Benfotiamine : A Potent AGE-Inhibitor
April 14, 2006 -
James South, MA
http://vitamin-resou...tail.cfm?id=491Something else
Benfotiamine is the most potent of the allithiamines, a unique class of thiamine derivatives (vitamin B1) with a highly specific structure which enables them to pass easily through cell membranes. As such, it is much better absorbed (5-25 times better!) than thiamine and remains in the body for considerably longer. Benfotiamine is therefore much more effective at correcting traditional vitamin B1 deficiency (beri beri, alcoholism) than thiamine itself. However, its main benefits lie in a different area: Benfotiamine is remarkably effective at inhibiting the formation of AGE - Advanced Glycation Endproducts. It increases threefold the concentration of the endogenous enzyme transketolase which breaks down AGE and converts them into harmless compounds. AGE’s main targets are the nerves, blood vessels, eyes and kidneys, and since diabetics produce AGE in excess, this discovery is particularly significant for them. Regular supplementation with benfotiamine can significantly improve their quality of life as has been shown in controlled studies. Of course, benfotiamine, like carnosine or lipoic acid, is a valuable weapon for anyone wish to fight the inevitable process of tissue ‘caramelisation’. Glycation (caramelisation of cells), together with oxidation, is a basic mechanism of the biochemical breakdown associated with ageing, though the compounds capable of controlling it are fewer in number and less well-known. Benfotiamine is a remarkable AGE inhibitor, tested successfully not just in vitro and on animals, but actually on humans.
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Titre du document / Document title
Benfotiamine accelerates the healing of ischaemic diabetic limbs in mice through protein kinase b/akt-mediated potentiation of angiogenesis and inhibition of apoptosis
Auteur(s) / Author(s)
GADAU S. (1) ; EMANUELI C. (2 3) ; VAN LINTHOUT S. (1) ; GRAIANI G. (2) ; TODARO M. (4) ; MELONI M. (2) ; CAMPESI I. (2) ; INVERNICI G. (5) ; SPILLMANN F. (1) ; WARD K. (1) ; MADEDDU P. (1 6) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) Experimental Medicine and Gene Therapy, National Institute of Biostructures and Biosystems (INBB), Osilo, ITALIE
(2) Molecular and Cellular Medicine, National Institute of Biostructures and Biosystems (INBB), Alghero, ITALIE
(3) Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol BS2 8HW, ROYAUME-UNI
(4) Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, ITALIE
(5) Besta Neurological Institute, Milan, ITALIE
(6) Multimedica Research Institute, Milan, ITALIE
Résumé / Abstract
Aims/hypothesis: Benfotiamine, a vitamin Bl analogue, reportedly prevents diabetic microangiopathy. The aim of this study was to evaluate whether benfotiamine is of benefit in reparative neovascularisation using a type I diabetes model of hindlimb ischaemia. We also investigated the involvement of protein kinase B (PKB)/Akt in the therapeutic effects of benfotiamine. Methods: Streptozotocin-induced diabetic mice, given oral benfotiamine or vehicle, were subjected to unilateral limb ischaemia. Reparative neovascularisation was analysed by histology. The expression of Nos3 and Casp3 was evaluated by real-time PCR, and the activation state of PKB/Akt was assessed by western blot analysis and immunohistochemistry. The functional importance of PKB/Akt in benfotiamine-induced effects was investigated using a dominant-negative construct. Results: Diabetic muscles showed reduced transketolase activity, which was corrected by benfotiamine. Importantly, benfotiamine prevented ischaemia-induced toe necrosis, improved hindlimb periusion and oxygenation, and restored endothelium-dependent vasodilation. Histological studies revealed the improvement of reparative neovascularisation and the inhibition of endothelial and skeletal muscle cell apoptosis. In addition, benfotiamine prevented the vascular accumulation of advanced glycation end products and the induction of pro-apoptotic caspase-3, while restoring proper expression of Nos3 and Akt in ischaemic muscles. The benefits of benfotiamine were nullified by dominant-negative PKB/Akt. In vitro, benfotiamine stimulated the proliferation of human EPCs, while inhibiting apoptosis induced by high glucose. In diabetic mice, the number of circulating EPCs was reduced, with the deficit being corrected by benfotiamine. Conclusions/ interpretation: We have demonstrated, for the first time, that benfotiamine aids the post-ischaemic healing of diabetic animals via PKB/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis. In addition, benfotiamine combats the diabetes-induced deficit in endothelial progenitor cells.
