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.

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

“…27 Multiple kinases are account for Tau phosphorylation including PKA, PP2A and GSK3β. 24,41,43 Among these, GSK3β is a threonine and serine kinase, and activation of GSK3β could phosphorylate Tau in AD progression. 12 Moreover, the α-Synuclein deficiency mice were resistance to the MPTP.…”

Perspective of SGLT2 Inhibition in Treatment of Conditions Connected to Neuronal Loss: Focus on Alzheimer’s Disease and Ischemia-Related Brain Injury

“…BDNF supports differentiation, maturation, and survival of neurons in the nervous system [ 23 ], and presents neuroprotective properties under such conditions as: glutamatergic stimulation, cerebral ischemia, hypoglycemia, and neurotoxicity [ 31 , 32 ]. This mechanism has been previously proposed as responsible of neuroprotective properties of glucagon like peptide 1 agonist-liraglutide [ 33 , 34 ].…”

Adiponectin: The Potential Regulator and Therapeutic Target of Obesity and Alzheimer’s Disease

“…In an AD mice model, Val(8)GLP-1, liraglutide, and exidin-4 (GLP-1 analogs, well known for the upregulation of adiponectin) treatments rescued synaptic plasticity by preventing synaptic degradation, which is also correlated with the increased learning ability of new spatial tasks [ 155 , 156 , 157 , 158 ]. Several studies have also shown the beneficiary effect of GLP-1 analogs for AD [ 159 , 160 , 161 ].…”