Effects of alpha-lipoic acid on microcirculation in patients with peripheral diabetic neuropathy

Summary:

Diabetic polyneuropathy is a serious complication in patients with diabetes mellitus. In addition to the maintenance of a sufficient metabolic control, α-lipoic acid (ALA) (Thioctacid®, Asta Medica) is known to have beneficial effects on diabetic polyneuropathy although the exact mechanism by which ALA exerts its effect is unknown. In order to study the effect of ALA on microcirculation in patients with diabetes mellitus and peripheral neuropathy one group of patients (4 female, 4 male, age 60 ± 3 years, diabetes duration 19 ± 4 years, BMI 24.8 ± 1.3 kg/m²) received 1200 mg ALA orally per day over 6 weeks (trial 1). A second group of patients (5 female, 4 male, age 65 ± 3 years, diabetes duration 14 ± 4 years, BMI 23.6 ± 0.7 kg/m² ) was studied before and after they had received 600 mg ALA or placebo intravenously over 15 minutes in order to investigate whether ALA has an acute effect on microcirculation (trial 2). Patients were investigated by nailfold video-capillaroscopy. Capillary blood cell velocity was examined at rest and during postreactive hyperemia (occlusion of the wrist for 2 minutes, 200 mmHg) which is a parameter of the perfusion reserve on demand.

The oral therapy with ALA resulted in a significant decrease in the time to peak capillary blood cell velocity (tpCBV) during postocclusive hyperemia (trial 1: 12.6 ± 3.1 vs 35.4 ± 10.9 s, p < 0.05). The infusion of ALA also decreased the tpCBV in patients with diabetic neuropathy (trial 2: before: 20.8 ± 4,5, ALA: 11.74 ± 4.4, placebo: 21.9 ± 5.0 s, p < 0.05 ALA vs both placebo and before infusions) indicating that ALA has an acute effect on microcirculation. Capillary blood cell velocity at rest (rCBV), hemodynamic parameters, hemoglobinA_1c and local skin temperature remained unchanged in both studies. These results demonstrate that in patients with diabetic polyneuropathy ALA improves microcirculation as indicated by an increased perfusion reserve on demand. The observed effects are apparently acute effects. With the restriction of the pilot character of this investigation the findings support the assumption that ALA might exert its beneficial effects at least partially by improving microcirculation which is likely to occur also at the level of the vasa nervorum.

Key words:

