Therapeutic benefit of intrathecal injection of insulin-like growth factor-1 in a mouse model of amyotrophic lateral sclerosis

Kazunori Miyazaki, Isao Nagano, Hristelina Ilieva, Mito Shiote, Tetsuro Murakami, Masataka Yokoyama, Mikio Shoji, Koji Abe

Research output: Contribution to journalArticle

Abstract

Background. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by selective motor neuron loss and death within 3-5 yaers after onset. Although most of the cases occur sporadically, 10% of these are familial. 10-20% of familial cases are associated with missense mutation or small deletions in the Cu/Zn superoxide disumutase (SOD1) gene, one of the main free radical scavenging enzymes that protects cells against oxidative stress. There are many hypothesis about the cause of this disease. However, the mechanism were still obscure and therapeutic strategies are required.Insulin- like growth factor (IGF)-1 has been shown to have a protective effect on motor neurons both in vitro and in vivo, but has limited efficacy in patients with ALS when given subcutaneously. We hypothesized that direct infusion of IGF-1 into the intrathecal space could improve the drug delivery and may strengthen its efficacy against motor neuron death in ALS. Material and method. To examine the possible effectiveness of IGF-1 in a mouse model of familial ALS, transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) with a G93A mutation were treated by continuous IGF-1 delivery into the intrathecal space of the lumbar spinal cord. Dissolved IGF-1 was give 1 mg/kg body weight/day as a high-dose treatment (n=6) or 100 μg/kg body weight/day as a low-dose treatment (n=6). Five mice were treated with vehicle (aCSF) as controls. Continuous intrathecal infusion into the lumbar spinal cord region was continued at 140 days of age to the end stage of the disease. Rotarod test and wheel-running test was performed for behavioral studies. For histological studies, the region of the spinal cord spanning L4?L5 was segmented and stained for motor neuron counting. For immunohistochemistry, frozen transverse sections were treated with polyclonal antibodies against p-AKT, p-ERK and p-bcl-2. Immunoblot analysis was performed to detect p-AKT and anti-p-ERK. Result. We found that the intrathecal administration of IGF-1 improved motor performance, delayed the onset of clinical disease, and extended survival in the G93A transgenic mice. Furthermore, it increased the expression of phosphorylated Akt and ERK in spinal motor neurons, and partially prevented motor neuron loss in these mice. Discussion and conclusion. Taken together, the results suggest that direct administration of IGF-1 into the intrathecal space may have a therapeutic benefit for ALS. However, it is uncertain whether this treatment is beneficial in human ALS, since the therapy was started before the Tg mice developed the disease. In addition, it is possible that Tg animal models may not reflect the sporadic form of human ALS. Nevertheless, this treatment with IGF-1 could be a new therapeutic strategy for the treatment of human ALS, although the optimal dose and timing for humans remain to be determined in the future.

Original languageEnglish
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue numberSUPPL. 1
Publication statusPublished - Nov 13 2007

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Spinal Injections
Amyotrophic Lateral Sclerosis
Somatomedins
Motor Neurons
Spinal Cord
Therapeutics
Transgenic Mice
Rotarod Performance Test
Body Weight
Frozen Sections
Missense Mutation
Superoxides
Neurodegenerative Diseases
Free Radicals
Oxidative Stress
Animal Models
Immunohistochemistry
Mutation
Survival
Antibodies

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

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Therapeutic benefit of intrathecal injection of insulin-like growth factor-1 in a mouse model of amyotrophic lateral sclerosis. / Miyazaki, Kazunori; Nagano, Isao; Ilieva, Hristelina; Shiote, Mito; Murakami, Tetsuro; Yokoyama, Masataka; Shoji, Mikio; Abe, Koji.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 27, No. SUPPL. 1, 13.11.2007.

Research output: Contribution to journalArticle

Miyazaki, Kazunori ; Nagano, Isao ; Ilieva, Hristelina ; Shiote, Mito ; Murakami, Tetsuro ; Yokoyama, Masataka ; Shoji, Mikio ; Abe, Koji. / Therapeutic benefit of intrathecal injection of insulin-like growth factor-1 in a mouse model of amyotrophic lateral sclerosis. In: Journal of Cerebral Blood Flow and Metabolism. 2007 ; Vol. 27, No. SUPPL. 1.
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AU - Shiote, Mito

AU - Murakami, Tetsuro

AU - Yokoyama, Masataka

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N2 - Background. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by selective motor neuron loss and death within 3-5 yaers after onset. Although most of the cases occur sporadically, 10% of these are familial. 10-20% of familial cases are associated with missense mutation or small deletions in the Cu/Zn superoxide disumutase (SOD1) gene, one of the main free radical scavenging enzymes that protects cells against oxidative stress. There are many hypothesis about the cause of this disease. However, the mechanism were still obscure and therapeutic strategies are required.Insulin- like growth factor (IGF)-1 has been shown to have a protective effect on motor neurons both in vitro and in vivo, but has limited efficacy in patients with ALS when given subcutaneously. We hypothesized that direct infusion of IGF-1 into the intrathecal space could improve the drug delivery and may strengthen its efficacy against motor neuron death in ALS. Material and method. To examine the possible effectiveness of IGF-1 in a mouse model of familial ALS, transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) with a G93A mutation were treated by continuous IGF-1 delivery into the intrathecal space of the lumbar spinal cord. Dissolved IGF-1 was give 1 mg/kg body weight/day as a high-dose treatment (n=6) or 100 μg/kg body weight/day as a low-dose treatment (n=6). Five mice were treated with vehicle (aCSF) as controls. Continuous intrathecal infusion into the lumbar spinal cord region was continued at 140 days of age to the end stage of the disease. Rotarod test and wheel-running test was performed for behavioral studies. For histological studies, the region of the spinal cord spanning L4?L5 was segmented and stained for motor neuron counting. For immunohistochemistry, frozen transverse sections were treated with polyclonal antibodies against p-AKT, p-ERK and p-bcl-2. Immunoblot analysis was performed to detect p-AKT and anti-p-ERK. Result. We found that the intrathecal administration of IGF-1 improved motor performance, delayed the onset of clinical disease, and extended survival in the G93A transgenic mice. Furthermore, it increased the expression of phosphorylated Akt and ERK in spinal motor neurons, and partially prevented motor neuron loss in these mice. Discussion and conclusion. Taken together, the results suggest that direct administration of IGF-1 into the intrathecal space may have a therapeutic benefit for ALS. However, it is uncertain whether this treatment is beneficial in human ALS, since the therapy was started before the Tg mice developed the disease. In addition, it is possible that Tg animal models may not reflect the sporadic form of human ALS. Nevertheless, this treatment with IGF-1 could be a new therapeutic strategy for the treatment of human ALS, although the optimal dose and timing for humans remain to be determined in the future.

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