The regulation of post-ischemic
hyperglycemia plays an important role in suppressing neuronal damage in therapeutic strategies for
cerebral ischemia. We previously reported that the cerebral
sodium-glucose transporter (SGLT) was involved in the post-ischemic
hyperglycemia-induced exacerbation of cerebral ischemic neuronal damage. Cortical SGLT-1, one of the cerebral SGLT
isoforms, is dramatically increased by focal
cerebral ischemia. In this study, we focused on the involvement of cerebral SGLT-1 in the development of cerebral ischemic neuronal damage. It was previously reported that activation of 5'-adenosine monophosphate-activated
protein kinase (AMPK) increases SGLT-1 expression. Moreover, ischemic stress-induced activation of AMPK exacerbates cerebral ischemic neuronal damage. Therefore, we directly confirmed the relationship between cerebral SGLT-1 and cerebral AMPK activation using in vitro primary culture of mouse cortical neurons. An in vivo mouse model of focal
cerebral ischemia was generated using a
middle cerebral artery occlusion (MCAO). The development of
infarct volume and behavioral abnormalities on day 3 after MCAO were ameliorated in cerebral SGLT-1 knock down mice. Cortical and striatal SGLT-1 expression levels were significantly increased at 12h after MCAO. Immunofluorescence revealed that SGLT-1 and the neuronal
nuclear antigen (NeuN) were co-localized in the cortex and striatum of MCAO mice. In the in vitro study, primary cortical neurons were cultured for five days before each treatment with
reagents. Concomitant treatment with
hydrogen peroxide and
glucose induced the elevation of SGLT-1 and phosphorylated AMPK/AMPK ratio, and this elevation was suppressed by compound C, an AMPK inhibitor in primary cortical neurons. Moreover, compound C suppressed neuronal cell death induced by concomitant
hydrogen peroxide/
glucose treatment in primary cortical neurons. Therefore, we concluded that enhanced cerebral SGLT-1 function mediated by post-ischemic
hyperglycemia exacerbates the development of cerebral ischemic neuronal damage. One of the mechanisms of cerebral SGLT-1 up-regulation may be involved in the AMPK activation after
cerebral ischemia.