transforming-growth-factor-alpha and Brain-Injuries

Neurogenesis is stimulated in the subventricular zone (SVZ) of mice with cortical brain injuries. In most of these injuries, newly generated neuroblasts attempt to migrate toward the injury, accumulating within the corpus callosum not reaching the perilesional area.. We use a murine model of mechanical cortical brain injury, in which we perform unilateral cortical injuries in the primary motor cortex of adult male mice. We study neurogenesis in the SVZ and perilesional area at 7 and 14 dpi as well as the expression and concentration of the signaling molecule transforming growth factor alpha (TGF-α) and its receptor the epidermal growth factor (EGFR). We use the EGFR inhibitor Afatinib to promote neurogenesis in brain injuries.. We show that microglial cells that emerge within the injured area and the SVZ in response to the injury express high levels of TGF-α leading to elevated concentrations of TGF-α in the cerebrospinal fluid. Thus, the number of neuroblasts in the SVZ increases in response to the injury, a large number of these neuroblasts remain immature and proliferate expressing the epidermal growth factor receptor (EGFR) and the proliferation marker Ki67. Restraining TGF-α release with a classical protein kinase C inhibitor reduces the number of these proliferative EGFR. Our results indicate that in response to an injury, microglial cells activated within the injury and the SVZ release TGF-α, activating the EGFR present in the neuroblasts membrane inducing their proliferation, delaying maturation and negatively regulating migration. The inactivation of this signaling pathway stimulates neuroblast migration toward the injury and enhances the quantity of neuroblasts within the injured area. These results suggest that these proteins may be used as target molecules to regenerate brain injuries.

Topics: Animals; Brain Injuries; Cell Movement; ErbB Receptors; Male; Mice; Neural Stem Cells; Neurogenesis; Transforming Growth Factor alpha

Neural precursor cells (NPCs) are activated in central nervous system injury. However, despite being multipotential, their progeny differentiates into astrocytes rather than neurons in situ. We have investigated the role of epidermal growth factor receptor (EGFR) in the generation of non-neurogenic conditions. Cultured mouse subventricular zone NPCs exposed to differentiating conditions for 4 days generated approximately 50% astrocytes and 30% neuroblasts. Inhibition of EGFR with 4-(3-chloroanilino)-6,7-dimethoxyquinazoline significantly increased the number of neuroblasts and decreased that of astrocytes. The same effects were observed upon treatment with the metalloprotease inhibitor galardin, N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide (GM 6001), which prevented endogenous transforming growth factor-α (TGF-α) release. These results suggested that metalloprotease-dependent EGFR-ligand shedding maintained EGFR activation and favored gliogenesis over neurogenesis. Using a disintegrin and metalloprotease 17 (ADAM-17) small interference RNAs transfection of NPCs, ADAM-17 was identified as the metalloprotease involved in cell differentiation in these cultures. In vivo experiments revealed a significant upregulation of ADAM-17 mRNA and de novo expression of ADAM-17 protein in areas of cortical injury in adult mice. Local NPCs, identified by nestin staining, expressed high levels of ADAM-17, as well as TGF-α and EGFR, the three molecules necessary to prevent neurogenesis and promote glial differentiation in vitro. Chronic local infusions of GM6001 resulted in a notable increase in the number of neuroblasts around the lesion. These results indicate that, in vivo, the activation of a metalloprotease, most probably ADAM-17, initiates EGFR-ligand shedding and EGFR activation in an autocrine manner, preventing the generation of new neurons from NPCs. Inhibition of ADAM-17, the limiting step in this sequence, may contribute to the generation of neurogenic niches in areas of brain damage.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Astrocytes; Brain Injuries; Cell Differentiation; Cell Proliferation; Dipeptides; Enzyme Activation; ErbB Receptors; Female; Immunohistochemistry; Intermediate Filament Proteins; Male; Mice; Nerve Tissue Proteins; Nestin; Neural Stem Cells; Neurogenesis; Neurons; Quinazolines; RNA, Messenger; RNA, Small Interfering; Transfection; Transforming Growth Factor alpha; Tyrphostins

Evidence is presented to show that cells of the ependymal layer surrounding the ventricles of the mammalian (rat) forebrain act as neural stem cells (NSCs), and that these cells can be activated to divide by a combination of injury and growth factor stimulation. Several markers of asymmetric cell division (ACD), a characteristic of true stem cells, are expressed asymmetrically in the ependymal layer but not in the underlying subventricular zone (SVZ), and when the brain is treated with a combination of local 6-hydroxydopamine (6-OHDA) with systemic delivery of transforming growth factor-alpha (TGFalpha), ependymal cells divide asymmetrically and transfer progeny into the SVZ. The SVZ cells then divide as transit amplifying cells (TACs) and their progeny enter a differentiation pathway. The stem cells in the ependymal layer may have been missed in many previous studies because they are usually quiescent and divide only in response to strong stimuli.

Topics: Animals; Biomarkers; Brain Injuries; Bromodeoxyuridine; Cell Differentiation; Cell Division; Cell Movement; Cytokinesis; Ependyma; Lateral Ventricles; Male; Nerve Regeneration; Nerve Tissue Proteins; Neuronal Plasticity; Neurons; Oxidopamine; Rats; Recovery of Function; Stem Cells; Sympatholytics; Transforming Growth Factor alpha

Ischemia and systemic infection are implicated in the etiology of periventricular white matter injury, a major cause of adverse motor and cognitive outcome in preterm infants. Cytokines are signaling proteins that can be produced as part of the inflammatory response to both ischemia and infection. The aim of this study was to relate cerebrospinal fluid (CSF) concentrations of IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) to magnetic resonance-defined white matter injury in preterm infants. Relationships between CSF and plasma cytokine concentrations were also examined. Preterm infants (

Topics: Brain; Brain Injuries; Cytokines; Humans; Infant; Infant, Newborn; Infant, Premature; Interferon-gamma; Interleukin-10; Interleukin-6; Interleukin-8; Magnetic Resonance Imaging; Signal Transduction; Transforming Growth Factor alpha

To determine the exact role of TGF-alpha in glial activation after traumatic brain injury, we investigated the astroglial and microglial responses after cortical stab wound injury in TGF-alpha overexpressing mice. Adult male B6D2-TgN (MMTVTGFA) 29RjC transgenic mice were used for the subjects. This transgenic line carries a TGF-alpha cDNA under the control of the dexamethasone-inducible MMTV promoter. Thus, exogenous administration of dexamethasone induces TGF-alpha overexpression. Male B6D2F1/J mice at the same age served as wild-type animals. After the cortical stab wound injury, expression of glial fibrillary acidic protein, CD-11b and interleukine-6 were investigated immunohistochemically. The results indicate that TGF-alpha might affect astrocytic hypertrophy without affecting microgliosis not only in the normal condition, but also in the pathological condition. Moreover, overexpression of TGF-alpha induced obvious expression of IL-6 around the lesion. This fact might indicate possible role of TGF-alpha in affecting neuronal function.

Topics: Animals; Astrocytes; Brain Injuries; CD11b Antigen; Gene Expression; Glial Fibrillary Acidic Protein; Hypertrophy; Interleukin-6; Male; Mice; Mice, Transgenic; Transforming Growth Factor alpha; Wounds, Stab