetic neuropathy in the future.

 

Effect of α-lipoic acid on platelet reactivity in type 1 diabetic patients.

Diabetes Care. 2012 Feb;35(2):196-7.

Mollo R, Zaccardi F, Scalone G, Scavone G, Rizzo P, Navarese EP, Manto A, Pitocco D, Lanza GA, Ghirlanda G,Crea F.

OBJECTIVE: Type 1 diabetes is associated with increased platelet reactivity. We investigated whether α-lipoic acid (ALA) has any effect on platelet reactivity in these patients.

RESEARCH DESIGN AND METHODS: We randomly assigned 51 type 1 diabetic patients to ALA (600 mg once daily) or placebo for 5 weeks. Platelet reactivity was evaluated by the PFA-100 method and by measuring CD41 and CD62 platelet expression. C-reactive protein (CRP) and 8-iso-prostaglandin F2α serum levels also were measured.

RESULTS: Baseline variables were similar in the two groups. After treatment, closure time was longer (P = 0.006) and CD62P platelet expression was lower, both before (P = 0.002) and after (P = 0.009) ADP stimulation in the ALA group compared with the placebo group. CRP and 8-iso-prostaglandin F2α levels showed no differences between the two groups.

CONCLUSIONS: Our data show that ALA reduces measures of platelet reactivity ex vivo in type 1 diabetic patients, independently of antioxidant or anti-inflammatory effects.

 

Effect of alpha-lipoic acid on blood glucose, insulin resistance and glutathione peroxidase of type 2 diabetic patients.

Saudi Med J. 2011 Jun;32(6):584-8.

Ansar H, Mazloom Z, Kazemi F, Hejazi N.

OBJECTIVE: To examine the effects of alpha-lipoic acid (ALA) treatment over a period of 2 months on fasting blood glucose (FBG), insulin resistance (IR), and glutathione peroxidase (GH-Px) activity in type 2 diabetes (T2DM) patients.

METHODS: This study took place in Motahari Clinic, Shiraz, Iran, which is affiliated to Shiraz University of Medical Sciences from May to October 2006. Type 2 DM patients (n=57) were divided into 2 groups to receive either ALA (300 mg daily) or placebo by systematic randomization, and were followed-up for 8 weeks. After an overnight fasting and 2 hours after breakfast, patients’ blood samples were drawn and tested for FBG, 2 hours PPG, serum insulin level, and GH-Px activity.

RESULTS: The result of the study showed a significant decrease in FBG and PPG levels, IR-Homeostasis Model Assessment (IR-HOMA index) and GH-Px level in the ALA group. The comparison of differences between FBG and IR at the beginning and at the end of study in the ALA treated group and the placebo group were also significant.

CONCLUSION: This study supports the use of ALA as an antioxidant in the care of diabetic patients.

 

 [Efficacy and safety of high-dose α-lipoic acid in the treatment of diabetic polyneuropathy]. [Article in Chinese]

Zhonghua Yi Xue Za Zhi. 2010 Sep 21;90(35):2473-6.

Gu XM, Zhang SS, Wu JC, Tang ZY, Lu ZQ, Li H, Liu C, Chen L, Ning G.

OBJECTIVE: To evaluate the efficacy and safety of high-dose α-lipoic acid in the treatment of diabetic polyneuropathy with regards to sensory symptoms and nerve conduction velocity.

METHODS: A total of 236 diabetics with symptomatic polyneuropathy were enrolled into this 5-center, randomized, double-blind and placebo-controlled study of α-lipoic acid 1800 mg daily (n = 117) or matching placebo (n = 119) for 12 weeks. The primary outcome was total symptom score (TSS). Secondary end points included nerve conduction velocity, individual symptom score, HbA1c and safety parameters. The above parameters were reviewed and recorded at zero point and after treatment for 2, 4, 8, 12 weeks separately.