Revue / Journal Title
Diabetologia (Diabetologia) ISSN 0012-186X
Source / Source
2006, vol. 49, no2, pp. 405-420 [16 page(s) (article)] (52 ref.)
Langue / Language
Anglais
Editeur / Publisher
Springer, Berlin, ALLEMAGNE (1965) (Revue)
Mots-clés anglais / English Keywords
Vertebrata ; Mammalia ; Rodentia ; Micronutrient ; Cell death ; Endocrinopathy ; Cardiovascular disease ; Enzyme ; Hydrolases ; Peptidases ; Mouse ; Vitamin ; Precursor cell ; Endothelial cell ; Cysteine endopeptidases ; Caspase ; Diabetes mellitus ; Animal ; Ischemia ; Age ; Reaction product ; Apoptosis ; Inhibition ; Angiogenesis ; Akt protein kinase ;
Mots-clés français / French Keywords
Vertebrata ; Mammalia ; Rodentia ; Micronutriment ; Mort cellulaire ; Endocrinopathie ; Appareil circulatoire pathologie ; Enzyme ; Hydrolases ; Peptidases ; Souris ; Vitamine ; Cellule précurseur ; Cellule endothéliale ; Cysteine endopeptidases ; Caspase ; Diabète ; Animal ; Ischémie ; Age ; Produit réaction ; Apoptose ; Inhibition ; Angiogenèse ; Akt protein kinase ;
002b21e01a ;
Mots-clés espagnols / Spanish Keywords
Vertebrata ; Mammalia ; Rodentia ; Micronutriente ; Muerte celular ; Endocrinopatía ; Aparato circulatorio patología ; Enzima ; Hydrolases ; Peptidases ; Ratón ; Vitamina ; Célula precursor ; Célula endotelial ; Cysteine endopeptidases ; Caspase ; Diabetes ; Animal ; Isquemia ; Edad ; Producto reacción ; Apoptosis ; Inhibición ; Angiogénesis ; Akt protein kinase ;
Mots-clés d'auteur / Author Keywords
Advanced glycation end-products ; AGEs ; Angiogenesis ; Apoptosis ; Benfotiamine ; Caspase ; Diabetes ; Endothelial progenitor cells ; Ischaemia ; Vitamin B1 ;
Localisation / Location
INIST-CNRS, Cote INIST : 13012, 35400013572921.0210
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In Vitro Kinetic Studies of Formation of Antigenic Advanced Glycation End Products (AGEs)
NOVEL INHIBITION OF POST-AMADORI GLYCATION PATHWAYS
(Received for publication, September 6, 1996, and in revised form, October 30, 1996)
A. Ashley Booth , Raja G. Khalifah , Parvin Todd and Billy G. Hudson
From the Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160-7421
Nonenzymatic protein glycation (Maillard reaction) leads to heterogeneous, toxic, and antigenic advanced glycation end products ("AGEs") and reactive precursors that have been implicated in the pathogenesis of diabetes, Alzheimer's disease, and normal aging. In vitro inhibition studies of AGE formation in the presence of high sugar concentrations are difficult to interpret, since AGE-forming intermediates may oxidatively arise from free sugar or from Schiff base condensation products with protein amino groups, rather than from just their classical Amadori rearrangement products. We recently succeeded in isolating an Amadori intermediate in the reaction of ribonuclease A (RNase) with ribose (Khalifah, R. G., Todd, P., Booth, A. A., Yang, S. X., Mott, J. D., and Hudson, B. G. (1996) Biochemistry 35, 4645-4654) for rapid studies of post-Amadori AGE formation in absence of free sugar or reversibly formed Schiff base precursors to Amadori products. This provides a new strategy for a better understanding of the mechanism of AGE inhibition by established inhibitors, such as aminoguanidine, and for searching for novel inhibitors specifically acting on post-Amadori pathways of AGE formation. Aminoguanidine shows little inhibition of post-Amadori AGE formation in RNase and bovine serum albumin, in contrast to its apparently effective inhibition of initial (although not late) stages of glycation in the presence of high concentrations of sugar. Of several derivatives of vitamins B1 and B6 recently studied for possible AGE inhibition in the presence of glucose (Booth, A. A., Khalifah, R. G., and Hudson, B. G. (1996) Biochem. Biophys. Res. Commun. 220, 113-119), pyridoxamine and, to a lesser extent, thiamine pyrophosphate proved to be novel and effective post-Amadori inhibitors that decrease the final levels of AGEs formed. Our mechanism-based approach to the study of AGE inhibition appears promising for the design and discovery of novel post-Amadori AGE inhibitors of therapeutic potential that may complement others, such as aminoguanidine, known to either prevent initial sugar attachment or to scavenge highly reactive dicarbonyl intermediates.
