Neuroprotection after Transient Global Cerebral Ischemia in Wld<sup>s</sup> Mutant Mice

Gillingwater, Thomas H.; Haley, Jane E.; Ribchester, Richard R.; Horsburgh, Karen

doi:10.1097/01.wcb.0000095798.98378.34

Cited by 66 publications

(54 citation statements)

References 32 publications

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“…Although the protective effects of Wld S against axonal degeneration have been well documented [13][14][15][16][17], our studies provide evidence that it can protect against STZtriggered pancreatic beta cell death and subsequent diabetic symptoms and pathological events in mice. Wld S is expressed in islets, suggesting a direct protective effect on beta cells.…”

Section: Discussionmentioning

confidence: 78%

Wld S protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice

et al. 2011

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Aims/hypothesis We aimed to evaluate the effect of the mutant Wld S (slow Wallerian degeneration; also known as Wld) gene in experimental diabetes on early experimental peripheral diabetic neuropathy and diabetic retinopathy.Methods The experiments were performed in four groups of mice: wild-type (WT), streptozotocin (STZ)-induced diabetic WT, C57BL/Wld S and STZ-induced diabetic C57BL/Wld S . In each group, intraperitoneal glucose and insulin tolerance tests were performed; blood glucose, glycated haemoglobin and serum insulin were monitored. These mice were also subjected to the following behavioural tests: grasping test, hot-plate test and von Frey aesthesiometer test. For some animals, sciatic-tibial motor nerve conduction velocity, tail sensory nerve conduction velocity and eye pattern electroretinogram were measured. At the end of the experiments, islets were isolated to detect glucose-stimulated insulin secretion, ATP content and extent of apoptosis. The NAD/NADH ratio in islets and retinas was evaluated. Surviving retinal ganglion cells were estimated by immunohistochemistry. Results We found that the Wld S gene is expressed in islets and protects beta cells against multiple low doses of STZ by increasing the NAD/NADH ratio, maintaining the ATP concentration, and reducing apoptosis. Consistently, significantly higher insulin concentrations, lower blood glucose concentrations, and better glucose tolerance were observed in Wld S mice compared with WT mice after STZ treatment. Furthermore, Wld S alleviated abnormal sensory responses, nerve conduction, retina dysfunction and reduction of surviving retinal ganglion cells in STZinduced diabetic models. Conclusions/interpretation We provide the first evidence that expression of the Wld S gene decreases beta cell destruction and preserves islet function in STZ-induced diabetes, thus revealing a novel protective strategy for diabetic models.

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Section: Discussionmentioning

confidence: 78%

Wld S protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice

et al. 2011

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“…The expression of Wld s , Nmnat1, or Nmnat3 in neurons protects against axonal degeneration resulting from damage caused by mechanical, genetic, or chemical injury Wang et al, 2001a,b;Ferri et al, 2003;Samsam et al, 2003;Araki et al, 2004;Gillingwater et al, 2004;Mi et al, 2005;Sasaki et al, 2006;Zhai et al, 2006). The association between mitochondrial dysfunction and axonal degeneration in multiple neurological disorders encouraged us to investigate whether Nmnat expression could protect axons from damage caused by mitochondrial dysfunction.…”

