Circulating insulin-like growth factors and related binding proteins are selectively altered in amyotrophic lateral sclerosis and multiple sclerosis

Hosback, Sharah; Hardiman, Orla; Nolan, Catherine M.; Doyle, Maria A.; Gorman, G.; Lynch, Catherine; O’Toole, Orna; Jakeman, Philip M.

doi:10.1016/j.ghir.2007.06.002

Cited by 42 publications

(39 citation statements)

References 38 publications

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“…Previous cross-sectional studies in ALS patients showed normal IGFBP-3 levels as compared with controls [2,13,[18][19][20]. In our study, basal levels of IGFBP-3 were increased in ALS patients, and this was an unexpected finding since GH deficit is usually associated with lower IGFBP-3 levels [21].…”

Section: Discussionsupporting

confidence: 67%

A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results

et al. 2011

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Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease with motor neuron degeneration. Riluzole is the only available treatment. Two-thirds of ALS patients present with growth hormone (GH) deficiency. The aim of this study is to determine if add-on of GH to riluzole, with an individually regulated dose based on Insulin-like growth factor 1 (IGF-I) production, was able to reduce neuronal loss in the motor cortex, reduce mortality, and improve motor function of ALS patients. Patients with definite/probable ALS, in treatment with riluzole, aged 40-85 years, and with disease duration ≤3 years were enrolled. The study was randomized, placebo controlled, and double blind. Before treatment, patients were tested with a GH releasing hormone (GHRH) + arginine test. The initial dose of GH was 2 IU s.c. every other day, and was progressively increased to a maximum of 8 IU. Primary endpoint was N-acetylaspartate/(creatine + choline) (NAA/Cre + Cho) ratio in motor cortex assessed by magnetic resonance spectroscopy performed at months 0, 6, and 12. Secondary endpoints were mortality and ALS functional rating scale revised (ALSFRS-R). The NAA/(Cre + Cho) ratio decreased in all patients who completed the trial. No significant difference was noted between treated and placebo group. At baseline, although IGF-I levels were within the normal range, 73% of patients had GH deficiency, being severe in half of them. Compared with bulbar onset, spinal-onset patients showed more depressed GH response to the GHRH + arginine stimulation test (10.4 ± 7.0 versus 15.5 ± 8.1 ng/mL; p < 0.05). Insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] increased from 2.1 ± 1.0 at baseline to 4.6 ± 1.9 at 12 months (p < 0.001). Insulin-like growth factor (IGF) binding protein 3 (IGFBP-3) decreased from 8,435 ± 4,477 ng/mL at baseline to 3,250 ± 1,780 ng/mL at 12 months (p < 0.001). The results show that GH exerted no effect on cerebral NAA or clinical progression assessed by ALSFRS-R. Two-thirds of ALS patients had GH deficit, with higher levels in the bulbar-onset group. During follow-up, patients showed progressive increase in HOMA-IR and decrease in IGFBP-3 levels.

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Section: Discussionsupporting

confidence: 67%

A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results

et al. 2011

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“…Moreover, the soluble muscleand nerve-derived neurotropic factors IGF-I and IGF-II stimulate proteins-synthesis, promote survival and differentiation of motor neurons, and mediate anti-apoptotic signalling by inducting mitogen activated protein kinases (MAPK) as well as PI3K/AKT/mTOR signalling [140,141]. IGF-I levels were higher and IGF-II levels were significantly lower in patients with ALS than in healthy controls [142,143], suggesting that motor neuron degeneration could lead to a compensatory increase in IGF-I to provide additional support for motor neurons. On the other hand, decreased IGF-I levels were also found in cerebrospinal fluid of ALS patients [144], however, methodological differences and the lack of age-, gender-and BMI-matched control populations in these studies may account for these discrepancies.…”

Section: Endoplasmin (Grp94)mentioning

confidence: 99%

Calcium-dependent protein folding in amyotrophic lateral sclerosis

2013

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“…Basically, GHRP-6's neuroprotective effect is mediated by the induction of IGF-1 expression in some regions of CNS (de Delgado-Rubin et al 2006;Frago et al 2002). This fact represents a major advantage as in ALS has been demonstrated a significant increase of IGF-1-binding proteins (IGFBP) (Hosback et al 2007;Torres-Aleman et al 1998), which scavenge and clear the constitutive or exogenously administered IGF-1 precluding it to reach its target in the brain. IGF-1 is a bonna fide neurotrophic factor.…”

Section: Discussionmentioning

confidence: 99%

“…GHRP-6 induces insulin growth factor-1 (IGF-1) expression in different areas of the CNS (Frago et al 2005). IGF-1 is a well known important neurotrophic factor in both ALS and ALS's animal models (Lepore et al 2007;Lai et al 1997;Kaspar et al 2003;Hosback et al 2007). …”

Section: Introductionmentioning

confidence: 99%

Therapeutic Effect of the Combined Use of Growth Hormone Releasing Peptide-6 and Epidermal Growth Factor in an Axonopathy Model

et al. 2010

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Amyotrophic lateral sclerosis (ALS) is a disease of the central nervous system characterized by loss of spinal motor neurons, for which no effective treatment exists. Epidermal growth factor (EGF) and growth hormone releasing peptide-6 (GHRP-6) have been considered as good candidates for the treatment of this disease, due to their well documented effects in eliciting pleiotrophic and cell survival mechanisms. The aim of the present work was to evaluate the separate and combined effects of both peptides in an experimental animal model of ALS, the proximal axonopathy induced by 1,2 diacetylbenzene (1,2 DAB) in mice. The evaluations were conducted by means of behavioral tests (trapeze, tail suspension, gait pattern, and open field) and by recording the complex muscle action potential (CMAP) in three different hind limb segments: proximal S1, medial S2, and distal S3. Intraperitoneal daily administration of 1,2 DAB produced significant reduction in body weight, muscle strength, extensor reflex, spontaneous activity, and changes in gait pattern parameters. In parallel 1,2 DAB produced significant prolongation of onset latency and decrease in amplitude of CMAP and in the integrated complex action potential index. Daily administration of the separate compounds did not accelerate the recovery of the affected parameters, except for the gait pattern. The combined treatment produced significant improvement in behavioral parameters, as well as in electrophysiological recovery, particularly in the proximal segment of CMAP. The latter results confirm the proximal character of 1,2 DAB neuropathy, and suggest that combined therapy with EGF and GHRP-6 might be a good therapeutic strategy for the treatment of ALS.

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Circulating insulin-like growth factors and related binding proteins are selectively altered in amyotrophic lateral sclerosis and multiple sclerosis

Cited by 42 publications

References 38 publications

A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results

A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results

Calcium-dependent protein folding in amyotrophic lateral sclerosis

Therapeutic Effect of the Combined Use of Growth Hormone Releasing Peptide-6 and Epidermal Growth Factor in an Axonopathy Model

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