RESULTS: 73.27% patients with symptomatic polyneuropathy improved after treatment with α-lipoic acid for 12 weeks versus 18.27% with placebo. TSS declined by 2.6 ± 2.3 with α-lipoic acid. And it was more than 0.7 ± 1.4 versus placebo (P < 0.05). TSS decreased quickly after treatment with α-lipoic acid for 2 weeks (P < 0.05). And it was better than placebo. Individual symptom scores of pain, extremity numbness, burning sensation or resting abnormal sensations were significantly diminished as compared to those before treatment and placebo group (all P < 0.05). Nerve conduction velocity had no change. HbA1c further decreased at the end of trial after α-lipoic acid treatment (P < 0.05). The incidence rates of adverse effects were 25.4% vs 11.8% in the treatment and control groups. The major manifestation was burning sensation from throat to stomach (12.7%).

CONCLUSION: Oral treatment with high-dose α-lipoic acid for 12 weeks may improve symptoms in patients with diabetic polyneuropathy. Dose of 600 mg thrice daily for 2 weeks has marked effects with a reasonable safety.

 

Lipoic acid attenuates inflammation via cAMP and protein kinase A signaling.

PLoS One. 2010 Sep 28;5(9).

Salinthone S, Yadav V, Schillace RV, Bourdette DN, Carr DW.

BACKGROUND: Abnormal regulation of the inflammatory response is an important component of diseases such as diabetes, Alzheimer’s disease and multiple sclerosis (MS). Lipoic acid (LA) has been shown to have antioxidant and anti-inflammatory properties and is being pursued as a therapy for these diseases. We first reported that LA stimulates cAMP production via activation of G-protein coupled receptors and adenylyl cyclases. LA also suppressed NK cell activation and cytotoxicity. In this study we present evidence supporting the hypothesis that the anti-inflammatory properties of LA are mediated by the cAMP/PKA signaling cascade. Additionally, we show that LA oral administration elevates cAMP levels in MS subjects.

METHODOLOGY/PRINCIPAL FINDINGS: We determined the effects of LA on IL-6, IL-17 and IL-10 secretion using ELISAs. Treatment with 50 µg/ml and 100 µg/ml LA significantly reduced IL-6 levels by 19 and 34%, respectively, in T cell enriched PBMCs. IL-17 levels were also reduced by 35 and 50%, respectively. Though not significant, LA appeared to have a biphasic effect on IL-10 production. Thymidine incorporation studies showed LA inhibited T cell proliferation by 90%. T-cell activation was reduced by 50% as measured by IL-2 secretion. Western blot analysis showed that LA treatment increased phosphorylation of Lck, a downstream effector of protein kinase A. Pretreatment with a peptide inhibitor of PKA, PKI, blocked LA inhibition of IL-2 and IFN gamma production, indicating that PKA mediates these responses. Oral administration of 1200 mg LA to MS subjects resulted in increased cAMP levels in PBMCs four hours after ingestion. Average cAMP levels in 20 subjects were 43% higher than baseline.

CONCLUSIONS/SIGNIFICANCE: Oral administration of LA in vivo resulted in significant increases in cAMP concentration. The anti-inflammatory effects of LA are mediated in part by the cAMP/PKA signaling cascade. These novel findings enhance our understanding of the mechanisms of action of LA.

 

Chronic dietary a-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice.

Neurobiology of Aging. 2007;28:213-225.

Joseph F. Quinn, Joseph R. Bussiere, Rebecca S. Hammond, Thomas J. Montine, Edward Henson, Richard E. Jones, Robert W. Stackman Jr.

