The pleiotropic of GLP-1/GLP-1R axis in central nervous system diseases

AbstractGlucagon-like peptide-1(GLP-1) is a multifunctional polypeptide throughout the lifespan via activating Glucagon-like peptide-1 receptor (GLP-1R).GLP-1 can affect food ingestion, enhance the secretion of insulin from pancreatic islets induced by glucose and be utilized to treat type 2 diabetes mellitus(T2DM).But, accumulating evidences from the decades suggest that activation GLP-1R can not only regulate the blood glucose, but also sustain the homeostasis of intracellular environment and protect neuron from various damaged responses such as oxidative stress, inflammation, excitotoxicity, ischemia and so on. And more and more pre-clinical and clinical studies identified that GLP-1 and its analogues may play a significant role in improving multiple central nervous system (CNS) diseases including neurodegenerative diseases, epilepsy, mental disorders, ischemic stroke, hemorrhagic stroke, traumatic brain injury, spinal cord injury, chronic pain, addictive disorders, other diseases neurological complications and so on. In order to better reveal the relationship between GLP-1/GLP-1R axis and the growth, development and survival of neurons, herein, this review is aimed to summarize the multi-function of GLP-1/GLP-1R axis in CNS diseases.Keywords: GLP-1GLP-1RCNS diseasesneuroprotection AcknowledgementsWe thank all colleagues for their contributions to this review.Disclosure statementAuthors declare no conflict of interest.Figure 1. Cerebral GLP-1s drive from multiple sources. GLP-1s from PPG neurons, as a peptide neurotransmitter, regulate the function of various brain nuclei via activating GLP-1Rs.Periperal treatment with GLP-1R agonists can permeate BBB and get access to cerebral nuclei, besides this, intestinal GLP-1s secreted by L cells cooperation with intestinal microorganisms transport to cerebrum for neuroprotection through Gut-Brain-axis.Display full sizeFigure 2. Aβ deposition and tau hyperphosphorylation are the main pathophysiological changes of AD. BACE1 can catalyze the APP cleavage at β-site, which induces the production of Aβ. GlcNAc can inhibit the degradation of BACE1 by lysosome and GlcNAc is the enzymatic product of GnT-Ш (a glycosyltransferase), furthermore, the level of GnT-Ш is increased in AD patients. However, GLP-1/GLP-1R axis can improve AD via activating AKt/GSK-3β/β-catenin pathway, which can inhibit GnT-Ш/GlcNAc/BACE1 cascades. Defective brain insulin signaling, such as elevated levels of serine phosphorylation of insulin receptor substrate -1 (IRS-1pSer), has been proven to contribute to the cognitive disability in patients with AD. Double-stranded RNA-dependent protein kinase (PKR) and IκB kinase (IKK) are two stress-sensitive kinases that mediate serine phosphorylation of IRS-1.GLP-1R activation can sustain normal insulin signaling through reversing the increased IRS-1pSer and the decreased IRS-1pTyr by attenuating the elevated pJNK, PKR, pIKKβ induced by Aβ oligomers.Display full sizeFigure 3. Activation of GLP-1/GLP-1R signaling pathway can promote neurons growth, survival, repair and protect cells from inflammation, oxidative stress as well as adjust apoptosis, autophagy mediated with regulating multiple signal pathways, which is favourable to improve multiple CNS disorders including AD, PD, HD, stroke, SCI, TBI, hyperalgesia and so on.Display full sizeFigure 4. GLP-1R activation can enhance the activity of adenylate cyclase (AC) and activate cAMP/PKA/CREB signaling pathway which can maintain the CNS homostasis, protect neurons from numerous injurious reactions and promote the neurovascular reconstruction that is beneficial to attenuate various CNS diseases. In addition to this, GLP-1/GLP-1R signaling axis can keep the balance of neurotransmitters including excitatory and inhibitory, monoamine neurotransmitters, which can enhance synaptic plasticity, inhibit abnormal neuroelectric activity and relieve excitotoxicity that is advantageous to improve epilepsy, schizophrenia, anxiety and depression and so on.Display full sizeAdditional informationFundingThis work was financially supported by grants from National Natural Science Foundation of China 81571053 and 81974170.