Prevention of spinal motor neuron death by IGF-1 associating with the signal transduction systems in SODG93A transgenic mice

Background and aims: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease that is characterized by selective loss of central and peripheral motor neurons. There are many hypotheses about the underlying cause of this disease: one theory is that motor neurons lack crucially needed trophic factors, resulting in neuronal degeneration, cell death, and atrophy of target muscles. The role of insulin-like growth factor-1 (IGF-1) in ALS and its mechanism of action are important from both pathogenic and therapeutic points of view. Methods: The present study investigated the changes of IGF-1R? and the key intracellular downstream protein insulin receptor substrate-1 (IRS-1) using SOD1 G93A transgenic mice with continuous intrathecal IGF-1 injection. We made up the number of mice for the histological studies, non-Tg littermates and Tg mice treated with vehicle, low-dose (0.1mg/kg) or high-dose (1mg/kg) IGF-1 at 240 days of age. Results: The number of lumbar spinal motor neurons was preserved with IGF-1 treatment in a dose dependent manner (1215.0 ± 97.2 ( /mm thickness, mean ± SD) in wild type mice, 281.5 ± 36.4 in Tg mice, 715.0 ± 46.5 in Tg mice with low dose IGF-1 treatment and 900.0 ± 346.7 in Tg mice with high dose). The number of immunopositive motor neurons in the anterior horn for IGF-1R? was not significantly different between wild type and Tg mice. However, treatment of Tg mice with IGF-1 decreased the number of immunopositive motor neurons in a dose-dependent manner with low dose (74.0 ± 9.2) and high dose (20.0 ± 1.6). On the other hand, the percentage of immunopositive motor neurons per total living motor neurons in vehicle treatment mice (69.3 ± 11.6%) was greatly increased as compared with wild type mice (12.3 ± 3.5%). With IGF-1 treatment, the ratios were dramatically decreased in a dose-dependent manner with low dose (10.3 ± 1.4%) and high dose (2.2 ± 1.0%). The number of immunopositive motor neurons in the anterior horn for IRS-1 was 196.5 ± 25.9 in wild type, which were not different in Tg mice (217.5 ± 12.1). In contrast, treatment with IGF-1 decreased the number of immunopositive motor neurons of Tg mice in a dose-dependent manner with low dose (52.8 ± 15.3) and high dose (45.0 ± 7.2). The ratio of immunopositive motor neurons per the total number of living motor neurons for IRS-1 in wild type mice was 16.7 ± 2.6%, which greatly increased to 74.6 ± 13.1% in Tg mice. With IGF-1 treatment, the ratios of immunopositive motor neurons were again dramatically decreased in a dose-dependent manner with low dose (7.3 ± 2.2%) and high dose (5.0 ± 2.4%). Conclusions: We investigated signal transduction systems in SODG93A Tg mice that received continuous intrathecal injection of IGF-1 and observed the percentage of IGF-1R? and IRS-1 immunopositive motor neurons in Tg mice increased then decreased with IGF-1 treatment. These results suggest that IGF-1 treatment prevents motor neuron loss by affecting the signal transduction system through IGF-1R and the main downstream signal IRS-1.