Alpha-lipoic acid - capillaroscopy - diabetic neuropathy - microcirculation

References

• 1 Biewenga G P, Haenen G R, Bast A. The pharmacology of the antioxidant lipoic acid.  General Pharmacology. 29 315-331 1997; 
• 2 Bollinger A, Butti P, Barras J P, Trachsler H, Siegenthaler W. Red blood cell velocity in nailfold capillaries of man measured by a television microscopy technique.  Microvasc Res. 7 61-72 1974; 
• 3 Bollinger A, Fagrell B. Clinical capillaroscopy - A guide to its use in clinical research and practice. Lewitson, Hogrefe & Huber 1990
• 4 Cameron N E, Cotter M A, Horrobin D H, Tritschler H J. Effects of alpha-lipoic acid on neurovascular function in diabetic rats: interaction with essential fatty acids.  Diabetologia. 41 390-399 1998; 
• 5 Cameron N E, Cotter M A. Interaction between oxidative stress and gamma-linolenic acid in impaired neurovascular function of diabetic rats.  Am J Physiol. 271 E471-E476 1996; 
• 6 Cameron N E, Cotter M A. Metabolic and vascular factors in the pathogenesis of diabetic neuropathy.  Diabetes. 46 S31-S37 1997; 
• 7 Collier A, Rumley A, Rumley A G, Paterson J R, Leach J P, Lowe G D, Small M. Free radical activity and hemostatic factors in type 2 diabetes mellitus patients with and without microalbuminuria.  Diabetes. 41 909-913 1992; 
• 8 Fagrell B, Östergren J. Reactive hyperemia response in human skin capillaries after varying occlusion duration.  Bibl Anat. 20 692-696 1981; 
• 9 Furchgott R F, Zawadzki J V. The obligatory role of endothelial cells in the relaxion of arterial smooth muscle by acetylcholine.  Nature. 288 373-376 1980; 
• 10 Gasser P. Video-nailfold-microscopy and local cold test: Morphological and hemdynamic correlates in 124 healthy subjects.  VASA. 20 244-251 1991; 
• 11 Greene D A, Simva A AF, Stevens M J, Feldmann E L, Lattimer S A. Complications: neuropathy, pathogenetic considerations.  Diabetes care. 15 1902-1925 1992; 
• 12 Jung F, Wappler M, Nüttgens H P, Kiesewetter H, Wolf S, Müller G. Video capillary microscopy: Determination of geometrical and dynamic parameters.  Biomed Tech. 32 204-213 1987; 
• 13 Kähler W, Kuklinski B, Rühlmann Ch, Plötz Ch. Diabetes mellitus - eine mit freien Radikalen assoziierte Erkrankung. Resultate einer adjuvanten Antioxidantiensupplementation.  Innere Medizin. 48 223-232 1993; 
• 14 Kihara M, Low P A. Impaired vasoreactivity to nitric oxide in experimental diabetic neuropathy.  Exp Neurology. 132 180-185 1995; 
• 15 Klein W. Die Behandlung der Neuropathia diabetica mit oralen Gaben von Alpha-Liponsäure.  Münch Med Wschr. 117 22 1975; 
• 16 Luft D. Therapeutische Strategien bei der diabetischen Neuropathie: Pathogenetisch begründbare Therapieansätze der peripheren, sensiblen, symmetrischen Neuropathie.  Med Klin. 91 295-305 1996; 
• 17 Nagamatsu M, Nickander K K, Schmelzer J D, Raya A, Wittrock D A, Tritschler H, Low P A. Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy.  Diabetes Care. 18 1160-1167 1995; 
• 18 Packer L, Tritschler H J, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid.  Free Radical Biology and Medicine. 22 359-378 1997; 
• 19 Reschke B, Zeuzem R, Rosak C, Petzoldt R, Althoff P H, Ulrich H, Schöffling K. Hochdosierte Langzeitbehandlung mit Thioctsäure bei der diabetischen Polyneuropathie - Ergebnisse einer kontrollierten, randomisierten Studie unter Berücksichtigung der autonomen Neuropathie. In: Borbe H. O., Ulrich H. (Hrsg.): Neue biochemische, pharmakologische und klinische Erkenntnisse der Thioctsäure. pmi-Verlag. Frankfurt 318-334 1989
• 20 Richardson D. Effects of tobacco smoke inhalation on capillary blood flow in human skin.  Arch Environ Health. 42 19-27 1987; 
• 21 Rubanyi G M, Romero C, Vanhoutte P M. Flow-induced release of endothelium-derived relaxing factor.  Am J Physiol. 250 1115-1119 1986; 
• 22 Sachse G, Willms B. Efficacy of thioctic acid in the therapy of peripheral diabetic neuropathy.  Horm Metab Res. 9 105-108 1980; 
• 23 Stevens M J, Feldmann E L, Greene D A. The aetiology of diabetic neuropathy: the combined roles of metabolic and vascular defects.  Diab Med. 12 566-579 1995; 
• 24 Tesfamariam B, Cohen R A. Free radicals mediate endothelial cell dysfunction caused by elevated glucose.  Am J Physiol. 263 321-326 1992; 
• 25 Yoshida K, Hirokawa J, Tagami S, Kawakami Y, Urata Y, Kondo T. Weakened cellular scavenging activity against oxidative stress in diabetes mellitus: regulation of glutathione synthesis and efflux.  Diabetologia. 38 201-210 1995; 
• 26 Ziegler D, Hanefeld M, Ruhnau K J, Meißner H P, Lobisch M, Schütte K, Gries F A. The ALADIN Study Group: Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant α-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study).  Diabetologia. 38 1425-1433 1995; 
• 27 Ziegler D, Mayer P, Gries F. Evaluation of thermal, pain, and vibration sensation thresholds in newly diagnosed Type 1 diabetic patients.  J of Neurology, Neurosurgery, and Psychiatry. 51 1402-1424 1988; 
• 28 Ziegler D, Mayer P, Mühlen H, Gries F A. Effekte einer Therapie mit Alpha-Liponsäure gegenüber Vitamin B1 bei der diabetischen Neuropathie.  Diabetes u. Stoffw. 2 443-448 1993; 
• 29 Ziegler D, Mayer P, Wiefels K, Gries F. Assessment of small and large fiber function in long-term type 1 (insulin-dependent) diabetic patients with and without painful neuropathy.  Pain. 34 1-10 1988; 
• 30 Ziegler D. Diagnosis, staging, and epidemiology of diabetic peripheral neuropathy.  Diab Nutr Metab. 7 342-348 1994;