Primary preventive and secondary interventionary effects of acetyl-L-carnitine on diabetic neuropathy in the bio-breeding Worcester rat.

Sima, Anders A. F.; Ristic, Helen; Merry, Andrew; Kamijo, Mikiko; Lattimer, S. A.; Stevens, Martin J.; Greene, Douglas A.

doi:10.1172/jci118621

Cited by 90 publications

(76 citation statements)

References 28 publications

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“…Our results are in contrast to studies that demonstrate neuroprotective and pro-regenerative ALCAR effects in other nerve injury models (Fernandez et al, 1991;Pacifici et al, 1992;Lowitt et al, 1995;Sima et al, 1996Sima et al, , 2005Hart et al, 2002Hart et al, , 2004aHart et al, , 2004bDeGrandis and Minardi, 2002;Wilson et al, 2003Wilson et al, , 2007Chiechio et al, 2006;Youle et al, 2007). Pisano et al (2003) showed that a prophylactic ALCAR treatment protocol prevented the decrease in the sensory nerve conduction velocity (SNCV) seen after paclitaxel and cisplatin.…”

Section: Alcar and The Paclitaxel-evoked Degeneration Of Ienfscontrasting

confidence: 96%

“…Paclitaxel also causes degeneration of the sensory neurons' intraepidermal terminal arbors, without degeneration of the parent axons in the peripheral nerve, and it activates cutaneous Langerhans cells . ALCAR has been shown to have neuroprotective and pro-regenerative effects following primary afferent neuron axotomy (Fernandez et al, 1991;Chiechio et al, 2006;Hart et al, 2002Hart et al, , 2004aWilson et al, 2003Wilson et al, , 2007, in the peripheral neuropathy produced by antiretroviral chemotherapy (Hart et al, 2004b;Youle et al, 2007), and in diabetic peripheral neuropathy (Lowitt et al, 1995;Pacifici et al, 1992;Sima et al, 1996Sima et al, , 2005DeGrandis and Minardi, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-l-carnitine: Effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells

Jin

Flatters

Xiao

et al. 2008

Experimental Neurology

143

132

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Prophylactic treatment with acetyl-L-carnitine (ALCAR) prevents the neuropathic pain syndrome that is evoked by the chemotherapeutic agent, paclitaxel. The paclitaxel-evoked pain syndrome is associated with degeneration of the intraepidermal terminal arbors of primary afferent neurons, with the activation of cutaneous Langerhans cells, and with an increased incidence of swollen and vacuolated axonal mitochondria in A-fibers and C-fibers. Previous work suggests that ALCAR is neuroprotective in other nerve injury models and that it improves mitochondrial dysfunction. Thus, we examined whether the prophylactic efficacy of ALCAR was associated with the prevention of intraepidermal terminal arbor degeneration, the inhibition of Langerhans cell activation, or the inhibition of swelling and vacuolation of axonal mitochondria. In animals with a confirmed ALCAR effect, we found no evidence of a neuroprotective effect on the paclitaxel-evoked degeneration of sensory terminal arbors or an inhibition of the paclitaxel-evoked activation of Langerhans cells. However, ALCAR treatment completely prevented the paclitaxel-evoked increase in the incidence of swollen and vacuolated C-fiber mitochondria, while having no effect on the paclitaxel-evoked changes in A-fiber mitochondria. Our results suggest that the efficacy of prophylactic ALCAR treatment against the paclitaxel-evoked pain may be related to a protective effect on C-fiber mitochondria.

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Section: Alcar and The Paclitaxel-evoked Degeneration Of Ienfscontrasting

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-l-carnitine: Effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells

Jin

Flatters

Xiao

et al. 2008

Experimental Neurology

143

132

View full text Add to dashboard Cite

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“…This system is programmed to assess the total complement of sural nerve myelinated fibres and provides the following parameters: fascicular area (μm 2 ), number of fibres, fibre density (number/mm 2 ), mean fibre area (μm 2 ), mean axonal area (μm 2 ), mean myelin area (μm 2 ), axon/myelin ratio, and index of circularity and fibre occupancy rate (in %) as previously described [19].…”

Section: Methodsmentioning

confidence: 99%

Degeneration of the Golgi and neuronal loss in dorsal root ganglia in diabetic BioBreeding/Worcester rats

