Overexpression of SOD1 in Transgenic Rats Protects Vulnerable Neurons Against Ischemic Damage After Global Cerebral Ischemia and Reperfusion

Chan, Pak H.; Kawase, Makoto; Murakami, Kensuke; Chen, Sylvia F.; Li, Yibing; Calagui, Bernard; Reola, Liza; Carlson, Elaine J.; Epstein, Charles J.

doi:10.1523/jneurosci.18-20-08292.1998

Cited by 315 publications

(257 citation statements)

References 33 publications

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“…Three days after tGCI, however, more than 80% of the CA1 neurons were degenerated in the Wt rats, as described previously (Chan et al, 1998;Sugawara et al, 1999).…”

Section: Delayed Hippocampal Ca1 Neuronal Death Occurred 72 H After Tsupporting

confidence: 69%

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Activation of the Akt/GSK3β Signaling Pathway Mediates Survival of Vulnerable Hippocampal Neurons after Transient Global Cerebral Ischemia in Rats

Endo

Nito

Kamada

et al. 2006

J Cereb Blood Flow Metab

173

113

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Recent studies have revealed that the phosphatidylinositol 3-kinase (PI3-K) pathway is involved in apoptotic cell death after experimental cerebral ischemia. The serine-threonine kinase, Akt, functions in the PI3-K pathway and prevents apoptosis by phosphorylation at Ser473 after a variety of cell death stimuli. After phosphorylation, activated Akt inactivates other apoptogenic factors, including glycogen synthase kinase-3b (GSK3b), thereby inhibiting cell death. However, the role of Akt/GSK3b signaling in the delayed death of hippocampal neurons in the CA1 subregion after transient global cerebral ischemia (tGCI) has not been clarified. Transient global cerebral ischemia for 5 mins was induced by bilateral common carotid artery occlusion combined with hypotension. Western blot analysis showed a significant increase in phospho-Akt (Ser473) and phospho-GSK3b (Ser9) in the hippocampal CA1 subregion after tGCI. Immunohistochemistry showed that expression of phospho-Akt (Ser473) and phospho-GSK3b (Ser9) was markedly increased in the vulnerable CA1 subregion, but not in the ischemic-tolerant CA3 subregion. Double staining with phospho-GSK3b (Ser9) and terminal deoxynucleotidyl transferase-mediated uridine 5 0 -triphosphate-biotin nick end labeling showed different cellular distributions in the CA1 subregion 3 days after tGCI. Phosphorylation of Akt and GSK3b was prevented by LY294002, a PI3-K inhibitor, which facilitated subsequent DNA fragmentation 3 days after tGCI. Moreover, transgenic rats that overexpress copper/zinc-superoxide dismutase, which is known to be neuroprotective against delayed hippocampal CA1 injury after tGCI, had enhanced and persistent phosphorylation of both Akt and GSK3b after tGCI. These findings suggest that activation of the Akt/GSK3b signaling pathway may mediate survival of vulnerable hippocampal CA1 neurons after tGCI.

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“…Three days after tGCI, however, more than 80% of the CA1 neurons were degenerated in the Wt rats, as described previously (Chan et al, 1998;Sugawara et al, 1999).…”

Section: Delayed Hippocampal Ca1 Neuronal Death Occurred 72 H After Tsupporting

confidence: 69%

“…We have reported on the neuroprotection of SOD1 overexpression against delayed hippocampal CA1 neuronal death after tGCI in rats (Chan et al, 1998).…”

Section: Phosphatidylinositol 3-kinase Inhibitor Blocked Phosphorylatmentioning

confidence: 99%

Activation of the Akt/GSK3β Signaling Pathway Mediates Survival of Vulnerable Hippocampal Neurons after Transient Global Cerebral Ischemia in Rats

Endo

Nito

Kamada

et al. 2006

J Cereb Blood Flow Metab

173

113

View full text Add to dashboard Cite

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“…**Indicates signi®cant di erence (P50.01) between injured-untreated and injured-treated groups been shown to reach the injury site through blood circulation. 36 The current study shows that HE is capable of penetrating the spinal cord tissue in the absence of blood¯ow, by direct di usion. This demonstrates the versatility of this dye in di erent biological samples.…”

