Mechanisms of cell death of neural progenitor cells caused by trophic support deprivation

Niidome, Takuro; Morimoto, Noriko; Iijima, Sohgo; Akaike, Akinori; Kihara, Takeshi; Sugimoto, Hachiro

doi:10.1016/j.ejphar.2006.07.052

Cited by 7 publications

(5 citation statements)

References 38 publications

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“…All the mechanisms known to disturb motor neuron in ALS (oxidative damage, mitochondrial dysfunction, growth factor deficiency, glial cell pathology, and glutamate excitotoxicity) constitute therapeutic targets of EGF neuroprotective mechanisms (Niidome et al 2006;Peng et al 1998;Yamada et al 1995;Matthieu et al 1992;Hicks et al 1998;Dreyfus et al 1998). EGF has also demonstrated to exhibit protective action against glutamic acid excitotoxicity probably by increasing glutamate re-uptake (Casper and Blum 1995), what it is one of the most relevant targets related to ALS pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…EGF protects neurons and other cells against apoptosis (Casper and Blum 1995;Niidome et al 2006;Peng et al 1998;Satoh et al 1998) and versus glutamic acid exitotoxicity (Casper and Blum 1995). GHRP-6 induces insulin growth factor-1 (IGF-1) expression in different areas of the CNS (Frago et al 2005).…”

Section: Introductionmentioning

confidence: 97%

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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“…The EGF+GHRP6 combined therapy for stroke was designed to activate a cascade of endogenous neuroprotection mechanisms, including regeneration of adult neural stem cells and repair in the penumbra zone ( 26 – 31 , 57 , 71 , 72 ). The activation of these pathways could explain the clinical (neurological, functional, and survival) outcomes evidenced in this study, which had been previously demonstrated in stroke animal models ( 17 – 19 ).…”

Section: Discussionmentioning

confidence: 99%

“…Both molecules cross the blood-brain barrier ( 20 – 23 ), and their receptors are widely distributed in brain tissues ( 24 , 25 ). EGF and GHRP6 share common properties such as anti-apoptotic ( 26 , 27 ) and anti-excitotoxic effects ( 28 , 29 ). In addition, both molecules have independent biological effects.…”

Section: Introductionmentioning

confidence: 99%

Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

Hernández-Bernal,

Estenoz-García,

Gutiérrez-Ronquillo

et al. 2024

Front. Neurol.

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ObjectiveThis study tested the hypothesis that a neuroprotective combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) could be safe for acute ischemic stroke patients, admitting up to 30% of serious adverse events (SAE) with proven causality.MethodsA multi-centric, randomized, open-label, controlled, phase I-II clinical trial with parallel groups was conducted (July 2017 to January 2018). Patients aged 18–80 years with a computed tomography-confirmed ischemic stroke and less than 12 h from the onset of symptoms were randomly assigned to the study groups I (75 μg rEGF + 3.5 mg GHRP6 i.v., n=10), II (75 μg rEGF + 5 mg GHRP6 i.v., n=10), or III (standard care control, n=16). Combined therapy was given BID for 7 days. The primary endpoint was safety over 6 months. Secondary endpoints included neurological (NIHSS) and functional [Barthel index and modified Rankin scale (mRS)] outcomes.ResultsThe study population had a mean age of 66 ± 11 years, with 21 men (58.3%), a baseline median NIHSS score of 9 (95% CI: 8–11), and a mean time to treatment of 7.3 ± 2.8 h. Analyses were conducted on an intention-to-treat basis. SAEs were reported in 9 of 16 (56.2%) patients in the control group, 3 of 10 (30%) patients in Group I (odds ratio (OR): 0.33; 95% CI: 0.06–1.78), and 2 of 10 (20%) patients in Group II (OR: 0.19; 95% CI: 0.03–1.22); only two events in one patient in Group I were attributed to the intervention treatment. Compliance with the study hypothesis was greater than 0.90 in each group. Patients treated with EGF + GHRP6 had a favorable neurological and functional evolution at both 90 and 180 days, as evidenced by the inferential analysis of NIHSS, Barthel, and mRS and by their moderate to strong effect size. At 6 months, proportion analysis evidenced a higher survival rate for patients treated with the combined therapy. Ancillary analysis including merged treated groups and utility-weighted mRS also showed a benefit of this combined therapy.ConclusionEGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study.Clinical Trial RegistrationRPCEC00000214 of the Cuban Public Registry of Clinical Trials, Unique identifier: IG/CIGB-845I/IC/1601.

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“…19 There are some indications of a potential therapeutic option of GHRP-6 in the prevention and treatment of heart failure, 20,21 an effect that seems to be related to an enhanced non-ischemic compensatory mechanism and mediated via specic GH secretagogue receptors rather than via the GH/IGF-1 pathway. Besides, a recent study indicates that the combined administration of the GHRP-6 peptide and EGF (epidermal growth factor), which can protect cells from apoptosis, 22 resulted in an effective alternative for recovery from amyotrophic lateral sclerosis (ALS), 23 although further preclinical investigation must be carried out. 23 Of note, ALS is a central nervous system (CNS) disease characterized by irreversible loss of spinal motor neurons with an evolution of the patient to death in a few years, 24,25 with no effective treatment reported until now.…”

Section: Introductionmentioning

confidence: 99%

How does growth hormone releasing hexapeptide self-assemble in nanotubes?

et al. 2014

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Growth hormone releasing peptide, GHRP-6, a hexapeptide (His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH2, MW = 872.44 Da) that belongs to a class of synthetic growth hormone secretagogues, can stimulate growth hormone secretion from somatotrophs in several species including humans. In the present study, we demonstrate that GHRP-6 dispersed in aqueous solution, at pH 7.0, room temperature of 22 °C, is able to form long nanotubes, which is evidenced by combining small angle X-ray scattering (SAXS), transmission electron microscopy and molecular dynamics simulation results. Such nanotubes possess inner and outer cross-sections equal to 6.7(2) nm and 13.4(5) nm, respectively. The mechanism of peptide self-assembly was determined by molecular dynamics simulations revealing that the peptides self-assemble like amphiphilic molecules in aqueous solution in a partially interdigitated structure. In this case, the position of the positively charged amino terminus is located at the peptide-water interface, whereas the neutral NH2-capped carboxy terminus remains buried at the hydrophobic core. In contrast, the long side chain of Lys-6 stretches out of the hydrophobic core positioning its positive charge near the cylinder surface. The peptide configuration in the nanotube wall comes from the interplay between the hydrophobic interactions of the aromatic side chains of GHRP-6 and the electrostatic repulsion of its cationic charges. On increasing the peptide concentration, the long nanotubes self-arrange in solution displaying a bi-dimensional hexagonal-like packing in the SAXS curves, with a center-to-center distance of ∼15 nm. Further, we also show that the nanostructure formed in solution is quite stable and is preserved following transfer to a solid support.

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Mechanisms of cell death of neural progenitor cells caused by trophic support deprivation

Cited by 7 publications

References 38 publications

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

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

Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

How does growth hormone releasing hexapeptide self-assemble in nanotubes?

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