Neural Dysfunction and Metabolic Imbalances in Diabetic Rats: Prevention by Acetyl-L-Carnitine

Abstract

The rationale for these experiments is that administration of L-carnitine and/or short-chain acylcarnitines attenuates myocardial dysfunction 1) in hearts from diabetic animals (in which L-carnitine levels are decreased); 2) induced by ischemia-reperfusion in hearts from nondiabetic animals; and 3) in nondiabetic humans with ischemic heart disease. The objective of these studies was to investigate whether imbalances in carnitine metabolism play a role in the pathogenesis of diabetic peripheral neuropathy. The major findings in rats with streptozotocin-induced diabetes of 4-6 weeks duration were that 24-h urinary carnitine excretion was increased approximately twofold and L-carnitine levels were decreased in plasma (46%) and sciatic nerve endoneurium (31%). These changes in carnitine levels/excretion were associated with decreased caudal nerve conduction velocity (10-15%) and sciatic nerve changes in Na(+)-K(+)-ATPase activity (decreased 50%), Mg(2+)-ATPase (decreased 65%), 1,2-diacyl-sn-glycerol (DAG) (decreased 40%), vascular albumin permeation (increased 60%), and blood flow (increased 65%). Treatment with acetyl-L-carnitine normalized plasma and endoneurial L-carnitine levels and prevented all of these metabolic and functional changes except the increased blood flow, which was unaffected, and the reduction in DAG, which decreased another 40%. In conclusion, these observations 1) demonstrate a link between imbalances in carnitine metabolism and several metabolic and functional abnormalities associated with diabetic polyneuropathy and 2) indicate that decreased sciatic nerve endoneurial ATPase activity (ouabain-sensitive and insensitive) in this model of diabetes is associated with decreased DAG.

Altered [3H]ouabain binding to cardiac muscle in insulin‐dependent and non‐insulin‐dependent diabetic rats

“…Similar results were obtained by Schmidt et al in rat soleus muscle . Reduction in the Na+,K+-ATPase activity observed in earlier reports was approximately 50% in both nerve and vascular smooth muscle, (Llewelyn et al 1991;Tesfamariam, Gupta, Oates, Ruderman & Cohen, 1993;Ido et al 1994), which is also consistent with the present results.…”

“…This enzyme is responsible for the reuptake and extrusion of potassium and sodium ions, respectively, during muscular activity. Na+,K+-ATPase activity was found to be significantly altered under several physiological or pathological conditions like pregnancy (Larsen, Schmidt & Kjeldsen, 1994), ageing (Turi, Mullner, Szanto & Marcsek, 1994) hypertonia (McDonough, Azuma, Hensley & Magyar, 1994), hypoor hyperthyreosis (McDonough et al 1994;Norgaard, Kjeldsen & Hansen, 1995) and diabetes mellitus (Fedorak, Cortas & Field, 1991), including experimental models of diabetes (Llewelyn, Patel, Wright & Thomas, 1991;Ottlecz, Garcia, Eichberg & Fox, 1993;Ido et al 1994;Issautier, Kovacic, Gallice, Raccah, Vague & Crevat, 1994;Schmidt, Hasselbalch, Farrell, Vestergaard & Kjeldsen, 1994). Decreased Na+,K+-ATPase activity is claimed to play a central role in many chronic complications of diabetes mellitus, such as neuropathy, retinopathy or cardiomyopathy (Greene, Yagihashi, Lattimer & Sima, 1984;Scarpini, Bianchi, Moggio, Sciacco, Fiori & Scarlato, 1993).…”

Integrative neuromuscular medicine: Neuropathy and neuropathic pain: Consider the alternatives

“…[97][98][99] ALC is vital for normal mitochondrial function and is known to be deficient in diabetes. 100 ALC potentiates nerve growth factor actions and promotes peripheral nerve regeneration and nerve conduction in animal models. 101 In studies of chronic diabetic neuropathy, patients treated with an ALC dose of 500-1,000 mg 3 times daily showed significant improvements on the visual analog scale (VAS) for pain as well as in vibration perception in both the fingers and toes; in addition, morphometric analyses of sural nerve biopsies showed increases in nerve fiber numbers and regenerating nerve fiber clusters at 52 weeks.…”

Novel protein kinase C‐β isoform selective inhibitor JTT‐010 ameliorates both hyper‐ and hypoalgesia in streptozotocin‐ induced diabetic rats

“…After 12 weeks of administration, animals were anaesthetized with halothane (Fluothane 1 ; Takeda, Osaka, Japan) and nerve conduction velocities were measured as follows: tail motor NCV (MNCV) was measured according to previously described methods [16][17][18] with some modifications. Tail was placed on a heated pad maintaining a surface temperature of 37 AE 0.5 C. Tail nerve was stimulated with an electronic stimulator (SEN-7103, intensity ¼ 100 V; Nihon-Koden, Tokyo, Japan) through a bipolar electrode (MT Giken, Tokyo, Japan) placed 1 cm from the anus.…”