Expression of insulin-like growth factor-1 (IGF-1) and IGF-binding protein 2 (IGF-BP2) in the hippocampus following cytotoxic lesion of the dentate gyrus

Abstract

Receptor binding and gene expression of several members of the IGF gene family were examined in the rat brain following lesion of the hippocampal dentate gyrus granular cells by intradentate colchicine injection. Dentate granular cell loss was accompanied by extensive reactive gliosis in the lesioned hippocampus and damaged overlying cortex, as verified by the increase in GFAP mRNA and BS-1 lectin binding. At 4 days post-lesion, 125I-IGF-2 binding was dramatically increased within the lesioned dentate gyrus and damaged overlying cortex, and corresponded temporally and anatomically with increased IGF-BP2 gene expression following the lesion. Increased IGF-BP3 gene expression was only observed in the overlying cortex at 10 days post-lesion, and corresponded with an increase in 125I-IGF-1 binding at the injured surface of the cortex. Type-2 IGF receptor mRNA expression was reduced to background levels in the lesioned dentate gyrus, suggesting that IGF-BP2 was a major component of the observed increase in 125I-IGF-2 binding. In situ hybridization also revealed a prominent increase in IGF-1 mRNA expression by 4 days post-lesion, which was localized within the lesioned dentate gyrus and damaged cortical areas, and was shown to be expressed by microglia. While no IGF-2 mRNA expression was observed within the CNS, either prior to, or following the lesion, IGF-2 mRNA expression was observed in the choroid plexus, meningeal membranes, and in blood vessel endothelium, providing a potential source for the transport of IGF-2 into the CNS. In the injured CNS, increased IGF-BP2 expression may act to maintain or transport IGF-1 or IGF-2, as well as modulate the local autocrine and paracrine actions of the IGFs. Increased microglial IGF-1 expression following colchicine treatment correlates with the timing of a number of post-traumatic events within the CNS, suggesting that IGF-1 may have a role as a neuroprotectant for surviving neurons and signal for local neuronal sprouting, as well as a role in reactive astrogliosis.

Insulin-like growth factor-I and its receptor in the frontal cortex, hippocampus, and cerebellum of normal human and Alzheimer disease brains

“…Multiple lines of evidence indicate that IGF-I plays an important role not only in protecting neurons from a variety of surgical and pharmacological intervention, but also participate in neuronal growth and synaptic reorganization that follows injury (Gluckman et al, 1993;Kar et al, 1993a;Breese et al, 1996;Woods et al, 1998). Exogenously applied IGF-I has been shown to: 1) rescue motoneurons following peripheral axotomy (Neff et al, 1993), 2) enhance regeneration of the sciatic nerve (Ishii et al, 1994), and 3) reduce neuronal loss following brain ischemia (Guan et al, 1995).…”

“…Evidence indicates that mRNAs for both IGFs are reduced in the aged rat brain, whereas IGF-I receptor mRNA is upregulated in the rat hippocampus as a function of aging and cognitive deficits (Park and Buetow, 1991;Kitraki et al, 1993;Stenvers et al, 1996). Studies with animal models of brain injury, some of which are of relevance to AD, suggest possible involvement of IGFs in the repair of damaged nervous tissues (Gluckman et al, 1993;Kar et al, 1993a;Breese et al, 1996;Woods et al, 1998). Furthermore, a number of in vitro studies indicated that IGFs, particularly IGF-I, protect cultured neurons against toxicity induced by hydrogen peroxide, glucose deprivation and A␤ peptides (Cheng and Mattson, 1992;Doré et al, 1997b).…”

Insulin‐like growth factor‐I gene therapy increases hippocampal neurogenesis, astrocyte branching and improves spatial memory in female aging rats

“…Thus, IGF‐I is known to be induced in the central nervous system (CNS) after ischemia (Beilharz et al ., ), neocortical lesions (Walter et al ., ; Li et al ., ) and spinal cord injury (Yao et al ., ). Cytotoxic damage to the hippocampus is associated with a large increase in the production of IGF‐I and IGF‐I binding protein 2, by the microglia, a finding that suggests a neuroprotective role of IGF‐I in the brain (Breese et al ., ). Intracerebroventricular (ICV) infusion of IGF‐I in the lateral ventricle improves reference and working memory in aging rats (Markowska et al ., ).…”

A unifying hypothesis of Alzheimer's disease. II. Pathophysiological processes

“…IGFBP-6 seems to inhibit IGF action and has been implicated in growth inhibition [Babajko et al, 1997]. Since upregulation of the brain IGFBP-2 has been characterized as an injury-related response [Klempt et al, 1992;Breese et al, 1996] this ®nding is in keeping with the metabolic stress state of AD and possibly indicates a functional de®ciency of IGFs in the brain. An intriguing, but not yet investigated, possibility may be that the IGFBPs are phosphorylated which transforms them into inhibitors of the IGF action [Coverley and Baxter, 1997].…”