Acetyl-l-carnitine corrects the altered peripheral nerve function of experimental diabetes

doi:10.1016/0026-0495(95)90128-0

Metabolism

Volume 44, Issue 5, May 1995, Pages 677-680

https://doi.org/10.1016/0026-0495(95)90128-0 Get rights and content

Abstract

Acetyl-l-carnitine (ALC) has been shown to facilitate the repair of transected sciatic nerves. The effect of ALC (50 mg/kg/d) on the diminished nerve conduction velocity (NCV) of rats with streptozotocin (STZ)-induced hyperglycemia of 3 weeks' duration was evaluated. The aldose reductase inhibitor, sorbinil, which is reported to normalize the impaired NCV associated with experimental diabetes, was used as a positive control. Aldose reductase inhibitors are thought to have an effect by decreasing peripheral nerve sorbitol content and increasing nerve myo-inositol. Treatment of STZ-diabetic rats with either ALC or sorbinil resulted in normal NCV. Sorbinil treatment was associated with normalized sciatic nerve sorbitol and myo-inositol; ALC treatment did not reduce the elevated sorbitol levels, but sciatic nerve myo-inositol content was no different from nondiabetic levels. Both ALC and sorbinil treatment of STZ-diabetic rats were associated with a reduction in the elevated malondialdehyde (MDA) content of diabetic sciatic nerve, indicating reduced lipid peroxidation. The beneficial effects of sorbinil and ALC on the altered peripheral nerve function associated with diabetes were similar, but their effects on the polyol pathway (frequently implicated in the pathogenesis of peripheral neuropathy) were different.

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Low temperature is an important environmental factor affecting the breeding industry. Due to sudden cold waves or seasonal changes, huge losses have been caused to the breeding industry all over the world. We investigated the effect of temperature gradient (25, 19, and 13 °C) and time (0, 6, 24, and 96 h) on the histomorphology, antioxidant enzyme activity, mitogen-activated protein kinase pathway, and lipidomics of the skeletal muscle from T. fasciatus. The results showed that low temperature damaged muscle microstructure and caused antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase and catalase) upregulation. The mitogen-activated protein kinase (MAPK), including extracellular regulated protein kinases (ERK), c-Jun N-terminal kinase (JNK), and p38MAPK, was upregulated under cold stress. The expression of genes involved in lipogenesis [6-phosphate glucose dehydrogenase, glucose-6-phosphate dehydrogenase, fatty acid synthase, acetyl-coa-carboxylase, lipoprteinlipase, sterol-regulatory element binding protein-1], lipolysis [hormone-sensitive lipase, and carnitine palmitoyltransferase-1], and transcription [peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor γ] were upregulated. Lipidomics results showed that phospholipid metabolites increased under cold stress, which compensated for the integrity of cell membranes. Overall, this study showed that T. fasciatus may adjust fat metabolism through MAPK to compensate for cell membrane damage in muscles caused by low temperature. Our results reveal the possibility that phospholipid metabolites can be used as potential feeds, and further reveal the mechanism of resistance to low temperatures.
Mechanisms of diabetic neuropathy: Schwann cells
2014, Handbook of Clinical Neurology
Citation Excerpt :
In these studies, a variety of antioxidants and/or mitochondrial metabolites have been shown to ameliorate biochemical and functional nerve defects in experimental diabetes and, in a few cases, human diabetes. These include glutathione and a precursor for glutathione biosynthesis (Bravenboer et al., 1992; Love et al., 1996a), lipid-soluble antioxidants (Cameron et al., 1993, 1994), metal chelators (Cameron and Cotter, 2001; Love et al., 1996b), α-lipoic acid (Nagamatsu et al., 1995; Low et al., 1997; Cameron et al., 1998; Stevens et al., 2000; for review see also Vincent et al., 2004), and acetyl-L-carnitine (Cotter et al., 1995; Lowitt et al., 1995; Sima et al., 1996; De Grandis and Minardi, 2002). Importantly, these antioxidants have effects on indices of diabetic neuropathy that are similar to those of inhibitors of aldose reductase, nonenzymatic glycosylation, and protein kinase C, emphasizing the interrelationship of these metabolic defects.
As ensheathing and secretory cells, Schwann cells are a ubiquitous and vital component of the endoneurial microenvironment of peripheral nerves. The interdependence of axons and their ensheathing Schwann cells predisposes each to the impact of injury in the other. Further, the dependence of the blood–nerve interface on trophic support from Schwann cells during development, adulthood, and after injury suggests these glial cells promote the structural and functional integrity of nerve trunks. Here, the developmental origin, injury-induced changes, and mature myelinating and nonmyelinating phenotypes of Schwann cells are reviewed prior to a description of nerve fiber pathology and consideration of pathogenic mechanisms in human and experimental diabetic neuropathy. A fundamental role for aldose-reductase-containing Schwann cells in the pathogenesis of diabetic neuropathy, as well as the interrelationship of pathogenic mechanisms, is indicated by the sensitivity of hyperglycemia-induced biochemical alterations, such as polyol pathway flux, formation of reactive oxygen species, generation of advanced glycosylation end products (AGEs) and deficient neurotrophic support, to blocking polyol pathway flux.
Acetyl-l-carnitine treatment following spinal cord injury improves mitochondrial function correlated with remarkable tissue sparing and functional recovery
2012, Neuroscience
We have recently documented that treatment with the alternative biofuel, acetyl-l-carnitine (ALC, 300 mg/kg), as late as 1 h after T10 contusion spinal cord injury (SCI), significantly maintained mitochondrial function 24 h after injury. Here we report that after more severe contusion SCI centered on the L1/L2 segments that are postulated to contain lamina X neurons critical for locomotion (the “central pattern generator”), ALC treatment resulted in significant improvements in acute mitochondrial bioenergetics and long-term hind limb function. Although control-injured rats were only able to achieve slight movements of hind limb joints, ALC-treated animals produced consistent weight-supported plantar steps 1 month after injury. Such landmark behavioral improvements were significantly correlated with increased tissue sparing of both gray and white matter proximal to the injury, as well as preservation of choline acetyltransferase (ChAT)-positive neurons in lamina X rostral to the injury site. These findings signify that functional improvements with ALC treatment are mediated, in part, by preserved locomotor circuitry rostral to upper lumbar contusion SCI. Based on beneficial effects of ALC on mitochondrial bioenergetics after injury, our collective evidence demonstrate that preventing mitochondrial dysfunction acutely “promotes” neuroprotection that may be associated with the milestone recovery of plantar, weight-supported stepping.
Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity
2012, Biochimica et Biophysica Acta - Molecular Basis of Disease
Citation Excerpt :
ALC has also been found to protect against lipid peroxidation and membrane breakdown [374,375]. In streptozotocin-induced diabetic rats, treatment with ALC improved nerve conduction velocities (the speed of signal through the nerves), and this was associated with a reduction in elevated malonyldialdehyde (MDA) content, an indicator of lipid peroxidation [376]. When administered via the perfusate to ischemia-reperfused rat hearts, carnitine derivatives were able to scavenge peroxyl or superoxide radicals [377].
Modulation of endogenous cellular defense mechanisms represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. This paper introduces the emerging role of exogenous molecules in hormetic-based neuroprotection and the mitochondrial redox signaling concept of hormesis and its applications to the field of neuroprotection and longevity. Maintenance of optimal long-term health conditions is accomplished by a complex network of longevity assurance processes that are controlled by vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, such as polyphenols and L-carnitine/acetyl-L-carnitine, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. Hormesis provides the central underpinning of neuroprotective responses, providing a framework for explaining the common quantitative features of their dose response relationships, their mechanistic foundations, their relationship to the concept of biological plasticity as well as providing a key insight for improving the accuracy of the therapeutic dose of pharmaceutical agents within the highly heterogeneous human population. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways including sirtuin, Nrfs and related pathways that integrate adaptive stress responses in the prevention of neurodegenerative diseases. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
Endocrinology
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^☆: Supported by the Health Program Office, Health and Rehabilitative Services, State of Florida, and Sigma Tau, Rome, Italy.

