Low-dose sodium-glucose cotransporter 2 inhibitor ameliorates ischemic brain injury in mice through pericyte protection without glucose-lowering effects

Takashima, Masamitsu; Nakamura, Kuniyuki; Kiyohara, Takuya; Wakisaka, Yoshinobu; Hidaka, Masaoki; Takaki, Hayato; Yamanaka, Kei; Shibahara, Tomoya; Wakisaka, Masanori; Ago, Tetsuro; Kitazono, Takanari

doi:10.1038/s42003-022-03605-4

Cited by 23 publications

(17 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, our study demonstrates the potential of a post-stroke intervention with SGLT2i to improve recovery in T2D. Of interest in this respect was a recent study of Takashima and colleagues, demonstrating that a low-dose pre-stroke treatment with Luseogli ozin in non-diabetic mice, not affecting urinary glucose levels, could signi cantly decrease infarct size and improve neurological recovery (29).…”

Section: Discussionmentioning

confidence: 55%

The SGLT2 inhibitor Empagliflozin promotes post-stroke functional recovery in diabetic mice

Vercalsteren,

Karampatsi,

Buizza

et al. 2023

Preprint

View full text Add to dashboard Cite

Type-2 diabetes (T2D) worsens stroke recovery, amplifying post-stroke disabilities. Currently, there are no therapies targeting this important clinical problem. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are potent glucose-lowering drugs for the treatment of T2D that also efficiently reduce cardiovascular death and heart failure. In addition, SGLT2i facilitate several processes implicated in stroke recovery. However, the potential efficacy of SGLT2i to improve stroke recovery in T2D has not been investigated. Therefore, we determined whether a post-stroke intervention with the SGLT2i Empagliflozin could improve stroke recovery in T2D mice. T2D was induced in C57BL6J mice by 8 months of high-fat diet feeding. Hereafter, animals were subjected to transient middle cerebral artery occlusion and treated with vehicle or the SGLTi Empagliflozin (10 mg/kg/day) starting from 3 days after stroke. Stroke recovery was assessed using the forepaw grip strength test. To identify potential mechanisms involved in the Empagliflozin-mediated effects, several metabolic parameters were assessed. Additionally, neuronal survival, neuroinflammation, neurogenesis and cerebral vascularization were analyzed using immunohistochemistry/quantitative microscopy. Empagliflozin significantly improved stroke recovery in association with lowered glycemia, increased serum levels of fibroblast growth factor-21 (FGF-21), and the normalization of T2D-induced aberration of parenchymal pericyte density. The global T2D-epidemic and the fact that T2D is a major risk factor for stroke are drastically increasing the number of people in need of efficacious therapies to improve stroke recovery. Our data provide a strong incentive for the potential use of SGLT2i for the treatment of post-stroke sequelae in T2D.

show abstract

Section: Discussionmentioning

confidence: 55%

The SGLT2 inhibitor Empagliflozin promotes post-stroke functional recovery in diabetic mice

Vercalsteren,

Karampatsi,

Buizza

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The effect of SGLT2i on an ischemic stroke is controversial. However, a recent study has shown that inhibition of SGLT2 prior to stroke increases ischemic tolerance in pericytes and improves ischemic brain injury . Atherosclerosis is a chronic inflammatory vascular disease in which plaques form in the intima of the vessels involving various cells, lipids, and debris .…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Acute Coronary Syndrome

Song,

Liu,

et al. 2024

ACS Pharmacol. Transl. Sci.

