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.
Highlights
There are many disease states whose occurrence is connected to neural damage
The insulin receptor substrate (IRS) has multiple potential phosphorylation sites, which implies that insulin/IGF-1 signaling pathway can be regulated by ligand-independent processes [15]
Zhu et al [29] suggested that the anti-apoptotic effect of liraglutide may be linked to an impact of GLP-1 receptor activation on intracellular pathways associated with apoptosis, including PI3K/AKT and MAPK
Summary
There are many disease states whose occurrence is connected to neural damage. The second most common cause of death in the world is stroke, which kills 6 million people a year. Acute results like insulin secretion, exocytosis, and augmentation in intracellular calcium concentration are, to a large extent, mediated by cAMP (cyclic adenosine monophosphate) and subsequent PKA (phosphorylase kinase A) activation [17] Chronic effects, such as gene expression modulation, cellular growth enhancement, and antiapoptotic activity, can be ascribed to PI3K pathway, which overlaps with insulin/IGF-1 signaling. Zhu et al [29] suggested that the anti-apoptotic effect of liraglutide may be linked to an impact of GLP-1 receptor activation on intracellular pathways associated with apoptosis, including PI3K/AKT and MAPK. Other researchers observed a similar effect of liraglutide consisting in the activation of the PI3K/AKT pathway [49], ERK [50], as well as inhibition of JNK [51] and phosphorylated p38 [52]
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