Oxidative stress may play a key role in Alzheimer’s disease (AD) neuropathology. Here, the effects of the antioxidant, alpha-lipoic acid (ALA) were tested on the Tg2576 mouse, a transgenic model of cerebral amyloidosis associated with AD. Ten-month old Tg2576 and wild type mice were fed an ALA-containing diet (0.1%) or control diet for 6 months and then assessed for the influence of diet on memory and neuropathology. ALA-treated Tg2576 mice exhibited significantly improved learning, and memory retention in the Morris water maze task compared to untreated Tg2576 mice. Twenty-four hours after contextual fear conditioning, untreated Tg2576 mice exhibited significantly impaired context-dependent freezing. ALA-treated Tg2576 mice exhibited significantly more context freezing than the untreated Tg2576 mice. Assessment of brain soluble and insoluble beta-amyloid levels revealed no differences between ALA-treated and untreated Tg2576 mice. Brain levels of nitrotyrosine, a marker of nitrative stress, were elevated in Tg2576 mice, while F2 isoprostanes and neuroprostanes, oxidative stress markers, were not elevated in the Tg2576 mice relative to wild type. These data indicate that chronic dietary ALA can reduce hippocampal-dependent memory deficits of Tg2576 mice without affecting beta-amyloid levels or plaque deposition.

 

Development of a sustained release dosage form for alpha-lipoic acid. II. Evaluation in human volunteers.

Drug Dev Ind Pharm. 2004 Jan;30(1):35-42.

Bernkop-Schnürch A, Reich-Rohrwig E, Marschütz M, Schuhbauer H, Kratzel M.

Within this study an oral sustained release dosage form of alpha-lipoic acid (thioctic acid) has been generated and evaluated in healthy volunteers. A granulate comprising 56.8% alpha-lipoic acid and 43.2% chitosan acetate was compressed to tablets (weight: 0.45 g; diameter: 10.0 mm; thickness: 4 mm). Three of these tablets were administered at once orally to each volunteer. Prior to administration and then every hour for 12 hours blood samples were taken from the antebrachial vein. alpha-Lipoic acid concentrations in plasma were quantified via precolumn derivatization and reversed-phase high-performance liquid chromatography (HPLC). Results demonstrated that an increased plasma level of alpha-lipoic acid can be achieved by this formulation for at least 12 hours. Within this time period at least two maximum plasma concentrations were reached. The first one is based on the release of alpha-lipoic acid, which is not ionically and therefore only loosely bound to chitosan, whereas a second maximum is based on the release of the drug during the enzymatic degradation of the chitosan matrix in the colon. The AUC(0-12) was determined to be 183.8 /- 101.4 microg x min/mL (mean /- SD; n = 8). Because of the pulsed sustained release of alpha-lipoic acid, the dosage form described here seems to be highly beneficial in order to stimulate the glucose uptake in the case of diabetes type II.

 

(R)-alpha-lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: evidence for increased cysteine requirement for GSH synthesis.

Arch Biochem Biophys. 2004 Mar 1;423(1):126-35.

Suh JH, Wang H, Liu RM, Liu J, Hagen TM.

Age-related depletion of GSH levels and perturbations in its redox state may be especially deleterious to metabolically active tissues, such as the heart and brain. We examined the extent and the mechanisms underlying the potential age-related changes in cerebral and myocardial GSH status in young and old F344 rats and whether administration of (R)-alpha-lipoic acid (LA) can reverse these changes. Our results show that GSH/GSSG ratios in the aging heart and the brain declined by 58 and 66% relative to young controls, respectively (p < 0.001). Despite a consistent loss in GSH redox status in both tissues, only cerebral GSH levels declined with age (p < 0.001). To discern the potential mechanisms underlying this differential loss, the levels and the activities of gamma-glutamylcysteine ligase (GCL) and cysteine availability were determined. There were no significant age-related changes in substrate or enzyme levels, or GCL activity when saturating amounts of substrates were provided. However, kinetic analysis of GCL in brains of old rats displayed a significant increase (p < 0.05) in the apparent [Km] for cysteine (Km cys) vs. young rats (84.3 /-25.4 vs. 179.0 /-49.0; young and old, respectively), resulting in a 40% loss in apparent catalytic turnover of the enzyme. Thus, the age-related decline in total GSH appears to be mediated, in part, by a general decrement in GCL catalytic efficiency. Treating old rats with LA (40 mg/kg body wt; by i.p.) markedly increased tissue cysteine levels by 54% 12 h following treatment and subsequently restored the cerebral GSH levels. Moreover, LA improved the age-related changes in the tissue GSH/GSSG ratios in both heart and the brain. These results demonstrate that LA is an effective agent to restore both the age-associated decline in thiol redox ratio as well as increase cerebral GSH levels that otherwise decline with age.

