Linagliptin is a recently approved

Linagliptin is a recently approved dipeptidyl peptidase-4 (DPP-4) inhibitor and widely considered as first-line treatment for patients with type 2 diabetes. DPP-4 is responsible for the inactivation of incretin hormones, such as glucagon-like peptide 1 (GLP-1). GLP-1 is released by the intestine after food intake and stimulates insulin secretion by the pancreas. Thus, by inhibiting DPP-4, Linagliptin allows GLP-1 to act longer, thereby releasing more insulin. In studies, linagliptin significantly protected against Aβ-induced cytotoxicity and prevented the activation of GSK3β and tau hyperphosphorylation by restoring downstream insulin signaling. Furthermore, linagliptin alleviated Aβ-induced mitochondrial dysfunction and intracellular ROS generation, which may be due to the activation of AMPK-SIRT1 signaling. These results indicate that DPP-4 inhibitors have therapeutic potential for reducing Aβ-induced impairment of insulin signaling and neurotoxicity in the pathogenesis of Alzheimer's (Kornelius et al., 2015). Some studies also indicate that AMPK has a neuroprotective effect and may be a potential target for preventing/counteracting diabetic encephalopathy. Marein, which is a major SKL2001 from the hypoglycemic plant Coreopsis tinctoria, protected against methylglyoxal (MG), which is an endogenous toxic compound that plays an important role in diabetic complications that affect cells. Marein attenuated PC12 cell damage induced by MG through AMPK signaling. Marein enhanced phospho-AMPKα (Thr172) and Bcl-2 expression and diminished the activation of Bax, caspase-3 and inhibitor of caspase-activated deoxyribonuclease (ICAD). Molecular docking simulation showed that marein interacted with the γ subunit of AMPK (Jiang et al., 2016). Another study showed that chikusetsusaponin IVa (CHS) increased the production of adiponectin, which subsequently activated AdipoR1. Activated AdipoR1 promoted the phosphorylation of LKB/AMPK, inducing the inhibitory phosphorylation of GSK-3β. These effects suppressed apoptosis, inflammation and oxidative stress, thereby protecting against cerebral I/R injury (Duan et al., 2016).
Demyelinating diseases Multiple sclerosis is a chronic, inflammatory, autoimmune disease that compromises the central nervous system and is characterized by demyelinating lesions associated with inflammatory infiltrate, the activation of glial cells as well as the rupture of the blood-brain barrier (Chiaravalloti and DeLuca, 2008). This demyelinating disease involves an autoimmune reaction by myelin-specific CD4+ Th1 and Th17 cells, which initiate the neuropathology (Procaccini et al., 2015). According to the new paradigm, the IL-23/Th17/IL-17A axis is the autoimmune pathogenesis of the central nervous system. Th17 cells activated by IL-23 enter the central nervous system, where they secrete IL-17A, which affects the blood-brain barrier, causing the circulating immune cells to enter the central nervous system, where they stimulate astrocytes and microglia to produce inflammatory mediators (Jones et al., 2016, Rostami and Ciric, 2013). According to Nath et al. (2005), AMPK signaling attenuates the inflammatory response in an experimental autoimmune encephalomyelitis (EAE) model by protecting neurons and modulating T cell immune function. Treatment with AICAR decreased clinical symptoms and inflammatory infiltrate, reducing the expression of Th1 cytokines (IFN-γ, TNF-α, IL-1β and IL-6) and NO levels, which are associated with the severity of EAE. Moreover, treatment with AICAR induced the expression of anti-inflammatory Th2 cytokines (IL-4 and IL-10). Nath et al. (2009a) examined the activity of AMPK isoforms at the peak of symptoms in the EAE model and found a significant decrease in AMPK and its subunits when compared to normal mice. Knockouts for AMPKα1−/− and AMPKα2−/− were used to analyze the activity of these isoforms in the EAE model. The authors found that symptoms and inflammatory infiltrate were greater in AMPKα1−/− animals when compared to wild animals. However, AMPKa2−/− mice showed no worsening of symptoms, suggesting that this isoform does not play an important role in the development of EAE. In another study, the same authors found that metformin attenuated the progression of symptoms and inflammatory infiltrate in the EAE model by inhibiting inflammatory cytokines and chemokines in central nervous system as well as the expression of iNOS and MMP-9 (Nath et al., 2009b).