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

Autor: Alfred Bach, Christian Plaas, Hannelore Ehrenreich, Wolf-Rüdiger Schäbitz, Friederike Kirsch, Robert Spoelgen, Claudia Pitzer, Stefan Kastner, Armin Schneider, Carola Krüger, Alexandre Henriques, Rico Laage, Ralph Müller, Stefanie Suess, Tanjew Dittgen
Rok vydání: 2008
Předmět:
Genetically modified mouse
Filgrastim
SOD1
Drug Evaluation
Preclinical
Apoptosis
Mice
Transgenic
Infusions
Subcutaneous
drug candidate
functional outcome
Mice
Superoxide Dismutase-1
Atrophy
Neurotrophic factors
Granulocyte Colony-Stimulating Factor
medicine
Animals
Humans
Amyotrophic lateral sclerosis
Cells
Cultured
Motor Neurons
Denervation
biology
Reverse Transcriptase Polymerase Chain Reaction
Superoxide Dismutase
business.industry
Amyotrophic Lateral Sclerosis
growth factor
Original Articles
motoneuron survival
medicine.disease
Recombinant Proteins
Granulocyte colony-stimulating factor
Mice
Inbred C57BL
Disease Models
Animal
Treatment Outcome
Spinal Cord
nervous system
Mutation
Receptors
Granulocyte Colony-Stimulating Factor
Immunology
Disease Progression
Cancer research
biology.protein
Female
Neurology (clinical)
ALS
business
Neurotrophin
Zdroj: Brain
ISSN: 1460-2156
0006-8950
DOI: 10.1093/brain/awn243
Popis: 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.
Databáze: OpenAIRE
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