Insulin-like growth factor-I for the treatment of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects both upper and lower motorneurons (MN) resulting in weakness, paralysis and subsequent death. Insulin-like growth factor-I (IGF-I) is a potent neurotrophic factor that has neuroprotective properties in the central and peripheral nervous systems. Due to the efficacy of IGF-I in the treatment of other diseases and its ability to promote neuronal survival, IGF-I is being extensively studied in ALS therapeutic trials. This review covers in vitro and in vivo studies examining the efficacy of IGF-I in ALS model systems and also addresses the mechanisms by which IGF-I asserts its effects in these models, the status of the IGF-I system in ALS patients, results of clinical trials, and the need for the development of better delivery mechanisms to maximize IGF-I efficacy. The knowledge obtained from these studies suggests that IGF-I has the potential to be a safe and efficacious therapy for ALS.

Figure 1

Mutliple facets of research on IGF-I efficacy for ALS. Numerous approaches have been taken in an attempt to understand the mechanisms and therapeutic efficacy of IGF-I in ALS. Studies range from in vitro and in vivo studies to patient and clinical trials have all contributed to our understanding of how IGF-I functions in the cells affected by ALS and have offered insight into the clinical potential of IGF-I for ALS therapy. Results at these multiple levels will be discussed in this review.

Figure 2

IGF-I receptor expression in primary motor neurons. Purified MN in culture express IGF-IR. After one or seven days in culture, MN were fixed and double-stained for IGF-IR and the MN markers SMI-32 or islet-1. The figure shows representative MN identified by the islet-1 marker. The axons appear shorter and less mature at one day than seven days and there was no change in IGF-IR expression or islet-1 over time. MN were double-labeled for islet-1 in the cell body and IGF-IR throughout the cell and notably in punctate sites on the axons. After seven days, most of the punctate localizations of IGF-IR are at the ends of the axons. Using two MN markers (SMI-32 and islet-1) also demonstrated colocalization in the same cells (not shown). (Reproduced with permission from (16)).

Figure 3

Sites and mechanisms of IGF-I action in ALS. IGF-I can impact various aspects of MN degeneration and survival in ALS. IGF-I effects are mediated in MN, muscle and glia via activation of the IGF-IR, subsequent activation of IRS, and downstream activation of major survival-related pathways including PI3K/Akt and p44/42 MAPK signaling pathways (as represented in the MN cell body). Activation of these pathways can function in an autocrine manner directly promoting the survival of the MN themselves, or act in a paracrine fashion through its effects on support cells by mediating the release of toxic or inflammatory molecules, or on muscle fibers functioning to aid in maintenance of neuromuscular junctions and ultimately MN survival. One, or likely all, of these effects could be key players in the role of IGF-I as an efficacious therapy for ALS.