Expression of axotomy-inducible and apoptosis-related genes in sensory nerves of rats with experimental diabetes

Rc, Burnand; Price, Shirley C.; Mr, McElhaney; Barker, DL; Tomlinson,

doi:10.1016/j.molbrainres.2004.05.002

Cited by 25 publications

(18 citation statements)

References 44 publications

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“…At the same time, our data provide clear indication that development of diabetic sensory neuropathy in rats with shortterm STZ-induced diabetes is not associated with neuronal apoptosis. The absence of neuronal apoptosis in STZinduced diabetic rats in our study is consistent with two other reports (47,48). However, the area remains a subject of debate (22,(47)(48)(49)(50), and thus it would be of interest to explore the effects of PARP inhibition on functional and structural (reduced skin fiber density) manifestations of sensory loss and to correlate them with the rates of neuronal apoptosis, if any, in rats with longer durations of diabetes.…”

Section: Discussionsupporting

confidence: 92%

Poly(ADP-Ribose) Polymerase Inhibition Alleviates Experimental Diabetic Sensory Neuropathy

et al. 2006

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Poly(ADP-ribose) polymerase (PARP) activation is emerging as a fundamental mechanism in the pathogenesis of diabetes complications including diabetic neuropathy. This study evaluated the role of PARP in diabetic sensory neuropathy. The experiments were performed in control and streptozotocin-induced diabetic rats treated with or without the PARP inhibitor 1,5-isoquinolinediol (ISO; 3 mg ⅐ kg ؊1 ⅐ day ؊1 i.p.) for 2 weeks after 2 weeks without treatment. Diabetic rats developed thermal hyperalgesia (assessed by paw-withdrawal and tail-flick tests), mechanical hyperalgesia (von Frey anesthesiometer/rigid filaments and Randall-Sellito tests), tactile allodynia (flexible von Frey filaments), and increased flinching behavior in phases 1 and 2 of the 2% formalin pain test. They also had clearly manifest increase in nitrotyrosine and poly(ADPribose) immunoreactivities in the sciatic nerve and increased superoxide formation (hydroxyethidine method) and nitrotyrosine immunoreactivity in vasa nervorum. ISO treatment alleviated abnormal sensory responses, including thermal and mechanical hyperalgesia and tactile allodynia as well as exaggerated formalin flinching behavior in diabetic rats, without affecting the aforementioned variables in the control group. Poly(ADP-ribose) and, to a lesser extent, nitrotyrosine abundance in sciatic nerve, as well as superoxide and nitrotyrosine formation in vasa nervorum, were markedly reduced by ISO therapy. Apoptosis in dorsal root ganglion neurons (transferase-mediated dUTP nick-end labeling assay) was not detected in any of the groups. In conclusion, PARP activation contributes to early diabetic sensory neuropathy by mechanisms that may include oxidative stress but not neuronal apoptosis.

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Section: Discussionsupporting

confidence: 92%

Poly(ADP-Ribose) Polymerase Inhibition Alleviates Experimental Diabetic Sensory Neuropathy

et al. 2006

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“…Indirect evidence for the lack of apoptotic neuronal death is the finding that neither the downstream DNA repair enzyme PARP nor cleaved PARP, as an indicator of DNA damage [32], was increased. This is in keeping with the finding that axotomy of sensory nerves of the STZ-D rats fails to induce apoptosis-related genes [33]. Taken together with the lack of structural evidence of apoptosis in this study, we speculate that apoptotic stresses do occur in long-term diabetic rats, but that these are counterbalanced by anti-apoptotic elements such as Bcl-xl, HSP27 and HSP40, which were unaltered, despite considerable neuronal loss.…”

Section: Discussionsupporting

confidence: 91%

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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“…nNOS is expressed in many cell types in peripheral nervous system including Schwann cells of peripheral nerve (36), DRG neurons (37,38), and motoneurons, oligodendrocytes, and astrocytes of spinal cord (39,40). One can not exclude that it is also expressed in vasa nervorum considering recent report of the presence of nNOS in vascular endothelium (41).…”

Section: Discussionmentioning

confidence: 99%

Peripheral neuropathy in mice with neuronal nitric oxide synthase gene deficiency

Vareniuk

Pacher²,

Pavlov³

et al. 2009

Int J Mol Med

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Abstract. Evidence for the important role of the potent oxidant peroxynitrite in peripheral diabetic neuropathy and neuropathic pain is emerging. This study evaluated the contribution of neuronal nitric oxide synthase (nNOS) to diabetes-induced nitrosative stress in peripheral nerve and dorsal root ganglia, and peripheral nerve dysfunction and degeneration. Control and nNOS -/-mice were made diabetic with streptozotocin, and maintained for 6 weeks. Peroxynitrite injury was assessed by nitrotyrosine and poly(ADP-ribose) immunoreactivities. Peripheral diabetic neuropathy was evaluated by measurements of sciatic motor and hind-limb digital sensory nerve conduction velocities, thermal algesia, tactile allodynia, and intraepidermal nerve fiber density. Control nNOS -/-mice displayed normal motor nerve conduction velocity and thermal response latency, whereas sensory nerve conduction velocity was slightly lower compared with non-diabetic wild-type mice, and tactile response threshold and intraepidermal nerve fiber density were reduced by 47 and 38%, respectively. Both diabetic wild-type and nNOS -/-mice displayed enhanced nitrosative stress in peripheral nerve. In contrast to diabetic wild-type mice, diabetic nNOS -/-mice had near normal nitrotyrosine and poly(ADP-ribose) immunofluorescence in dorsal root ganglia. Both diabetic wild-type and nNOS -/-mice developed motor and sensory nerve conduction velocity deficits and thermal hypoalgesia although nNOS gene deficiency slightly reduced severity of the three disorders. Tactile response thresholds were similarly decreased in control and diabetic nNOS -/-mice compared with non-diabetic wild-type mice. Intraepidermal nerve fiber density was lower by 27% in diabetic nNOS -/-mice compared with the corresponding nondiabetic group, and by 20% in diabetic nNOS -/-mice compared with diabetic wild-type mice. In conclusion, nNOS is required for maintaining the normal peripheral nerve function and small sensory nerve fibre innervation. nNOS gene deficiency does not protect from development of nerve conduction deficit, sensory neuropathy and intraepidermal nerve fiber loss.

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Expression of axotomy-inducible and apoptosis-related genes in sensory nerves of rats with experimental diabetes

Cited by 25 publications

References 44 publications

Poly(ADP-Ribose) Polymerase Inhibition Alleviates Experimental Diabetic Sensory Neuropathy

Poly(ADP-Ribose) Polymerase Inhibition Alleviates Experimental Diabetic Sensory Neuropathy

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

Peripheral neuropathy in mice with neuronal nitric oxide synthase gene deficiency

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