2006

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Aims/hypothesis The aim of this study was to evaluate the nature and extent of neuronal loss in dorsal root ganglia (DRG) in diabetic polyneuropathy. Materials and methods We examined 10-month diabetic BioBreeding/Worcester (BB/Wor) rats with respect to DRG ultrastructure and morphometry, sural nerve morphometry, pro-and anti-apoptotic proteins, the expression of neurotrophic factors and their receptors, and sensory nerve functions. Results In diabetic rats, DRG neurons decreased to 73% of normal, owing to loss of substance P and calcitonin generelated peptide-positive neurons. Levels of pro-apoptotic active caspase-3, Bax and low-affinity nerve growth factor (NGF) were increased in DRG. The concentration of anti-apoptotic heat shock protein (HSP) 70 in DRG was decreased, whereas concentrations of Bcl-xl and HSP27 were unaltered. Levels of poly(ADP-ribose) polymerase (PARP) and cleaved PARP were unaltered. Levels of NGF in sciatic nerve and concentrations of the high-affinity NGF receptor, insulin receptor and IGF-I receptor in DRG were significantly decreased. Sensory nerve conduction velocity decreased to 78% of normal. Hyperalgesia increased up to 6 months. Myelinated and unmyelinated fibre numbers of the sural nerve were significantly decreased in diabetic rats. DRG examinations revealed no evidence of apoptosis, mitochondrial changes or abnormalities of the endoplasmic reticulum. Instead, neurons demonstrated progressive vacuolar degenerative changes of the Golgi apparatus, with fragmentation and formation of large cytoplasmic vacuoles. These data show that sustained apoptotic stress is present in DRG of chronically diabetic BB/Wor rats, but fails to proceed to apoptotic cell death. Conclusions/interpretation Progressive DRG neuronal loss, particularly of small neurons, occurs in the type 1 diabetic BB/Wor rat. This is associated with neurotrophic withdrawal and progressive degeneration of the Golgi apparatus.

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“…α-lipoic acid, acetylcysteine and α-tocopherol) [27][28][29], γ-linolenic acid-containing oils [30] or acetyl-L-carnitine [31] have also been shown to produce some benefits on nerve function and even morphology in experimental diabetic models. However, a more detailed description of the diverse range of interventions would far exceed the scope of this text.…”

Section: Experimental Datamentioning

confidence: 99%

Advanced Diabetic Neuropathy: A Point of no Return?

Bouc̆ek¹

2006

Rev Diabetic Stud

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■ AbstractDiabetic peripheral neuropathy is the most common complication of long-standing diabetes mellitus which frequently results in clinically significant morbidities e.g. pain, foot ulcers and amputations. During its natural course it progresses from initial functional changes to late, poorly reversible, structural changes. Various interconnected pathogenetic concepts of diabetic neuropathy have been proposed based on metabolic and vascular factors, mostly derived from long-term hyperglycemia. These pathogenetic mechanisms have been targeted in several experimental and clinical trials. This review summarizes available, mainly morphological data from interventions designed to halt the progression or achieve the reversal of established diabetic neuropathy, which include the recovery of normoglycemia by pancreas or islet transplantation, polyol pathway blockade by aldose reductase inhibitors, mitigation of oxidative stress by the use of antioxidants or correction of abnormalities in essential fatty acid metabolism. Unfortunately, to date, no treatment based on pathogenic considerations has shown clear positive effects and thus early institution of optimal glycemic control remains the only available measure with proven efficacy in preventing or halting progression of diabetic neuropathy. Further experimental and clinical research employing objective reproducible parameters is clearly needed. Novel noninvasive or minimally invasive methods e.g. corneal confocal microscopy or epidermal nerve fiber counts may represent potentially useful instruments for the objective assessment of nerve damage and monitoring of treatment effects.

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Primary preventive and secondary interventionary effects of acetyl-L-carnitine on diabetic neuropathy in the bio-breeding Worcester rat.

Cited by 90 publications

References 28 publications

Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-l-carnitine: Effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells

Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-l-carnitine: Effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells

Degeneration of the Golgi and neuronal loss in dorsal root ganglia in diabetic BioBreeding/Worcester rats

Advanced Diabetic Neuropathy: A Point of no Return?

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