 

Pre-treatment with R-lipoic acid alleviates the effects of GSH depletion in PC12 cells: implications for Parkinson’s disease therapy.

Neurotoxicology. 2002 Oct;23(4-5):479-86.

Bharat S, Cochran BC, Hsu M, Liu J, Ames BN, Andersen JK.

Oxidative stress is believed to play a key role in the degeneration of dopaminergic neurons in the substantia nigra (SN) of Parkinson’s disease (PD) patients. An important biochemical feature of PD is a significant early depletion in levels of the thiol antioxidant compound glutathione (GSH) which may lead to the generation of reactive oxygen species (ROS), mitochondrial dysfunction, and ultimately to subsequent neuronal cell death. In earlier work from our laboratory, we demonstrated that depletion of GSH in dopaminergic PC12 cells affects mitochondrial integrity and specifically impairs the activity of mitochondrial complex I. Here we report that pre-treatment of PC12 cells with R-lipoic acid acts to prevent depletion of GSH content and preserves the mitochondrial complex I activity which normally is impaired as a consequence of GSH loss.

 

Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid.

FASEB J. 2001 Mar;15(3):700-6.

Suh JH, Shigeno ET, Morrow JD, Cox B, Rocha AE, Frei B, Hagen TM.

Oxidative stress has been implicated as a causal factor in the aging process of the heart and other tissues. To determine the extent of age-related myocardial oxidative stress, oxidant production, antioxidant status, and oxidative DNA damage were measured in hearts of young (2 months) and old (28 months) male Fischer 344 rats. Cardiac myocytes isolated from old rats showed a nearly threefold increase in the rate of oxidant production compared to young rats, as measured by the rates of 2,7-dichlorofluorescin diacetate oxidation. Determination of myocardial antioxidant status revealed a significant twofold decline in the levels of ascorbic acid (P = 0.03), but not alpha-tocopherol. A significant age-related increase (P = 0.05) in steady-state levels of oxidative DNA damage was observed, as monitored by 8-oxo-2′-deoxyguanosine levels. To investigate whether dietary supplementation with (R)-alpha-lipoic acid (LA) was effective at reducing oxidative stress, young and old rats were fed an AIN-93M diet with or without 0.2% (w/w) LA for 2 wk before death. Cardiac myocytes from old, LA-supplemented rats exhibited a markedly lower rate of oxidant production that was no longer significantly different from that in cells from unsupplemented, young rats. Lipoic acid supplementation also restored myocardial ascorbic acid levels and reduced oxidative DNA damage. Our data indicate that the aging rat heart is under increased mitochondrial-induced oxidative stress, which is significantly attenuated by lipoic acid supplementation.

 

(R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate.

FASEB J 1999 Feb; 13(2): 411-8.

Hagen TM, Ingersoll RT, Lykkesfeldt J, Liu J, Wehr CM, Vinarsky V, Bartholomew JC, Ames AB.

A diet supplemented with (R)-lipoic acid, a mitochondrial coenzyme, was fed to old rats to determine its efficacy in reversing the decline in metabolism seen with age. Young (3 to 5 months) and old (24 to 26 months) rats were fed an AIN-93M diet with or without (R)-lipoic acid (0.5% w/w) for 2 wk, killed, and their liver parenchymal cells were isolated. Hepatocytes from untreated old rats vs. young controls had significantly lower oxygen consumption (P

 

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