Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide

Figure 2 Overview of the main pathways induced by a peripheral administration of liraglutide in neurons. When liraglutide enters the body, it will move through the bloodstream and activate glucagon-like peptide-1 receptors (GLP-1R) widely expressed throughout tissues. In pancreas, GLP-1R activation exert insulinotropic effects, thus increasing insulin levels, which may migrate into the brain, crossing the blood-brain-barrier (BBB) and will activate insulin receptor (IR) or insulin-like growth factor-1 receptors (IGF-1R) expressed in neurons. Liraglutide by itself may also cross the BBB and activate GLP-1R present in the brain. Neuronal IR/IGF-1R and GLP-1R mediated intracellular signaling transduction pathways show several overlapping downstream targets. Activation of these pathways may mediate several biological responses in the central nervous system, such as control of cell metabolism and energy homeostasis, inhibition of apoptosis, reduction of inflammatory responses, modulation of synaptic neurotransmission, regulation of gene transcription, cell growth, synapse growth, cell repair and regeneration, facilitation of long-term potentiation and memory formation, among others. AC: Adenyl cyclase; Akt: Protein kinase B; Bcl-2: B-cell lymphoma 2; BAD: (Bcl-2) antagonist of death; Bcl-XL: B-cell lymphoma extra-large; Ca²⁺: Calcium; cAMP: Cyclic adenosine monophosphate; CREB: cAMP response element-binding protein; Foxo: Forkhead box O; GLUT: Glucose transporter; GRB2/SOS: Growth factor receptor-bound protein 2/son of sevenless; GSK-3β: Glycogen synthase 3 beta; GTP: Guanosine triphosphate; IRS-1: Insulin receptor substrate 1; IRS-2: Insulin receptor substrate 2; JNK: C-Jun N-terminal kinase; MAPK: Mitogen associated protein kinase; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K: Phosphoinositide 3-kinase; PKA: Protein kinase A; Shc: Src homology-2/a-collagen-related protein.