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Spatial and Temporal Changes in the Insulin-Like Growth Factor (IGF) Axis Indicate Autocrine/Paracrine Actions of IGF-I within Wounds of the Rat Brain¹

Department of Medicine (H.J.W., A.L.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Anatomy and Cell Biology (M.B.), UMDS, Guy’s Hospital, London SE1 9RT, United Kingdom; Department of Medicine, Physiology and Paediatrics (D.J.H.), Lawson Research Institute, London, Ontario N6A 4V2, Canada

Address all correspondence and requests for reprints to: Ann Logan, Department of Medicine, The University of Birmingham, Wolfson Research Laboratories, Queen Elizabeth Medical Centre, Edgbaston, Birmingham, B15 2TH, United Kingdom. E-mail: a.logan{at}bham.ac.uk

A precise role for insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and IGF-receptors (IGF-Rs) in damaged central nervous system (CNS) tissue has not been elucidated, although their expression in the ischemic brain has been demonstrated. However, little is known of IGF responses after CNS trauma. In this study, we have used ribonuclease protection assay, in situ hybridization, and immunohistochemistry to demonstrate that IGF-I, IGFBPs, and IGF-1R expression alters in response to a penetrating CNS injury. Within penetrant cerebral wounds in the acute phase of the response (1–7 days post lesion; dpl), increased levels of IGF-I, IGFBP-1, -2, -3, -6, and IGF-1R protein were localized to injury responsive astrocytes, neurons and cells of the monocyte lineage. IGF-I, IGFBP-2, and 3 showed a congruency in sites of messenger RNA (mRNA) and peptide expression, with IGF-I and IGFBP-2 mRNA expression predominating. IGF-I, IGFBP-1, and IGFBP-3 protein were also associated with the microvascular endothelium, which was accompanied by increased levels of IGFBP-3 mRNA. These early changes in IGFBP expression probably facilitate IGF-I action. Later in the wounding response (7–14 dpl), the expression of IGFBP-4 and IGFBP-5 peaked within astrocytes and neurons, with IGFBP-5 mRNA being specifically localized to the glia limitans within the wound, suggesting an inhibitory role for these proteins, down-regulating the effects of IGF-I chronically. Our evidence suggests that within penetrating CNS wounds, IGF-I acts in an autocrine/paracrine manner to regulate cellular responses, with its spatial and temporal availability being modulated by the differential presence of stimulatory vs. inhibitory IGFBPs.

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