ASTROCYTES EXPRESS INSULIN-LIKE GROWTH-FACTOR-I (IGF-I) AND ITS BINDING-PROTEIN, IGFBP-2, DURING DEMYELINATION INDUCED BY EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

To assess the distribution of insulin-like growtn-factor-related prote ins during autoimmune CNS demyelination and remyelination, experimenta l autoimmune encephalomyelitis was produced by injecting Lewis rats wi th an emulsion containing guinea pig spinal cord and complete Freund's adjuvant. Tail weakness appeared at 10-12 days and was followed by hi nd and forelimb weakness. Paraplegia and incontinence were observed in some animals. From 8-40 days postinoculation (dpi), spinal cord secti ons were used to correlate lesion location and severity with mRNA dist ributions of insulin-like growth factor I (IGF-I), IGF-binding protein 2 (IGFBP-2), IGF-I-receptor (IGFR-I), glial fibrillary acidic protein (GFAP), and myelin basic protein (MBP). These were determined semiqua ntitatively by in situ hybridization. Fourteen dpi, there were inflamm atory infiltrates and demyelination in both white matter (WM) and grey matter (GM). IGF-I and GFAP mRNAs were increased in these lesions and transcripts encoding myelin basic protein (MBP) were greatly reduced. Large lesions with extensive demyelination were evident in both WM an d GM when mRNA levels of GFAP and IGF-I peaked 26 dpi. MBP mRNA levels began increasing 21 dpi and peaked 26 dpi, when a few thin regenerati ng myelin sheaths were found morphologically. Astrocytes, identified b y their morphology and GFAP immunoreactivity, expressed very low level s of IGFBP-2 mRNA and peptide in normal controls; their levels were si gnificantly higher 14 dpi, peaked 26 dpi, and then gradually decreased . Some neurons, as well as oligodendroglia in areas undergoing remyeli nation, expressed IGFR-I. Although levels of IGF-I, IGFBP-2, and GFAP mRNAs were highest in lesion areas, levels were also elevated around l esions and in some normal-appearing areas of WM and GM 14-40 dpi. The gene expression of both IGF-I and IGFBP-2 by hypertrophic GFAP-positiv e astrocytes was demonstrated 14-40 dpi by combined in situ hybridizat ion and immunocytochemistry as well as by double immunostaining. Coexp ression of IGF-I and IGFBP-2 in the same astrocyte was a frequent find ing. Relative increases in both IGF-I, GFAP, IGFBP-2, IGFR-I, and MBP mRNAs peaked at about the same time. This suggests that during lesion progression and recovery, astrocytic expression of IGF-I-related pepti des may reduce immune-mediated myelin injury. We also suggest that ast rocytic IGFBP-2 in lesions may help target IGF-I to IGFR-I-expressing oligodendrocytes and promote remyelination of demyelinated axons. (C) 1994 Academic Press, Inc.