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Metabolism

Abstract

References (24)

Taurine prevents galactose-induced cataracts

J Diabetic Complications

Taurine: A role in osmotic regulation of mammalian brain and possible clinical significance

Life Sci

Systemic acetyl-l-carnitine elevates nigral levels of glutathione and GABA

Life Sci

Myo-inositol and sorbitol metabolism in relation to peripheral nerve function in experimental diabetes in the rat: The effect of aldose reductase inhibition

Diabetologia

Action of sorbinil in diabetic peripheral nerve: Relationship of polyol (sorbitol) pathway inhibition to a myo-inositol-mediated defect in sodium-potassium ATPase activity

Diabetes

Preventive effect of long-term aldose reductase inhibition (ponalrestat) on nerve conduction and sural nerve structure in the spontaneously diabetic bio-breeding rat

J Clin Invest

Improvement in peripheral nerve function after one year of sorbinil

NeuroReport

Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil

N Engl J Med

Effects of l-carnitine, l-acetylcarnitine and gangliosides on the regeneration of the transected sciatic nerve in rats

Neurol Res

Studies on the degenerative and regenerative phenomena occurring after transection and repair of the sciatic nerve in rats: Effects of acetyl-l-carnitine

Int J Clin Pharmacol Res

Drugs producing diabetes through damage of the insulin secreting cells

Pharmacol Rev

Prevention of defects of axonal transport and nerve conduction velocity by oral administration of myo-inositol or an aldose reductase inhibitor in streptozotocin-diabetic rats

Diabetologia

Cited by (82)

Effect of cold stress on the MAPK pathway and lipidomics on muscle of Takifugu fasciatus

Mechanisms of diabetic neuropathy: Schwann cells

Acetyl-l-carnitine treatment following spinal cord injury improves mitochondrial function correlated with remarkable tissue sparing and functional recovery

Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity

Endocrinology

Endocrinology: Progression over time

Acetyl-l-carnitine corrects the altered peripheral nerve function of experimental diabetes☆

Abstract

J Diabetic Complications

Life Sci

Life Sci

Myo-inositol and sorbitol metabolism in relation to peripheral nerve function in experimental diabetes in the rat: The effect of aldose reductase inhibition

Diabetologia

Action of sorbinil in diabetic peripheral nerve: Relationship of polyol (sorbitol) pathway inhibition to a myo-inositol-mediated defect in sodium-potassium ATPase activity

Diabetes

Preventive effect of long-term aldose reductase inhibition (ponalrestat) on nerve conduction and sural nerve structure in the spontaneously diabetic bio-breeding rat

J Clin Invest

Improvement in peripheral nerve function after one year of sorbinil

NeuroReport

Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil

N Engl J Med

Effects of l-carnitine, l-acetylcarnitine and gangliosides on the regeneration of the transected sciatic nerve in rats

Neurol Res

Studies on the degenerative and regenerative phenomena occurring after transection and repair of the sciatic nerve in rats: Effects of acetyl-l-carnitine

Int J Clin Pharmacol Res

Drugs producing diabetes through damage of the insulin secreting cells

Pharmacol Rev

Prevention of defects of axonal transport and nerve conduction velocity by oral administration of myo-inositol or an aldose reductase inhibitor in streptozotocin-diabetic rats

Diabetologia