Granulocyte-Colony Stimulating Factor (G-CSF) Improves Motor Recovery in the Rat Impactor Model for Spinal Cord Injury

Granulocyte-colony stimulating factor (G-CSF) improves outcome after experimental SCI by counteracting apoptosis, and enhancing connectivity in the injured spinal cord. Previously we have employed the mouse hemisection SCI model and studied motor function after subcutaneous or transgenic delivery of the protein. To further broaden confidence in animal efficacy data we sought to determine efficacy in a different model and a different species. Here we investigated the effects of G-CSF in Wistar rats using the New York University Impactor. In this model, corroborating our previous data, rats treated subcutaneously with G-CSF over 2 weeks show significant improvement of motor function

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

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive loss of motoneurons, motor weakness and death within 1–5 years after disease onset. Therapeutic options remain limited despite a substantial number of approaches that have been tested clinically. In particular, various neurotrophic factors have been investigated. Failure in these trials has been largely ascribed to problems of insufficient dosing or inability to cross the blood–brain barrier (BBB). We have recently uncovered the neurotrophic properties of the haematopoietic protein granulocyte-colony stimulating factor (G-CSF). The protein is clinically well tolerated and crosses the intact BBB. This study examined the potential role of G-CSF in motoneuron diseases. We investigated the expression of the G-CSF receptor in motoneurons and studied effects of G-CSF in a motoneuron cell line and in the SOD1(G93A) transgenic mouse model. The neurotrophic growth factor was applied both by continuous subcutaneous delivery and CNS-targeted transgenic overexpression. This study shows that given at the stage of the disease where muscle denervation is already evident, G-CSF leads to significant improvement in motor performance, delays the onset of severe motor impairment and prolongs overall survival of SOD1(G93A)tg mice. The G-CSF receptor is expressed by motoneurons and G-CSF protects cultured motoneuronal cells from apoptosis. In ALS mice, G-CSF increased survival of motoneurons and decreased muscular denervation atrophy. We conclude that G-CSF is a novel neurotrophic factor for motoneurons that is an attractive and feasible drug candidate for the treatment of ALS

Listed are the different spinal cord injury models in rodents where G-CSF demonstrated beneficial effects.

<p>Given are the respective spinal cord injury models, the animal species, the application mode and the outcome of the experiment with the behavioural testings used (+: significant benefit; s.c. subcutaneously; i.v. intravenously; i.t. intrathecally; NSC: neural stem cells; SCF: Stem Cell Factor; MDI: Motor Deficit Index; BBB: Basso, Beattie and Bresnahan locomotor score).</p

Outcome analysis in rats subjected to weight drop.

<p>(<b>A</b>) Mean BBB scores in untreated (−) and G-CSF-treated (+) rats from 1 to 35 days, including all data (LOCF) (n = 24 for G-CSF treatment, n = 25 for vehicle treatment; p<0.05 for factor <i>treatment</i>, p<0.005 for interaction <i>treatment*time (days after injury)</i> by linear regression analysis). (<b>B</b>) Mean Grid Walk scores in untreated (−) and G-CSF-treated (+) rats from 7 to 35 days, including all data (LOCF) (p<0.05 for factor <i>treatment</i>, p<0.005 for interaction <i>treatment*time (days after injury)</i> by linear regression analysis). (<b>C</b>) Mean Swim Test scores in untreated (−) and G-CSF-treated (+) rats after 7 to 35 days, including all data (LOCF). Data is represented as mean ± SEM. This test.</p

The hematopoietic factor granulocyte-colony stimulating factor improves outcome in experimental spinal cord injury.

Granulocyte-colony stimulating factor (G-CSF) is a potent hematopoietic factor that drives differentiation of neutrophilic granulocytes. We have recently shown that G-CSF also acts as a neuronal growth factor, protects neurons in vitro and in vivo, and has regenerative potential in various neurological disease models. Spinal cord injury (SCI) following trauma or secondary to skeletal instability is a terrible condition with no effective therapies available at present. In this study, we show that the G-CSF receptor is up-regulated upon experimental SCI and that G-CSF improves functional outcome in a partial dissection model of SCI. G-CSF significantly decreases apoptosis in an experimental partial spinal transsection model in the mouse and increases expression of the anti-apoptotic G-CSF target gene Bcl-X(L). In vitro, G-CSF enhances neurite outgrowth and branching capacity of hippocampal neurons. In vivo, G-CSF treatment results in improved functional connectivity of the injured spinal cord as measured by Mn(2+)-enhanced MRI. G-CSF also increased length of the dorsal corticospinal tract and density of serotonergic fibers cranial to the lesion center. Mice treated systemically with G-CSF as well as transgenic mice over-expressing G-CSF in the CNS exhibit a strong improvement in functional outcome as measured by the BBB score and gridwalk analysis. We show that G-CSF improves outcome after experimental SCI by counteracting apoptosis, and enhancing connectivity in the injured spinal cord. We conclude that G-CSF constitutes a promising and feasible new therapy option for SCI

Forced arm use is superior to voluntary training for motor recovery and brain plasticity after cortical ischemia in rats

Schneider A, Rogalewski A, Wafzig O, et al. Forced arm use is superior to voluntary training for motor recovery and brain plasticity after cortical ischemia in rats. Experimental &amp; Translational Stroke Medicine. 2014;6(1): 3.This is an Open Access article distributed under the terms of the Creative Commons Attribution License [http://creativecommons.org/licenses/by/2.0](http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver [http://creativecommons.org/publicdomain/zero/1.0/](http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline

Item does not contain fulltextMemory impairment has been associated with age-related decline in adult hippocampal neurogenesis. Although Notch, bone morphogenetic protein, and Wnt signaling pathways are known to regulate multiple aspects of adult neural stem cell function, the molecular basis of declining neurogenesis in the aging hippocampus remains unknown. Here, we show that expression of the Wnt antagonist Dickkopf-1 (Dkk1) increases with age and that its loss enhances neurogenesis in the hippocampus. Neural progenitors with inducible loss of Dkk1 increase their Wnt activity, which leads to enhanced self-renewal and increased generation of immature neurons. This Wnt-expanded progeny subsequently matures into glutamatergic granule neurons with increased dendritic complexity. As a result, mice deficient in Dkk1 exhibit enhanced spatial working memory and memory consolidation and also show improvements in affective behavior. Taken together, our findings show that upregulating Wnt signaling by reducing Dkk1 expression can counteract age-related decrease in neurogenesis and its associated cognitive decline