Section: Rotenone Treatment Of Drg Neurons Results In Axonal Degeneramentioning

confidence: 99%

Nmnat Delays Axonal Degeneration Caused by Mitochondrial and Oxidative Stress

Press¹,

Milbrandt²

2008

J. Neurosci.

138

107

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Axonal degeneration is a prominent feature of many neurological disorders that are associated with mitochondrial dysfunction, including Parkinson's disease, motor neuron disease, and inherited peripheral neuropathies. Studies of the Wld s mutant mouse, which undergoes delayed Wallerian degeneration in response to axonal injury, suggest that axonal degeneration is an active process. Wld s mice also have slower axonal degeneration and disease progression in numerous models of neurodegenerative disease. The Wld s mutation results in the production of a chimeric protein that contains the full-length coding sequence of nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), which alone is sufficient for axonal protection in vitro. To test the effects of increased Nmnat expression on axonal degeneration induced by mitochondrial dysfunction, we examined dorsal root ganglion (DRG) neurons treated with rotenone. Rotenone induced profound axonal degeneration in DRG neurons; however, this degeneration was delayed by expression of Nmnat. Nmnatmediated protection resulted in decreased axonal accumulation and sensitivity to reactive oxygen species (ROS) but did not affect the change in the rate of rotenone-induced loss in neuronal ATP. Nmnat also prevented axonal degeneration caused by exposure to exogenous oxidants and reduced the level of axonal ROS after treatment with vincristine, further supporting the idea that Nmnat promotes axonal protection by mitigating the effects of ROS.

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“…Bilateral injuries to the striatum were in particular more frequent than those to the hippocampal CA1 subregion, another vulnerable brain region. Although striatal injury after tGCI has not received much attention, some authors have also reported that striatal neurons are the most vulnerable in C57BL/6 mouse brains after tGCI (Gillingwater et al, 2004;Olsson et al, 2003;Terashima et al, 1998;Yang et al, 1997;Yoshioka et al, 2010). Therefore, a striatal injury model that uses C57BL/6 mice can be appropriate for studying neuronal death after tGCI.…”

Section: Discussionmentioning

confidence: 99%

Consistent Injury to Medium Spiny Neurons and White Matter in the Mouse Striatum after Prolonged Transient Global Cerebral Ischemia

Yoshioka

Niizuma

Katsu

et al. 2011

Journal of Neurotrauma

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A reproducible transient global cerebral ischemia (tGCI) mouse model has not been fully established. Although striatal neurons and white matter are recognized to be vulnerable to ischemia, their injury after tGCI in mice has not been elucidated. The purpose of this study was to evaluate injuries to striatal neurons and white matter after tGCI in C57BL/6 mice, and to develop a reproducible tGCI model. Male C57BL/6 mice were subjected to tGCI by bilateral common carotid artery occlusion (BCCAO). Mice whose cortical cerebral blood flow after BCCAO decreased to less than 13% of the pre-ischemic value were used. Histological analysis showed that at 3 days after 22 min of BCCAO, striatal neurons were injured more consistently than those in other brain regions. Quantitative analysis of cytochrome c release into the cytosol and DNA fragmentation in the striatum showed consistent injury to the striatum. Immunohistochemistry and Western blot analysis revealed that DARPP-32-positive medium spiny neurons, the majority of striatal neurons, were the most vulnerable among the striatal neuronal subpopulations. The striatum (especially medium spiny neurons) was susceptible to oxidative stress after tGCI, which is probably one of the mechanisms of vulnerability. SMI-32 immunostaining showed that white matter in the striatum was also consistently injured 3 days after 22 min of BCCAO. We thus suggest that this is a tGCI model using C57BL/6 mice that consistently produces neuronal and white matter injury in the striatum by a simple technique. This model can be highly applicable for elucidating molecular mechanisms in the brain after global ischemia.

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Neuroprotection after Transient Global Cerebral Ischemia in Wld^s Mutant Mice

Cited by 66 publications

References 32 publications

Wld S protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice

Wld S protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice

Nmnat Delays Axonal Degeneration Caused by Mitochondrial and Oxidative Stress

Consistent Injury to Medium Spiny Neurons and White Matter in the Mouse Striatum after Prolonged Transient Global Cerebral Ischemia

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Neuroprotection after Transient Global Cerebral Ischemia in Wlds Mutant Mice

Cited by 66 publications

References 32 publications

Wld S protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice

Wld S protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice

Nmnat Delays Axonal Degeneration Caused by Mitochondrial and Oxidative Stress

Consistent Injury to Medium Spiny Neurons and White Matter in the Mouse Striatum after Prolonged Transient Global Cerebral Ischemia

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Neuroprotection after Transient Global Cerebral Ischemia in Wld^s Mutant Mice