engleski

Effects of uroguanylin’s signaling pathways on schemic lesion size

Introduction/Objectives: 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. 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. Participants, Materials/Methods: 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. Results: 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 lesions 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. Conclusions: Stronger activation of the Ca2+-dependent signaling pathway could lead to the development of larger ischemic lesions, possibly through upregulation of Na+/H+ exchanger, tissue acidification, and neuronal death.

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

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