Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis

Pitzer, Claudia; Krüger, Carola; Plaas, Christian; Kirsch, Friederike; Dittgen, Tanjew; Müller, Ralph; Laage, Rico; Kastner, Stefan; Suess, Stefanie; Spoelgen, Robert; Henriques, Alexandre Cruz; Ehrenreich, Hannelore; Schäbitz, Wolf‐Rüdiger; Bach, A.; Schneider, Armin

doi:10.1093/brain/awn243

Cited by 121 publications

(119 citation statements)

References 43 publications

(61 reference statements)

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“…G‐CSF is a traditional hematopoietic growth factor that was approved for granulocytopenia therapy. In addition to affecting the hematopoietic system, G‐CSF can exert anti‐inflammatory effects as well as promote neurogenesis in the CNS (Pitzer et al., 2008). However, GM‐CSF is regarded as a proinflammatory cytokine to facilitate proliferation and differentiation of inflammatory cells (Barbeito, Mesci, & Boillee, 2010).…”

Section: Discussionmentioning

confidence: 99%

Evaluating the levels of CSF and serum factors in ALS

et al. 2017

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ObjectivesThe aim of this study was to identify CSF and serum factors as biomarkers that may aid in distinguishing ALS patients from control subjects and predicting ALS progression as well as prognosis.MethodsSerum and CSF samples from 105 patients with ALS and 56 control subjects were analyzed for 13 factors using ELISA. The revised ALS functional rating scale (ALSFRS‐r) was used to evaluate the overall functional status of ALS patients, and we also followed up with ALS patients either by phone or with clinic visits for five years after enrollment in this study. Finally, we examined the correlations between factor levels and various clinical parameters and evaluated the predictive value for prognosis through a multivariate statistic model.ResultsA total of eight factors were obviously elevated in CSF, and twelve markers were increased in serum. In the correlation analyses, there were trends toward higher bFGF, VEGF, MIP‐1α levels in ALS with a longer disease duration and slower disease progression in both CSF and serum. Higher MCP‐1 levels were associated with worse disease severity and faster progression, and the IFN‐γ levels were positively associated with disease progression in either CSF or serum. Finally, a better prognosis was observed with higher levels bFGF in CSF and VEGF in CSF and serum; conversely, patients with higher levels of IFN‐γ in the CSF had shorter overall survival.ConclusionsWe demonstrated that a factor profile of ALS patients is distinct from control subjects and may be useful in clinical practice and therapeutic trials.

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Section: Discussionmentioning

confidence: 99%

Evaluating the levels of CSF and serum factors in ALS

et al. 2017

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“…As the immunohistochemical analysis of the SOD G93A mice is not the primary scope of this article please consult the original publication in which these transgenic mice have been characterized and more recent ones which study therapeutic approaches for further reference 1,5,6 . If therapeutic effects shall be differentiated on the immunohistological level clearly defined quantitative evaluation algorithms should be applied supported by a stereological software (for example see 7 ).…”

Section: Representative Resultsmentioning

confidence: 99%

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)

Günther

Suhr

Koch

et al. 2012

JoVE

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in progressive degeneration of motoneurons. Peak of onset is around 60 years for the sporadic disease and around 50 years for the familial disease. Due to its progressive course, 50% of the patients die within 30 months of symptom onset. In order to evaluate novel treatment options for this disease, genetic mouse models of ALS have been generated based on human familial mutations in the SOD gene, such as the SOD1 (G93A) mutation. Most important aspects that have to be evaluated in the model are overall survival, clinical course and motor function. Here, we demonstrate the clinical evaluation, show the conduction of two behavioural motor tests and provide quantitative scoring systems for all parameters. Because an in depth analysis of the ALS mouse model usually requires an immunohistochemical examination of the spinal cord, we demonstrate its preparation in detail applying the dorsal laminectomy method. Exemplary histological findings are demonstrated. The comprehensive application of the depicted examination methods in studies on the mouse model of ALS will enable the researcher to reliably test future therapeutic options which can provide a basis for later human clinical trials. Video LinkThe video component of this article can be found at http://www.jove.com/video/3936/ Protocol Animals were purchased from Jackson Laboratory (# 002726) 1 . They are clinically scored and subjected to a test of motor function (rotarod test) and of muscular strength (hanging wire test). All these tests and the later killing of the animals in order to prepare the spinal cord have been performed in very close accordance to the local guidelines for proper conduct of animal experiments.

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“…It can pass through the blood-brain barrier to enter the CNS. 34,35 Moreover, accumulating evidence has shown that G-CSF also has important non-hematopoietic functions in the CNS. 36,37 We reported previously that G-CSFR was expressed specifically 38 and in this study we find that autophagy also occurs in these neurons.…”

Section: Discussionmentioning

confidence: 99%

G-CSF promotes autophagy and reduces neural tissue damage after spinal cord injury in mice

Guo

Liu

Zhang

et al. 2015

Laboratory Investigation

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Granulocyte colony-stimulating factor (G-CSF) was investigated for its capacity to induce autophagy and related neuroprotective mechanisms in an acute spinal cord injury model. To accomplish this goal, we established a mouse spinal cord hemisection model to test the effects of recombinant human G-CSF. The results showed that autophagy was activated after spinal cord injury and G-CSF appears to induce a more rapid activation of autophagy within injured spinal cords as compared with that of non-treated animals. Apoptosis as induced in mechanically injured neurons with G-CSF treatment was enhanced after inhibiting autophagy by 3-methyladenine (3-MA), which partially blocked the neuroprotective effect of autophagy as induced by G-CSF. In addition, G-CSF inhibited the activity of the NF-κB signal pathway in neurons after mechanical injury. We conclude that G-CSF promotes autophagy by inhibiting the NF-κB signal pathway and protects neuronal structure after spinal cord injury. We therefore suggest that G-CSF, which rapidly induces autophagy after spinal cord injury to inhibit neuronal apoptosis, may thus provide an effective auxiliary therapeutic intervention for spinal cord injury.

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Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis

Cited by 121 publications

References 43 publications

Evaluating the levels of CSF and serum factors in ALS

Evaluating the levels of CSF and serum factors in ALS

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)

G-CSF promotes autophagy and reduces neural tissue damage after spinal cord injury in mice

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