Transgenic animal models expressing mutant SOD1 have been widely used to study ALS pathogenesis. ALS or SOD1 mediated pathology is accompanied by multiple cellular and subcellular abnormalities including deficits in the axonal transport and mitochondrial func tions. Abnormal SOD1 activity has also been shown to impair neuromuscular function. useful site Although the motoneuron degeneration is a hallmark of ALS the disease may actually initiate from the periphery. Deficits in neuromuscular function may precede motoneuron deficits and even the muscle restricted expression of mutant SOD1 may be sufficient to initiate the ALS pathology with subsequent motoneuron degeneration. Non neuronal cells, namely microglia and astrocytes, participate in CNS homeostasis by secreting trophic molecules and helping to maintain proper neuronal sig naling.
On the other hand, they may also secrete mole cules Inhibitors,Modulators,Libraries that disrupt the CNS homeostasis. Microglia Inhibitors,Modulators,Libraries and astrocytes thus play a crucial role in ALS pathology by regulating neuroinflammation. Also, the microglia turnover by myeloid cells from the circulation may play a role in neurodegenerative diseases as previously reviewed. In addition, peripherally derived myeloid cells may infiltrate not only into the CNS but also migrate into the peripheral nervous system or skeletal muscle and potentially participate in ALS progression. Myeloid cells exist in different pheno types, so called pro inflammatory and anti inflammatory forms, also known as classical and alternatively activated monocytes, which may contribute to inflammation and tissue regeneration in a different manner.
The treat ment modulating these monocyte subsets and thus inflammation may provide a potential therapy for neuro degenerative diseases. GCSF is a hematopoietic Inhibitors,Modulators,Libraries growth factor which is cur rently in clinical use to mobilize stem cells into the cir culation prior to apheresis and to treat neutropenia after cytostatic therapy. GCSF has a wide variety of actions, it reduces apoptosis, Inhibitors,Modulators,Libraries drives neurogenesis and angiogenesis and attenuates inflammation. GCSF is protective in myocardial infarction in animal models and it has also been tested for clinical use after acute and chronic ischemic heart diseases as reviewed by Kastrup et al. Moreover, GCSF has been shown to be protective in animal models of acute and chronic neurodegenerative diseases as reviewed in Diederich et al, including stroke, Alzheimers disease, Parkin sons disease and spinal cord injury.
GCSF was recently shown to be protective also in animal models of ALS, mediating its protective effects Inhibitors,Modulators,Libraries via P13 Akt pathway, an antiapoptotic transduction pathway down stream of GCSF signaling in neurons. GCSF was also shown to be neuroprotective figure 2 after peripheral axot omy. GCSF is conventionally administered as repeated daily injections of filgrastim.
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