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Potential Applications for Growth Hormone Secretagogues Treatment of Amyotrophic Lateral Sclerosis
Ramona Meanti1, Elena Bresciani1, Laura Rizzi1
1School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza, 20900, Italy.
Abstract:
Amyotrophic lateral sclerosis (ALS) arises from neuronal death due to complex interactions of genetic, molecular, and environmental factors. Currently, only two drugs, riluzole and edaravone, have been approved to slow the progression of this disease. However, ghrelin and other ligands of the GHS-R1a receptor have demonstrated interesting neuroprotective activities that could be exploited in this pathology. Ghrelin, a 28-amino acid hormone, primarily synthesized and secreted by oxyntic cells in the stomach wall, binds to the pituitary GHS-R1a and stimulates GH secretion; in addition, ghrelin is endowed with multiple extra endocrine bioactivities. Native ghrelin requires esterification with octanoic acid for binding to the GHS-R1a receptor; however, this esterified form is very labile and represents less than 10% of circulating ghrelin. A large number of synthetic compounds, the growth hormone secretagogues (GHS) encompassing short peptides, peptoids, and non-peptidic moieties, are capable of mimicking several biological activities of ghrelin, including stimulation of GH release, appetite, and elevation of blood IGF-I levels. GHS have demonstrated neuroprotective and anticonvulsant effects in experimental models of pathologies both in vitro and in vivo. To illustrate, some GHS, currently under evaluation by regulatory agencies for the treatment of human cachexia, have a good safety profile and are safe for human use. Collectively, evidence suggests that ghrelin and cognate GHS may constitute potential therapies for ALS.
Insights
Ghrelin and growth hormone secretagogues (GHS) show neuroprotective potential for amyotrophic lateral sclerosis (ALS). These compounds may offer new therapeutic avenues for ALS patients, complementing existing treatments.
Area of Science:
- Neuroscience
- Endocrinology
- Pharmacology
Background:
- Amyotrophic lateral sclerosis (ALS) involves complex neuronal death, with limited approved treatments like riluzole and edaravone.
- Ghrelin and its receptor (GHS-R1a) ligands exhibit neuroprotective properties relevant to ALS pathology.
- Native ghrelin's therapeutic use is limited by its labile esterified form.
Purpose of the Study:
- To explore the potential of ghrelin and growth hormone secretagogues (GHS) as novel therapies for amyotrophic lateral sclerosis (ALS).
- To review the neuroprotective activities and therapeutic implications of GHS-R1a receptor ligands in neurodegenerative diseases.
Main Methods:
- Review of existing literature on ghrelin, GHS, and their effects in experimental models.
- Analysis of GHS safety profiles and efficacy in preclinical studies.
- Examination of GHS-R1a receptor interactions and downstream signaling pathways.
Main Results:
- Ghrelin and synthetic GHS demonstrate significant neuroprotective and anticonvulsant effects in various experimental models.
- Certain GHS compounds possess favorable safety profiles and are suitable for human use, with some under regulatory evaluation for cachexia.
- GHS mimic ghrelin's biological activities, including growth hormone secretion and appetite stimulation.
Conclusions:
- Ghrelin and its cognate growth hormone secretagogues (GHS) represent promising therapeutic candidates for amyotrophic lateral sclerosis (ALS).
- Further research into GHS-R1a receptor modulation could lead to effective treatments for neurodegenerative conditions like ALS.
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