Glucagon-like peptide 1 receptor activation: anti-inflammatory effects in the brain

Abstract

The glucagon-like peptide 1 is a pleiotropic hormone that has potent insulinotropic effects and is key in treating metabolic diseases such as diabetes and obesity. Glucagon-like peptide 1 exerts its effects by activating a membrane receptor identified in many tissues, including different brain regions. Glucagon-like peptide 1 activates several signaling pathways related to neuroprotection, like the support of cell growth/survival, enhancement promotion of synapse formation, autophagy, and inhibition of the secretion of proinflammatory cytokines, microglial activation, and apoptosis during neural morphogenesis. The glial cells, including astrocytes and microglia, maintain metabolic homeostasis and defense against pathogens in the central nervous system. After brain insult, microglia are the first cells to respond, followed by reactive astrocytosis. These activated cells produce proinflammatory mediators like cytokines or chemokines to react to the insult. Furthermore, under these circumstances, microglia can become chronically inflammatory by losing their homeostatic molecular signature and, consequently, their functions during many diseases. Several processes promote the development of neurological disorders and influence their pathological evolution: like the formation of protein aggregates, the accumulation of abnormally modified cellular constituents, the formation and release by injured neurons or synapses of molecules that can dampen neural function, and, of critical importance, the dysregulation of inflammatory control mechanisms. The glucagon-like peptide 1 receptor agonist emerges as a critical tool in treating brain-related inflammatory pathologies, restoring brain cell homeostasis under inflammatory conditions, modulating microglia activity, and decreasing the inflammatory response. This review summarizes recent advances linked to the anti-inflammatory properties of glucagon-like peptide 1 receptor activation in the brain related to multiple sclerosis, Alzheimer's disease, Parkinson's disease, vascular dementia, or chronic migraine.

Figure 1

Downstream GLP-1 receptor activation signaling. Downstream GLP-1 receptor activation of the GLP-1 receptor promotes several cell-signaling cascades involved in GLP-1RAS effects: memory formation, synapse repair, neuroprotection, activation of Ca²⁺, and regeneration of neurotransmitter release. Reprinted with permission from Diz-Chaves et al. (2022b). AC: Adenylate cyclase; AMPK: AMP-activated protein kinase; Bax, Bik: Bcl2-interacting killer; Ca²⁺: calcium ions; c-Raf: cellular Raf gene (rapidly accelerated fibrosarcoma); CREB: cyclic AMP response element-binding protein; EPAC: exchange proteins directly activated by cAMP; ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase; MEK1/2: MAPK or Erk kinases; mTOR: mammalian target of rapamycin; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; P90RSK: ribosomal S6 kinase; PGC1α: peroxisome proliferator-activated receptor γ co-activator; PI3K: phospho- inositide 3 kinase; PKB: protein kinase B; PKC: protein kinase C; PKD: protein kinase D; SIRT1: sirtuin 1.

Figure 2

The activation of the GLP-1 receptor induces anti-inflammatory effects. The activation of the GLP-1 receptor by GLP-1 Ras promotes several anti-inflammatory mechanisms. Reprinted with permission from Diz-Chaves et al. (2022b). AMPK: Adenosine monophosphate-activated protein kinase; ASC: apoptosis-associated speck-like protein containing a CARD; GSMD: gasdermin D; ICAM: intracellular adhesion molecule-1; IKKK: IκB kinase kinase; IKKβ: IκB kinase β; IL-1β: interleukin-1β; IL-2: interleukin-2; IL-6: interleukin-6; MCP1: monocyte chemoattractant protein 1; NAD/NADH: nicotinamide adenine dinucleotide; NEK7: NIMA related kinase 7; NFκB: nuclear factor kappa B; pro-IL-18: pro-interleukin-18; pro-IL-1β: pro-interleukin-1β; SIRT1 sirtuin 1; VCAM: vascular cell adhesion molecule-1.

Figure 3

Chronic microglia activation facilitates changes in the astrocyte phenotype to the reactive A1. Microgliosis and astrocytosis induced by neurodegenerative diseases are blocked by GLP-1 receptor activation. Reprinted with permission from Diz-Chaves et al. (2022b). BAFF: B cell-activating factor of the TNF family; CCL2: C-C motif chemokine ligand 2; CCL5: CC chemokine ligand 5; Cq1: complement component 1q; CXCL-1: chemokine (C-X-C motif) ligand 1; CXCL2: chemokine (C-X-C motif) ligand 2; CXCL4: chemokine (C-X-C motif) ligand 4; IL-12: interleukin-12; IL-1β: interleukin-1β; IL-23: interleukin-23; IL-33: interleukin-33; IL-6: interleukin-6; NO: nitric oxide; ROS: reactive oxygen species; TNF-α: tumor necrosis factor α; VEGFB: vascular endothelial growth factor-B.