Insulin-like Growth Factor-I: Potential for Treatment of Motor Neuronal Disorders

• Published in: Experimental neurology Vol. 124; no. 1; pp. 73 - 88
• Main Authors: Lewis, Michael E., Neff, Nicola T., Contreras, Patricia C., Stong, David B., Oppenheim, Ronald W., Grebow, Peter E., Vaught, Jeffry L.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.11.1993; Elsevier
• Subjects: Amino Acid Sequence; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Biological and medical sciences; Cell Survival; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Humans; Insulin-Like Growth Factor I - pharmacology; Insulin-Like Growth Factor I - therapeutic use; Medical sciences; Models, Biological; Molecular Sequence Data; Motor Neuron Disease - drug therapy; Motor Neuron Disease - physiopathology; Motor Neurons - cytology; Motor Neurons - drug effects; Motor Neurons - physiology; Nervous System - drug effects; Nervous System Physiological Phenomena; Neurology; Receptor, IGF Type 1 - physiology; Nervous system diseases; Toxicity; Motor neuron disease; Biological activity; Chemotherapy; Treatment; Polypeptide; Central nervous system disease; Somatomedin; Degenerative disease; Mechanism of action; Spinal cord disease; Growth factor
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1006/exnr.1993.1177

Motor neuronal disorders, such as the loss of spinal cord motor neurons in amyotrophic lateral sclerosis or the degeneration of spinal cord motor neuron axons in certain peripheral neuropathies, present a unique opportunity for therapeutic intervention with neurotrophic proteins. Normally, such proteins do not cross the blood-brain barrier, but spinal cord motor neuron axons and nerve terminals lie outside the barrier and thus may be targeted by systemic administration of protein growth factors. Insulin-like growth factor-I (IGFI) receptors are present in the spinal cord, and, like members of the neurotrophin receptor family, IGF-I receptors mediate signal transduction via a tyrosine kinase domain. IGF-I was found to prevent the loss of choline acetyltransferase activity in embryonic spinal cord cultures, as well as to reduce the programmed cell death of motor neurons in vivo during normal development or following axotomy or spinal transection. Consistent with earlier reports that IGF-I enhances motor neuronal sprouting in vivo, subcutaneous administration of IGF-I increases muscle endplate size in rats. Subcutaneous injections of IGF-I also accelerate functional recovery following sciatic nerve crush in mice, as well as attenuate the peripheral motor neuropathy induced by chronic administration of the cancer chemotherapeutic agent vincristine in mice. Doses of IGF-I that accelerate recovery from sciatic nerve crush in mice result in elevated serum levels of IGF-I which are similar to those obtained following subcutaneous injections of formulated recombinant human IGF-I (Myotrophin) in normal human subjects. Based on these findings, together with evidence of safety in animals and man, clinical trials of recombinant human IGF-I have been initiated in patients with amyotrophic lateral sclerosis and are planned to begin soon in patients with chemotherapy-induced peripheral neuropathies.