RS1 (Rsc1A1) deficiency limits cerebral SGLT1 expression and delays brain damage after experimental traumatic brain injury

Abstract

Acute cerebral lesions are associated with dysregulation of brain glucose homeostasis. Previous studies showed that knockdown of Na -D-glucose cotransporter SGLT1 impaired outcome after middle cerebral artery occlusion and that widely expressed intracellular RS1 (RSC1A1) is involved in transcriptional and post-translational down-regulation of SGLT1. In the present study, we investigated whether SGLT1 is up-regulated during traumatic brain injury (TBI) and whether removal of RS1 in mice (RS1-KO) influences SGLT1 expression and outcome. Unexpectedly, brain SGLT1 mRNA in RS1-KO was similar to wild-type whereas it was increased in small intestine and decreased in kidney. One day after TBI, SGLT1 mRNA in the ipsilateral cortex was increased 160% in wild-type and 40% in RS1-KO. After RS1 removal lesion volume 1 day after TBI was reduced by 12%, brain edema was reduced by 28%, and motoric disability determined by a beam walking test was improved. In contrast, RS1 removal did neither influence glucose and glycogen accumulation 1 day after TBI nor up-regulation of inflammatory cytokines TNF-α, IL-1β and IL-6 or microglia activation 1 or 5 days after TBI. The data provide proof of principle that inhibition or down-regulation of SGLT1 by targeting RS1 in brain could be beneficial for early treatment of TBI.

Glucose transporters in brain in health and disease

“…The role of SGLT1/Sglt1 during diseases is enigmatic. In mice, cognitive impairment combined with damage of hippocampal neurons observed after chronic hypofusion was blunted when Sglt1 was removed [183], and a decreased cerebral expression of Sglt1 was protective during experimental TBI [366].…”

“…SGLT1/Sglt1 is expressed in heart, skeletal muscle, lung, liver, gall bladder, colon, rectum uterus, testes, pancreas, and brain [210]. SGLT1/ Sglt1 mRNA in brain was observed in human, pig, rabbit, rat, and mouse [110,118,227,290,305,330,366].…”

What does sodium‐glucose co‐transporter 1 inhibition add: Prospects for dual inhibition

“…In contrast to these beneficial effects, another study found that dual SGLT1/2 inhibition with T‐1095 in rats resulted in an exacerbation of cardiac dysfunction in response to myocardial infarction . In the brain, inhibiting or down‐regulating SGLT1 was shown to be beneficial for early treatment of traumatic brain injury . As originally described in the CANVAS trial, canagliflozin had an increased risk of below knee amputations.…”

Drug development in targeting ion channels for brain edema

“…Enhanced gene or protein expression of both GLUT1 and SGLT1 at the BBB has been implicated in experimental models of ischemic stroke and TBI [ 231 , 233 , 234 ]. Consistent with these findings, brain imaging studies have suggested elevated glucose uptake and glucose hypermetabolism during ischemic stroke, especially in peri-infarcted regions [ 234 , 235 ].…”

“…In fact, mice pretreated with SGLT inhibitor, phlorizin, showed reduced infarction volume and brain edema after pMCAO [ 231 ]. Downregulating SGLT1 was also shown to be beneficial in TBI in terms of reducing cerebral edema and contusion volume [ 233 ]. These protective effects of SGLT inhibition are potentially due to reduced Na + and water transport through the endothelial cell, as well as reduced acidosis and free radical production from the anaerobic metabolism of glucose [ 231 ].…”