Section: Discussionmentioning

confidence: 51%

The increase of reactive oxygen species and their inhibition in an isolated guinea pig spinal cord compression model

Luo

Robinson

et al. 2002

Spinal Cord

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Study design:In vitro studies using isolated guinea pig spinal cord. Objectives: To develop an alternative model using isolated guinea pig spinal cord, which can be used to screen antioxidants for in vivo SCI treatment. Setting: Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA. Methods: The compression injury was induced by a constant-displacement of 5-s compression of spinal cord using a modi®ed forceps possessing a spacer. Reactive oxygen species (ROS) were evaluated using three distinct methods:¯uorescence microscopy, lipid peroxidation assay, and¯ow cytometry. Results: The injury-mediated ROS increases are comparable with other in vivo studies and consistent with our previous observation using a similar injury model and measured with electrophysiological and anatomical technique. Further, ascorbic acid, hypothermia, or the combination of both signi®cantly suppressed superoxide and lipid peroxidation. The combination treatment was the most e ective when compared with ascorbic acid or hypothermia alone. Conclusion: This in vitro model has the advantage of replicating some of the in vivo conditions while gaining the ability to control the experimental conditions. This in vitro model is suitable to study the mechanisms of ROS generation and degradation and can also be used to critically evaluate the e ective suppressor of ROS in the contents of spinal cord traumatic injury.

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“…Transgenic rats expressing human superoxide dismutase‐1 (hSOD1 WT ) 20 were provided by Pak Chan (Stanford University) and maintained through in‐house breeding on a Sprague‐Dawley background. Genotyping was performed by PCR amplification of tail DNA (Table S1).…”

Section: Methodsmentioning

confidence: 99%

Protein production is an early biomarker for RNA‐targeted therapies

Self

Schoch

Alex

et al. 2018

Ann Clin Transl Neurol

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ObjectivesClinical trials for progressive neurodegenerative disorders such as Alzheimer's Disease and Amyotrophic Lateral Sclerosis have been hindered due to the absence of effective pharmacodynamics markers to assay target engagement. We tested whether measurements of new protein production would be a viable pharmacodynamics tool for RNA‐targeted therapies.MethodsTransgenic animal models expressing human proteins implicated in neurodegenerative disorders – microtubule‐associated protein tau (hTau) or superoxide dismutase‐1 (hSOD1) – were treated with antisense oligonucleotides (ASOs) delivered to the central nervous system to target these human mRNA transcripts. Simultaneously, animals were administered 13C6‐leucine via drinking water to measure new protein synthesis after ASO treatment. Measures of new protein synthesis and protein concentration were assayed at designated time points after ASO treatment using targeted proteomics.Results ASO treatment lowered hTau mRNA and protein production (measured by 13C6‐leucine‐labeled hTau protein) earlier than total hTau protein concentration in transgenic mouse cortex. In the CSF of hSOD1 transgenic rats, ASO treatment lowered newly generated hSOD1 protein driven by decreases in newly synthesized hSOD1 protein, not overall protein concentration, 30 days after treatment. At later time points, decreases in newly generated protein were still observed after mRNA lowering reached a steady state after ASO treatment.InterpretationMeasures of newly generated protein show earlier pharmacodynamics changes for RNA‐lowering therapeutics compared with total protein concentration. Early in ASO treatment, decreases in newly generated protein are driven by changes in newly synthesized protein. Measuring new protein production in CSF may be a promising early pharmacodynamics marker for RNA‐targeted therapeutics.

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Overexpression of SOD1 in Transgenic Rats Protects Vulnerable Neurons Against Ischemic Damage After Global Cerebral Ischemia and Reperfusion

Cited by 315 publications

References 33 publications

Activation of the Akt/GSK3β Signaling Pathway Mediates Survival of Vulnerable Hippocampal Neurons after Transient Global Cerebral Ischemia in Rats

Activation of the Akt/GSK3β Signaling Pathway Mediates Survival of Vulnerable Hippocampal Neurons after Transient Global Cerebral Ischemia in Rats

The increase of reactive oxygen species and their inhibition in an isolated guinea pig spinal cord compression model

Protein production is an early biomarker for RNA‐targeted therapies

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