IGF‐I and microglia/macrophage proliferation in the ischemic mouse brain

Abstract

We have used a model of hypoxic-ischemic brain injury in adult male C57BL/6 mice to study insulin-like growth factor-I (IGF-I) and IGF-binding protein (IGFBP) expression in response to cerebral hypoxia-ischemia (H/I) in the adult mouse. A period of 20 min of H/I that resulted in histopathology in cortex, striatum, and thalamus was correlated with induction of mRNA for IGF-I, IGFBP-2, IGFBP-3, IGFBP-5, and glial fibrillary acidic protein (GFAP) by 4 days of recovery. Increased IGF-I mRNA was located within damaged regions and was surrounded by IGFBP-2 mRNA expression. The results of combined immunostaining/in situ hybridzation showed that the cells expressing IGFBP-2 mRNA were also GFAP-positive and comprised a subset of activated astrocytes immediately surrounding areas of damage. In contrast, staining within damaged regions showed high numbers of cells immunopositive for F4/80 and lectin B(4) indicative of microglia and macrophages but no cells immunopositive for the astrocytic proteins GFAP or S-100beta. Microglia/macrophages within the damaged areas expressed IGF-I mRNA and were also immunopositive for the proliferating cell nuclear antigen. To determine whether expression of IGF-I could contribute to proliferation of microglia, we treated purified cultures of adult brain microglia with IGF-I in the presence of (3)H-thymidine. IGF-I stimulated a twofold increase in DNA synthesis in cultures of adult brain microglia. Taken together with previous data demonstrating that IGF-I promotes proliferation of peripheral macrophages, these data support the hypothesis that IGF-I is an autocrine/paracrine mitogen for microglia/macrophages after H/I.

Impaired Wound Healing after Cerebral Hypoxia—Ischemia in the Diabetic Mouse

“…Figure 1 also illustrates that astrocytic activation as evidenced by enhanced GFAP expression was diminished and delayed in the diabetic mice. As with bfl-1, the increased GFAP mRNA expression was apparent at 4 h in the ipsilateral hemisphere of the db/ + animals, with heightened expression in the striatum over the subsequent 24 h. GFAPpositive cells appear to 'surround' the region of bfl-1-positive microglia, as has been reported before in nondiabetic mouse brain (O'Donnell et al, 2002). In the diabetic mice the expression of GFAP mRNA was barely detectible at 4 h and significantly decreased throughout the ipsilateral hemisphere, indicative of tissue infarction.…”

Up‐regulated basigin‐2 in microglia induced by hypoxia promotes retinal angiogenesis

“…IGF‐1 has high binding affinity for IGFBP‐2, and this interaction is thought to play a significant role in modulating IGF‐1 localization to its receptor, protecting it from degradation, facilitating its transportation to the injury site. Although, cellular origins of IGFBP‐2 and mechanistically an IGF‐1‐dependent or independent pathway were still in doubt, previous reports have shown IGFBP‐2 increased after hypoxic‐ischaemic injury to the brain 33, and co‐localized with endogenous IGF‐1 at the injury site 32, 52.…”

Glutamate-related gene expression changes with age in the mouse auditory midbrain

“…IGF-1 is a naturally occurring peptide in the central nervous system. GPE is the N-terminal tripeptide of IGF-1 that naturally cleaved in the plasma and brain tissue and has a neuroprotective effect in various ischemic brain injuries (Guan et al, 1999(Guan et al, , 2004Alexi et al, 1999;Aberg et al, 2000;O'Donnell et al, 2002;Baker et al, 2005). Therefore, proline, in normal levels, is an essential amino acid for neural protection against oxidative metabolites, and Pycs deficiency in old age in the inferior colliculus may contribute to both glutamate accumulation and proline deficiency.…”