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  • The lack of effective strategies aiming to directly increase

    2019-09-05

    The lack of effective strategies, aiming to directly increase the neuronal survival, is reflected by the fact that the only available therapeutic interventions are indirect. They consist of acute therapeutic interventions involving chemical and/or surgical removal of the thrombotic clot (Taqi et al., 2012, Diener et al., 2013). These treatments are mostly effective up to 3–4.5 h after stroke and therefore they are not available for the vast majority of stroke patients, due to either late arrival to the hospital, delayed diagnosis, or contraindications (e.g. hypertension) (Crimmins et al., 2009, Herlitz et al., 2010, Kurz et al., 2013). Importantly, thrombolytic treatments increase the risk of hemorrhage that is often present in patients with common stroke comorbidities, such as hypertension and diabetes mellitus (Lansberg et al., 2007, Whiteley et al., 2012). Therefore, this further limits their clinical use. In conclusion, while thrombolytic treatments can be very effective within a short time-window after the initial insult, a substantial portion of the injured tissue remain damaged and only a limited number of patients can receive these treatments. As mentioned above, diabetes is a major risk factor for stroke (Alvarez-Sabin et al., 2004, Engelgau et al., 2004, Gilmore and Stead, 2006, Sander and Kearney, 2009). In addition, many stroke patients show diabetes or pre-diabetes upon admission to the hospital (Alvarez-Sabin et al., 2004, Engelgau et al., 2004, Gilmore and Stead, 2006, Sander and Kearney, 2009). Moreover, diabetes and stroke remain the major cause of morbidity and mortality (Engelgau et al., 2004). Interestingly, recent research suggests that the development of stroke therapeutics can benefit from prior diabetes research.
    Anti-diabetic effects mediated by GLP-1R agonists and DPP-4i The GLP-1R is a G-protein-coupled receptor expressed in a wide range of tissues including pancreas and caspofungin (Pujadas and Drucker 2016). It is activated by GLP-1 which is a small peptide hormone produced and released from intestinal L-cells and exerting numerous pleiotropic effects in the body (Pujadas and Drucker, 2016). The most studied and best-characterized properties of GLP-1 consist in the “incretin effect” of GLP-1, which consists in the enhancement of meal-stimulated insulin secretion from pancreatic β-cells in a glucose-dependent manner (Campbell and Drucker, 2013). In addition to the incretin effect that is responsible for the main part of the postprandial insulin secretion, GLP-1 regulates glycaemia by also decreasing glucagon secretion from the pancreas. Since these effects are glucose-dependent, the pharmacological activation of GLP-1R presents low risks of hypoglycemia. The signal transduction pathway of GLP-1 and its analogues has been characterized mainly in pancreatic β-cells and it occurs via adenylate cyclase and the cAMP/PKA pathways (Campbell and Drucker, 2013). Native GLP-1 could not be developed clinically for the treatment of diabetes since endogenous GLP-1 is rapidly degraded by the enzyme DPP-4. However, there are today several stable synthetic GLP-1R agonists resistant to DPP-4 degradation and DPP-4 inhibitors that are used clinically for the treatment of T2D (Ahren, 2011, Drucker, 2013). An important distinction that needs to be done, when it comes to these anti-diabetic drugs, is that while GLP-1R agonists directly target the GLP-1R, DPP-4i can inhibit the degradation of several substrates in addition to GLP-1, some also acting on glycaemia regulation as the glucose dependent insulinotropic polypeptide (GIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP) (Omar and Ahren, 2014). Therefore, while DPP-4i have been developed to treat T2D based on their well characterized GLP-1-mediated properties, this class of drugs likely mediates glycaemic effects also via other biological pathways.
    GLP-1R activation for the treatment of neurodegenerative and neurological disorders