engleski

Effects of uroguanylin’s signaling pathways on ischemic lesion size

Stroke is one of the leading causes of mortality and disability in industrialized countries. Guanylate cyclase (GC) A activation has a neuroprotective effect after ischemic stroke [1] therefore the aim of this study is to determine if agonists of GC-C have similar effects. Uroguanylin (UGN) activates guanylate cyclase C (GC-C) and a Ca2+-dependent signaling pathway [2]. In this study, middle cerebral artery occlusion (MCAO) was performed on wild type (WT), GC-C KO and UGN KO mice. Before and 24h after MCAO MR images were taken. 48h following MCAO brain slices were isolated and Ca2+ response to UGN stimulation was recorded. Immunohistochemical staining was performed with GC-C, NeuN, and GFAP antibodies. WT and UGN KO animals exhibit a stronger Ca2+ response to UGN stimulation in astrocytes of the ischemic penumbra in cerebral cortex but not in the unaffected hemisphere. This stronger activation is gone in GC-C KO animals which results in development of smaller ischemic le¬sions in GC-C KO mice compared to their WT littermates. Considering the fact that GC-C becomes expressed on penumbral astrocytes following ischemia, while in normoxic conditions it is expressed only in cortical neurons, effects of GC-C on intracellular Ca2+ concentration could be due to activation of cGMP-dependent Ca2+ channels in penumbral astrocytes [3]. Stronger activation of the Ca2+-dependent signaling pathway could lead to the development of larger ischemic lesions, possibly through upregula¬tion of Na+/H+ exchanger, tissue acidification, and neuronal death. [1] Dobrivojević M, Špiranec K, Gorup D, Erjavec I, Habek N, Radmilović M, Unfirer S, Ćosić A, Drenjančević I, Gajović S, Sinđić A (2016) Urodilatin reverses the detrimental influence of bradykinin in acute ischemic stroke. Exp Neurol 284:1-10. [2] Habek N, Ratko M, Dugandžić A (2021) Uroguanylin Increases Ca2+ Concentration in Astrocytes via Guanylate Cyclase C-independent Signalling Pathway. Croat Med J. In press. [3] Rappaport JA, Waldman SA (2018) The Guanylate Cyclase C-cGMP Signaling Axis Opposes Intestinal Epithe¬lial Injury and Neoplasia. Front Oncol 8:299. Funding: Research was funded by the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project “Experimental and clinical research of hypoxic- ischemic damage in perinatal and adult brain” ; GA KK01.1.1.01.0007 funded by the European Union through the European Regional Development Fund). The work of doctoral student Anja Barić has been fully supported by the “Young researchers’ career development project – training of doctoral students” and project BRADISCHEMIA (UIP-2017-05- 8082) of the Croatian Science Foundation funded by the European Union from the European Social Fund.

guanylate cyclase-C ; middle cerebral artery occlusion ; MR imaging ; Ca2+ signaling

nije evidentirano