Abstract
With our increasing appreciation of the true complexity of diseases and pathophysiologies, it is clear that this knowledge needs to inform the future development of pharmacotherapeutics. For many disorders, the disease mechanism itself is a complex process spanning multiple signaling networks, tissues, and organ systems. Identifying the precise nature and locations of the pathophysiology is crucial for the creation of systemically effective drugs. Diseases once considered constrained to a limited range of organ systems, e.g., central neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’ disease (HD), the role of multiple central and peripheral organ systems in the etiology of such diseases is now widely accepted. With this knowledge, it is increasingly clear that these seemingly distinct neurodegenerative disorders (AD, PD, and HD) possess multiple pathophysiological similarities thereby demonstrating an inter-related continuum of disease-related molecular alterations. With this systems-level appreciation of neurodegenerative diseases, it is now imperative to consider that pharmacotherapeutics should be developed specifically to address the systemic imbalances that create the disorders. Identification of potential systems-level signaling axes may facilitate the generation of therapeutic agents with synergistic remedial activity across multiple tissues, organ systems, and even diseases. Here, we discuss the potentially therapeutic systems-level interaction of the glucagon-like peptide 1 (GLP-1) ligand–receptor axis with multiple aspects of the AD, PD, and HD neurodegenerative continuum.
Highlights
Heptahelical G protein-coupled receptors (GPCRs) represent perhaps the most important single-protein class of pharmacotherapeutic targets
It has been demonstrated that intracerebrovascular injection of ghrelin improved cognitive ability in streptozotocin-induced diabetic-rats by increasing the expression of cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), and by attenuating the neuronal apoptosis in the hippocampus [27, 50]. These findings suggested that ghrelin plays a pivotal role in metabolic control and in regulating cognitive function and memory capacity
With respect to a receptor signaling that may be preferentially involved in regulating the generic neurodegenerative “super-axis” system, we have identified a potential ligand–receptor system, the glucagon-like peptide 1 (GLP-1) system that may be critical for regulating pathophysiology, and facilitating potential neurodegenerative remediation
Summary
Heptahelical G protein-coupled receptors (GPCRs) represent perhaps the most important single-protein class of pharmacotherapeutic targets. Given the recent emergence of appreciation of the importance of metabolic support to diseases such as AD, PD, and HD [107, 114, 122], it is evident that advanced therapeutic control of the GLP-1 super-axis could generate an excellent capacity to generate whole-organism systemic therapeutic actions.
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