• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • In the past few years neuroprotection via GLP R


    In the past few years, neuroprotection via GLP-1R activation has been shown in several animal models of stroke, Alzheimer\'s, Parkinson\'s, Huntington\'s, ALS and traumatic histamine-2 receptor antagonist injury. This research field is rapidly growing and several reviews have been recently published (Darsalia et al., 2014b, Foltynie and Aviles-Olmos, 2014, Garcia-Casares et al., 2014, Greig et al., 2014, Patrone et al., 2014, Stayte and Vissel, 2014, Calsolaro and Edison, 2015, Candeias et al., 2015, Darsalia et al., 2015, Ji et al., 2016, Tramutola et al., 2017). Moreover, the progress in the field is now updated in this special issue of Neuropharmacology. Herein, we specifically focus on data showing GLP-1R agonists/DPP-4i-mediated effects against stroke.
    Future directions The molecular and cellular mechanisms at the basis of the neuroprotective efficacy are still largely unknown and certainly different between GLP-1R agonists and DPP-4i since neuroprotection by DPP-4i can occur in absence of the GLP-1R (Darsalia et al., 2016). A common aspect is that both these types of drugs mediate anti-apoptotic and anti-inflammatory mechanisms involving microglia regulation. However, this is not surprising since the activation of these mechanisms is also needed for most neuroprotective substances. Furthermore, based on the reported studies, it is difficult to know whether anti-apoptotic and anti-neuroinflammatory effects are a cause or a consequence of the neuroprotective action of GLP-1R agonists and of DPP-4i treatments and future studies should be addressing these questions in the future. The reported clinical studies with both GLP-1R agonists and DPP-4i have not so far addressed whether T2D patients can purely benefit from the neuroprotective actions of these substances since these studies have mainly addressed potential effects in the primary outcome to reduce CV incidence and death (and not always focusing on stroke specifically). The SUSTAIN-6 study (Marso et al., 2016a) is perhaps more interesting in relation to stroke, since the semaglutide-mediated reduction in the composite endpoint was mainly driven by nonfatal stroke; although, there was no reduction in CV death or mortality, as it was for the LEADER study (Marso et al., 2016b). However, no specific data about death after stroke have been reported in these studies.
    Conflict of interest
    Introduction Dipeptidyl peptidase 4 (DPP-4) inactivates glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) (Deacon et al., 2001), which forms the bases for development of DPP-4 inhibition as a glucose lowering therapy in type 2 diabetes (Ahrén, 2007). The classical mechanism of DPP-4 inhibition is that they prevent the inactivation of the incretin hormones, which in turn stimulates islet function through direct islet effects achieved by their increased circulatory concentrations (Ahrén, 2007, Ahrén, 2012). However, also other mechanisms may contribute to the islet effects of DPP-4 inhibition because the circulatory levels of intact incretin hormones actually reaching the pancreas after a meal is only a small fraction of what is released from the enteroendocrine gut cells (Hansen et al., 1999, Vilsboll et al., 2006). This is supported by a study in pigs showing that DPP-4 inhibition raises portal GLP-1 levels by a much larger degree than peripheral levels (Hjollund et al., 2011). Furthermore, recent data for both sitagliptin (Waget et al., 2011) and vildagliptin (Omar and Ahrén, 2014) have also shown that these DPP-4 inhibitors indeed stimulate insulin secretion also at such low dose levels in which they do not increase circulating incretin hormones at all. A potential complementary mechanism which may contribute to the effects of DPP-4 inhibition is an indirect neural action. Indeed, the islets are innervated by autonomic nerves which regulate islet function (Ahrén, 2000) and newly released incretin hormones have the potential to activate autonomic afferent nerve fibers at the site of secretion in the gut and along the portal circulation and these neural effects may result in stimulation of insulin secretion, which is called the neuro-incretin mechanism (Ahrén, 2014). Such a hypothesis is supported by findings that receptors for GLP-1 exist in the nodose ganglion (Nakagawa et histamine-2 receptor antagonist al., 2004, Bucinskaite et al., 2009), which is the main ganglion of the afferent vagus nerve, and on vagal nerve fibers in the portal circulation (Vahl et al., 2007). Furthermore, portal vein infusion of GLP-1 in rats triggers both afferent and efferent vagal nerve fibers (Nishizawa et al., 1996), and sensory nerve-deactivation by capsaicin suppresses the insulin secretory effect of GLP-1 (Ahrén, 2004). Previously the parasympathetic nerves have been shown to be involved in the regulation by the liver of insulin action through nerve-induced production of the hepatic insulin sensitizing substance (HISS) which promotes insulin action in skeletal muscle (Lautt, 1999, Lautt, 2005). However, whether there is a contribution by neural activity also by GLP-1 which would contribute to the mechanism behind the glucose-lowering action of DPP-4 inhibition has not been demonstrated, and, furthermore, whether similar effects are initiated by GIP is not known.