View full text Add to dashboard Cite

The evidence for sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the treatment of type 2 diabetes or chronic heart failure was sufficient but lacking in acute coronary syndrome (ACS). Our aim was to investigate the effects of SGLT2i on cardiovascular outcomes in ACS patients. Studies of SGLT2i selection in ACS patients were searched and pooled. Outcomes included all-cause death, adverse cardiovascular events, cardiac remodeling as measured by the left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD), cardiac function as assessed by the left ventricular ejection fraction (LVEF) and NT-proBNP, and glycemic control. Twenty-four studies with 12,413 patients were identified. Compared to the group without SGLT2i, SGLT2i showed benefits in reducing all-cause death (OR 0.72, 95% CI [0.61, 0.85]), major adverse cardiovascular events (MACE) (OR 0.44, 95% CI [0.30, 0.64]), cardiovascular death (OR 0.66, 95% CI [0.54, 0.81]), heart failure (OR 0.52, 95% CI [0.44, 0.62]), myocardial infarction (OR 0.68, 95% CI [0.56, 0.83]), angina pectoris (OR 0.37, 95% CI [0.17, 0.78]), and stroke (OR 0.48, 95% CI [0.24, 0.96]). Results favored SGLT2i for LVEDD (MD −2.03, 95% CI [−3.29, −0.77]), LVEF (MD 3.22, 95% CI [1.71, 4.72]), and NT-proBNP (MD −171.53, 95% CI [−260.98, −82.08]). Thus, SGLT2i treatment reduces the risk of all-cause death and MACE and improves cardiac remodeling and function in ACS patients.

show abstract

“…SLC5A2, namely the SGLT2 gene, was reported to be the drug target for SGLT2 inhibitors, hence the spatial distribution of SLC5A2 would provide insights into the target tissues of SGLT2 inhibitors [ 34 ]. Takashima and colleagues have demonstrated that low-dose luseogliflozin ameliorates ischemic brain injury in mice without glucose-lowering effects [ 35 ]. Similarly, Joki et al have shown that tofogliflozin modulates pulmonary vascular remodelling in mice with left heart disease [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic variations in anti-diabetic drug targets and COPD risk: evidence from mendelian randomization

Su,

Zhang,

2024

BMC Pulm Med

View full text Add to dashboard Cite

Background Previous research has emphasized the potential benefits of anti-diabetic medications in inhibiting the exacerbation of Chronic Obstructive Pulmonary Disease (COPD), yet the role of anti-diabetic drugs on COPD risk remains uncertain. Methods This study employed a Mendelian randomization (MR) approach to evaluate the causal association of genetic variations related to six classes of anti-diabetic drug targets with COPD. The primary outcome for COPD was obtained from the Global Biobank Meta-analysis Initiative (GBMI) consortium, encompassing a meta-analysis of 12 cohorts with 81,568 cases and 1,310,798 controls. Summary-level data for HbA1c was derived from the UK Biobank, involving 344,182 individuals. Positive control analysis was conducted for Type 2 Diabetes Mellitus (T2DM) to validate the choice of instrumental variables. The study applied Summary-data-based MR (SMR) and two-sample MR for effect estimation and further adopted colocalization analysis to verify evidence of genetic variations. Results SMR analysis revealed that elevated KCNJ11 gene expression levels in blood correlated with reduced COPD risk (OR = 0.87, 95% CI = 0.79–0.95; p = 0.002), whereas an increase in DPP4 expression corresponded with an increased COPD incidence (OR = 1.18, 95% CI = 1.03–1.35; p = 0.022). Additionally, the primary method within MR analysis demonstrated a positive correlation between PPARG-mediated HbA1c and both FEV1 (OR = 1.07, 95% CI = 1.02–1.13; P = 0.013) and FEV1/FVC (OR = 1.08, 95% CI = 1.01–1.14; P = 0.007), and a negative association between SLC5A2-mediated HbA1c and FEV1/FVC (OR = 0.86, 95% CI = 0.74–1.00; P = 0.045). No colocalization evidence with outcome phenotypes was detected (all PP.H4 < 0.7). Conclusion This study provides suggestive evidence for anti-diabetic medications' role in improving COPD and lung function. Further updated MR analyses are warranted in the future, following the acquisition of more extensive and comprehensive data, to validate our results.

show abstract

Low-dose sodium-glucose cotransporter 2 inhibitor ameliorates ischemic brain injury in mice through pericyte protection without glucose-lowering effects

Cited by 23 publications

References 41 publications

The SGLT2 inhibitor Empagliflozin promotes post-stroke functional recovery in diabetic mice

The SGLT2 inhibitor Empagliflozin promotes post-stroke functional recovery in diabetic mice

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Acute Coronary Syndrome

Genetic variations in anti-diabetic drug targets and COPD risk: evidence from mendelian randomization

Contact Info

Product

Resources

About