M M Bilak1, A M Corse, R W Kuncl. 1. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-7519, USA.
Abstract
BACKGROUND: Both growth and survival of motor neurons may depend on multiple neurotrophic factors. Individually, insulin-like growth factor I (IGF-I) and glial cell line-derived neurotrophic factor (GDNF) are potent neurotrophic/survival factors for postnatal motor neurons. METHODS: We used an organotypic spinal cord model of glutamatergic degeneration in ALS to investigate whether IGF-I and GDNF interact to enhance motor neuron survival, their trophic effect on choline acetyltransferase (ChAT) activity, and their effect on neurite outgrowth. RESULTS: We show that the combination of IGF-I and GDNF at active doses (1) is additively neuroprotective, (2) completely rescues rat motor neurons from chronic glutamate-mediated toxicity, and (3) additively upregulates motor neuron ChAT activity. Further, IGF-I, which by itself does not promote neurite outgrowth in this model, potentiates the neurite promoting action of GDNF. CONCLUSION: The results predict that IGF-I combined with GDNF may provide a better therapy for the treatment of motor neuron disorders such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy.
BACKGROUND: Both growth and survival of motor neurons may depend on multiple neurotrophic factors. Individually, insulin-like growth factor I (IGF-I) and glial cell line-derived neurotrophic factor (GDNF) are potent neurotrophic/survival factors for postnatal motor neurons. METHODS: We used an organotypic spinal cord model of glutamatergic degeneration in ALS to investigate whether IGF-I and GDNF interact to enhance motor neuron survival, their trophic effect on choline acetyltransferase (ChAT) activity, and their effect on neurite outgrowth. RESULTS: We show that the combination of IGF-I and GDNF at active doses (1) is additively neuroprotective, (2) completely rescues rat motor neurons from chronic glutamate-mediated toxicity, and (3) additively upregulates motor neuron ChAT activity. Further, IGF-I, which by itself does not promote neurite outgrowth in this model, potentiates the neurite promoting action of GDNF. CONCLUSION: The results predict that IGF-I combined with GDNF may provide a better therapy for the treatment of motor neuron disorders such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy.