Liraglutide and its Neuroprotective Properties-Focus on Possible Biochemical Mechanisms in Alzheimer's Disease and Cerebral Ischemic Events

Abstract

Liraglutide is a GLP-1 analog (glucagon like peptide-1) used primarily in the treatment of diabetes mellitus type 2 (DM2) and obesity. The literature starts to suggest that liraglutide may reduce the effects of ischemic stroke by activating anti-apoptotic pathways, as well as limiting the harmful effects of free radicals. The GLP-1R expression has been reported in the cerebral cortex, especially occipital and frontal lobes, the hypothalamus, and the thalamus. Liraglutide reduced the area of ischemia caused by MCAO (middle cerebral artery occlusion), limited neurological deficits, decreased hyperglycemia caused by stress, and presented anti-apoptotic effects by increasing the expression of Bcl-2 and Bcl-xl proteins and reduction of Bax and Bad protein expression. The pharmaceutical managed to decrease concentrations of proapoptotic factors, such as NF-κB (Nuclear Factor-kappa β), ICAM-1 (Intercellular Adhesion Molecule 1), caspase-3, and reduced the level of TUNEL-positive cells. Liraglutide was able to reduce the level of free radicals by decreasing the level of malondialdehyde (MDA), and increasing the superoxide dismutase level (SOD), glutathione (GSH), and catalase. Liraglutide may affect the neurovascular unit causing its remodeling, which seems to be crucial for recovery after stroke. Liraglutide may stabilize atherosclerotic plaque, as well as counteract its early formation and further development. Liraglutide, through its binding to GLP-1R (glucagon like peptide-1 receptor) and consequent activation of PI3K/MAPK (Phosphoinositide 3-kinase/mitogen associated protein kinase) dependent pathways, may have a positive impact on Aβ (amyloid beta) trafficking and clearance by increasing the presence of Aβ transporters in cerebrospinal fluid. Liraglutide seems to affect tau pathology. It is possible that liraglutide may have some stem cell stimulating properties. The effects may be connected with PKA (phosphorylase kinase A) activation. This paper presents potential mechanisms of liraglutide activity in conditions connected with neuronal damage, with special emphasis on Alzheimer's disease and cerebral ischemia.

Keywords: Alzheimer’s disease; inflammation; liraglutide; neuroprotection; pathways; stroke.

Figure 1

Proposed mechanisms of liraglutide activity; ↓ = reduction, ↑ = increase, p-p38 = phosphorylated p38, JNK-c = jun-NH2-terminal kinase, AKT = protein kinase B, ERK = extracellular signal-adjusted kinases, Bcl-2 = B-cell lymphoma 2, Bax = bcl-2-like protein 4, Bcl-xl = B-cell lymphoma-extra-large, Bad = Bcl-2-associated death promoter, NFκB = Nuclear Factor-kappaB, ICAM-1 = Intercellular Adhesion Molecule 1 Nrf2/HO-1-nuclear factor erythroid 2-related factor/heme oxygenase-1, MDA = malondialdehyde, GSH = glutathione, SOD = superoxide dismutase, MPO = myeloperoxidase, ROS = Reactive oxygen species, eNOS = endothelial nitric oxide synthase, ET-1 = Endothelin-1, eNOS = endothelial nitric oxide synthase, IL-6 = Interleukin-6, ACAT-1 = acyl-CoA: cholesterol acyltransferase 1, IDE = insulin degrading enzyme, Aβ = amyloid β, NSCs = neuronal stem cells, cAMP/PKA = cyclic adenosine monophosphate/phosphorylase kinase A.

Figure 2

Proposed signaling transduction of liraglutide. GLP-1R = glucagon-like peptide-1 receptor, IR = insulin receptor, IRS-1 = Insulin receptor substrate 1, PI3K p110 = Phosphoinositide 3-kinase p110, PDK1 = Phosphoinositide-dependent kinase-1, JNK = c-jun-NH2-terminal kinase, AKT = protein kinase B, ERK = extracellular signal-adjusted kinases, Bcl-2 = B-cell lymphoma 2, Bax = bcl-2-like protein 4, Bcl-xl = B-cell lymphoma-extra-large, Bad = Bcl-2-associated death promoter, cAMP = cyclic adenosine monophosphate, PKA = phosphorylase kinase A, Bim = Bcl-2-like protein 11, FasL = Fas ligand or CD95L, FoxO = Forkhead box class O, mTOR = mammalian target of rapamycin, GSK3β = Glycogen synthase kinase 3 beta, IDE = Insulin-degrading enzyme, Aβ = amyloid beta.