Finally
Pharmacokinetics of thiamine derivatives especially of benfotiamine.
Int J Clin Pharmacol Ther 1996 Feb; 34(2): 47-50.
Loew D.
Pharmacokinetic data of orally administered lipid-soluble thiamine analogues like benfotiamine are reviewed and assessed. It is quite clear that benfotiamine is absorbed much more better than water-soluble thiamine salts: maximum plasma levels of thiamine are about 5 times higher after benfotiamine, the bioavailability is at maximum about 3.6 times as high as that of thiamine hydrochloride and better than other lipophilic thiamine derivates. The physiological activity (alphaETK) increased only after benfotiamine was given. Due to its excellent pharmacokinetic profile benfotiamine should be preferred in treatment of relevant indications.
A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy.
Exp Clin Endocrinol Diabetes 1996; 104(4): 311-6.
Stracke H, Lindemann A, Federlin K.
In a double-blind, randomized, controlled study, the effectiveness of treatment with a combination of Benfotiamine (an Allithiamine, a lipid-soluble derivative of vitamin B1 with high bioavailability) plus vitamin B6/B12 on objective parameters of neuropathy was studied over a period of 12 weeks on 24 diabetic patients with diabetic polyneuropathy. The results showed a significant improvement (p = 0.006) of nerve conduction velocity in the peroneal nerve and a statistical trend toward improvement of the vibration perception threshold. Long-term observation of 9 patients with verum over a period of 9 months support the results. Therapy-specific adverse effects were not seen. The results of this double-blind investigation, of the long-term observation and of the reports in the literature support the contention that the neurotropic benfotiamine-vitamin B combination represents a starting point in the treatment of diabetic polyneuropathy.
Benfotiamin inhibits intracellular formation of advanced Glycation endproducts in vivo.
Diabetes. 2000 May; 49(Suppl1): A143(P583).
Lin J, Alt A, Liersch J, Bretzel RG, Brownlee MA, Hammes HP.
We have demonstrated previously that intracellular formation of the advanced glycation end product (AGE) N-[Epsilon]-(carboxymethyl)lysine (CML) inversely correlates with diabetic vascular complications independently from glycemia (Diabetologia 42, 603, 1999). Here, we studied the effect of benfotiamine, a lipid-soluble thiamine derivative with known AGE-inhibiting properties in-vitro on the intracellular formation of (CML) and methylglyoxal-derived AGE in red blood cells. Blood was collected from 6 Type 1 diabetic patients (2m, 4f, age 31.8 ± 5.5 years; diabetes duration 15.3 ± 7.0 years) before and after treatment with 600 mg/day benfotiamine for 28 days. In addition to HbA1c (HPLC), CML and methylglyoxal were measured using specific antibodies and a quantitative blot technique. While treatment with benfotiamine did not affect HbA1c levels (at entry: 7.18 ± 0.86%; at conclusion 6.88 ± 0.88%; p not significant), levels of CML decreased by 40% (737 ± 51 arbitrary units/mg protein (AU) vs 470 ± 86 AU; p<0.01). The levels of intracellular methylglyoxal were reduced by almost 70% (1628 ± AU vs 500 ± 343 AU; p<0.01). The data indicate that thiamine derivatives are effective inhibitors of both intracellular glycoxidation and AGE formation.
Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.
Nat Med 2003 Mar; 9(3): 294-9.
Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M.
Three of the major biochemical pathways implicated in the pathogenesis of hyperglycemia induced vascular damage (the hexosamine pathway, the advanced glycation end product (AGE) formation pathway and the diacylglycerol (DAG)-protein kinase C (PKC) pathway) are activated by increased availability of the glycolytic metabolites glyceraldehyde-3-phosphate and fructose-6-phosphate. We have discovered that the lipid-soluble thiamine derivative benfotiamine can inhibit these three pathways, as well as hyperglycemia-associated NF-kappaB activation, by activating the pentose phosphate pathway enzyme transketolase, which converts glyceraldehyde-3-phosphate and fructose-6-phosphate into pentose-5-phosphates and other sugars. In retinas of diabetic animals, benfotiamine treatment inhibited these three pathways and NF-kappaB activation by activating transketolase, and also prevented experimental diabetic retinopathy. The ability of benfotiamine to inhibit three major pathways simultaneously might be clinically useful in preventing the development and progression of diabetic complications.
Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy.
Arzneimittelforschung 1999 Mar; 49(3): 220-4.
Winkler G, Pal B, Nagybeganyi E, Ory I, Porochnavec M, Kempler P.
The therapeutic effectiveness of a benfotiamine (CAS 22457-89-2)-vitamin B combination (Milgamma-N), administered in high (4 x 2 capsules/day, = 320 mg benfotiamine/day) and medium doses (3 x 1 capsules/day), was compared to a monotherapy with benfotiamine (Benfogamma) (3 x 1 tablets/day, = 150 mg benfotiamine/day) in diabetic patients suffering from painful peripheral diabetic neuropathy (DNP). In a 6-week open clinical trial, 36 patients (aged 40 to 70 yrs) having acceptable metabolic control (HbA1c < 8.0%) were randomly assigned to three groups, each of them comprising 12 participants. Neuropathy was assessed by five parameters: the pain sensation (evaluated by a modified analogue visual scale), the vibration sensation (measured with a tuning fork using the Riedel-Seyfert method) and the current perception threshold (CPT) onthe peroneal nerve at 3 frequencies: 5, 250 and 2000 Hz). Parameters were registered at the beginning of the study and at the end of the 3rd and 6th week of therapy. An overall bneneficial therapeutic effect on the neuropathy status was observed in all three groups during the study, and a significant improvement in most of the parameters studied appeared already at the 3rd week of therapy (p < 0.01). The greatest change occurred in the group of patients receiving the high dose of benfotiamine (p < 0.01 and 0.05, resp., compared to the othr groups). Metabolic control did not change over the study. It is concluded that benfotiamine is most effective in large doses, although even in smaller daily dosages, either in combination or in monotherapy, it is effective.
Prevention of cardiac autonomic neuropathy in dogs with Benfotiamin.
Koltai MZ.
In Gries FA, Federlin K. Benfotiamin in the Therapy of Polyneuropathy.
New York: Georg Thieme Verlag, 1998; 45-9.
Experimentally-induced diabetes of the dog leads to disturbances in the autonomous neurological function of the heart after approximately 3 months of continuously- observed diabetes. As signs of autonomic cardiac neuropathy, the heart rate variability and Valsalva ratio clearly fell in the untreated diabetic animals. Oral benfotiamin, administered from the sixth day after diabetes-induction, prevented or at least delayed these changes. According to the results, treatment with fat-soluble benfotiamin can play an important role in the therapy and prevention of cardiac autonomic neuropathy, apart from any effect on diabetic metabolic disturbances
