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Granulocyte-Colony-Stimulating Factor in Repair of Ischemic Stroke
Granulocyte-colony-stimulating factor and epidermal growth factor plus erythropoietin show promise for treating ischemic stroke, according to two separate studies presented at the annual meeting of the Society for Neuroscience.
In experiments with rats that underwent a transient occlusion of the middle cerebral artery, the volume of infarct significantly decreased when granulocyte-colony-stimulating factor (G-CSF) was administered either 2 or 4 hours after the onset of ischemia, reported Rico Laage, Ph.D., of Axaron Bioscience AG, Heidelburg, Germany. Similar results occurred when G-CSF was administered 1 hour after the onset of ischemia caused by transient occlusion of the common carotid artery and distal middle cerebral artery. G-CSF is normally used to treat neutropenic conditions.
In vitro studies have shown that G-CSF reduces apoptotic activity in human neurons and that the G-CSF receptor is expressed in the human brain and is upregulated in infarcted areas shortly after stroke in humans.
In Germany, Axaron is conducting a multicenter, randomized, double-blind, placebo-controlled phase II trial of G-CSF in patients who suffered an acute ischemic stroke in the region of the middle cerebral artery within the last 12 hours and are not receiving tissue plasminogen activator. Following a 3-day intravenous infusion of G-CSF, investigators measure thromboembolic complications up to discharge or day 4 and infection or other serious adverse events after 4 weeks. Neurological outcome is measured at 4 and 12 weeks after treatment while the growth of the ischemic lesion is measured from baseline to 3 months after treatment with MRI.
In another study, Trudi Stickland, at the University of Calgary, and her associates found that epidermal growth factor (EGF) and erythropoietin (EPO) stimulated the proliferation and differentiation of endogenous neural stem cells and repaired infarcted stroke regions in rats. The researchers induced ischemic strokes in the primary motor cortex that affected the forepaw contralateral to the side of the brain that was lesioned.
Intracerebroventricular infusions of EGF and EPO significantly increased gross motor functioning of the affected forepaw when rats spontaneously explored a cylindrical cage and fine motor functioning in a trained task that involved reaching through a narrow slot to grasp a food pellet.
Rats who received only serum albumin recovered very little function. After these behavioral tests (50 days after the stroke), the researchers found that stem cells had migrated to the lesion site in the motor cortex of rats that received EGF and EPO and initiated regrowth of cortical tissue. “We're not sure that these new neurons in the lesion site are necessarily functional,” Ms. Stickland said. Future experiments will determine if the new tissue is establishing new neural connections or is secreting agents that help the surrounding tissue take on new functions.
Dr. Caselli's comment: Neurologists have floundered for decades with anticoagulant therapies and have emphasized primary prevention in populations that already have advanced risk. The advent of IV recombinant tissue plasminogen activator (rTPA) ushered in the era of immediate, definitive intervention. For the first time, minutes mattered. The notion of “brain attack,” if not exactly born, finally let out a long-awaited cry that the world heard. Neurology has a long-standing reputation of being more of a diagnostic than a therapeutic specialty, leading many doctors and patients to have a nihilistic view of neurologic therapeutics. Invasive cerebrovascular techniques such as intraarterial TPA, stent coils, and other devices are changing that perception. In the two studies described above, different forms of growth factors and apoptosis inhibitors reduced stroke size when given immediately in rats.
While an intracerebroventricular avenue will not suffice clinically, especially for patients who may be eligible for thrombolysis, the notion of treating a patient with substances that immediately inhibit cell death and promote regeneration is a logical and potentially powerful next step. While more work is clearly needed, it is encouraging that some substances, such as G-CSF have reached the stage of human trials.