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ABSTRACT: Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF) are potent mitogens for endogenous neural stem cells (eNSC) and also induce angiogenesis. We infused the individual factors or their combination into the lateral ventricles of mice for 7 days after traumatic brain injury (TBI) in order to evaluate the effects on functional outcome and on eNSC proliferation and differentiation. The results show that VEGF induced a significant increment in the number of proliferating eNSC in the subventricular zone and in the perilesion cortex and that combination of FGF2 and VEGF did not augment the effects of VEGF alone. Fate analysis showed that most newborn cells differentiated into astrocytes and oligodendroglia while only a few cells differentiated into neurons. Functional outcome was significantly better in mice treated with VEGF, FGF2, or their combination as compared to vehicle. Injury size was significantly reduced only in mice treated with VEGF suggesting additional neuroprotective effects for VEGF. Combination therapy did not have an additive effect on outcome or neuronal differentiation. In conclusion, FGF2-VEGF combination does not augment neurogenesis and angiogenesis or reduce lesion volumes after TBI compared with individual factors. This may suggest the existence of a ceiling effect for brain regeneration.
Journal of Molecular Neuroscience 01/2012; 47(1):166-72. · 2.50 Impact Factor
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ABSTRACT: Traumatic brain injury (TBI) initiates acute and chronic inflammatory processes involving cyclooxygenase-2 (COX-2), which may have detrimental effects on outcome and especially on brain regeneration. Therefore we aimed to study whether carprofen, a COX-2 inhibitor, would improve outcome and increase neurogenesis after TBI. TBI was induced in Sabra mice that were then treated with vehicle or carprofen for 7 days. Functional outcome was evaluated with the Neurological Severity Score (NSS).Cytokine levels were assessed 4 h post-TBI and water content was measured 24 h post TBI. Mice were given BrdU to label newborn cells for 10 days. The animals were killed 90 days post-TBI and the lesion size as well as newborn cell fate were assessed. Carprofen significantly reduced lesion size (p=0.002), decreased water content in the lesioned cortex (p=0.03), reduced the number of microglia in the lesioned cortex (p<0.0001), and lowered the levels of proinflammatory cytokines (IL-1β, p=0.03; IL-6, p=0.02). Carprofen led to significantly larger improvements in functional outcome (p≤0.008) which were durable over 90 days. Carprofen also induced a threefold increase in the proliferation of new cells in the peri-lesion area (p≤0.002), but newborn cells differentiated mainly into glia in both groups. Carprofen is neuroprotective and induces cell proliferation and gliogenesis after TBI. Treatment with carprofen is consistently associated with better functional outcome. Our results imply that anti-inflammatory drugs may represent novel therapeutic options for TBI.
Journal of neurotrauma 05/2011; 29(2):375-84. · 4.25 Impact Factor
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ABSTRACT: Activation of endogenous stem cells has been proposed as a novel form of therapy in a variety of neurologic disorders including traumatic brain injury (TBI). Vascular endothelial growth factor (VEGF) is expressed in the brain after TBI and serves as a potent activator of angiogenesis and neurogenesis. In this study, we infused exogenous VEGF into the lateral ventricles of mice for 7 days after TBI using mini-osmotic pumps to evaluate the effects on recovery and functional outcome. The results of our study show that VEGF significantly increases the number of proliferating cells in the subventricular zone and in the perilesion cortex. Fate analysis showed that most newborn cells differentiated into astrocytes and oligodendroglia and only a few cells differentiated into neurons. Functional outcome was significantly better in mice treated with VEGF compared with vehicle-treated animals after TBI. Injury size was significantly smaller at 90 days after TBI in VEGF-treated animals, suggesting additional neuroprotective effects of VEGF. In conclusion, VEGF significantly augments neurogenesis and angiogenesis and reduces lesion volumes after TBI. These changes are associated with significant improvement in recovery rates and functional outcome.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 05/2010; 30(5):1008-16. · 5.46 Impact Factor
