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Srinivas Kantevari - One of the best experts on this subject based on the ideXlab platform.

Shogo Tokuyama - One of the best experts on this subject based on the ideXlab platform.

  • Activation of c-Jun N-terminal kinase and p38 after cerebral ischemia upregulates cerebral Sodium-Glucose Transporter type 1
    Journal of pharmacological sciences, 2018
    Co-Authors: Yui Yamazaki, Shinichi Harada, Kyoko Arita, Shogo Tokuyama
    Abstract:

    Abstract Cerebral ischemic stress increases cerebral Sodium-Glucose Transporter type 1 (SGLT-1). However, the mechanism by which cerebral ischemia leads to the up-regulation of SGLT-1 remains unclear. In peripheral tissue, the activation of mitogen-activated protein kinases (MAPKs) increases SGLT-1. MAPK pathways [c-Jun N-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated protein kinase (ERK)] are activated by cerebral ischemic stress. Therefore, we confirmed the involvement of MAPKs in the up-regulation of cerebral SGLT-1 after cerebral ischemia. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO). Protein expression was assessed by western blotting. Mice received an intracerebroventricular (i.c.v.) injection of SP600125 (JNK inhibitor), SB203580 (p38 inhibitor), and PD98059 (MEK inhibitor) immediately after reperfusion. The infarction and behavioral abnormalities were assessed on days 1 and 3 after MCAO. The MAPK inhibitors suppressed the activation of JNK, p38, and ERK 3 h after MCAO. SP600125 and SB203580 administration ameliorated cerebral ischemic neuronal damage, whereas PD98059 administration exacerbated cerebral ischemic neuronal damage. SP600125 and SB203580 significantly suppressed the increase in SGLT-1 12 h after MCAO. PD98059 had no effect on SGLT-1 expression after MCAO. Our results indicate that the activation of JNK and p38 participate in the up-regulation of cerebral SGLT-1 after MCAO.

  • Potential of the Cerebral Sodium-Glucose Transporter as a Novel Therapeutic Target in Cerebral Ischemia
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 2018
    Co-Authors: Yui Yamazaki, Shinichi Harada, Shogo Tokuyama
    Abstract:

    Cerebral ischemic stress often induces a hyperglycemic condition. This postischemic hyperglycemia exacerbates the development of cerebral ischemic neuronal damage, although the mechanism of this exacerbation remains to be clarified. We previously discovered that the cerebral Sodium-Glucose Transporter (SGLT) was closely involved in the development of cerebral ischemic neuronal damage. SGLT is a member of the Glucose Transporter family and moves Glucose together with Sodium ions. SGLT-1, -3, -4, and -6 are distributed in the brain. We conducted further experiments to elucidate the detailed mechanism of the exacerbation of cerebral ischemia by cerebral SGLT. The results clarified: 1) the relationship between cerebral SGLT and postischemic hyperglycemia; 2) the involvement of cerebral SGLT-1 (a cerebral SGLT isoform) in cerebral ischemic neuronal damage; and 3) the effects of Sodium influx through cerebral SGLT on the development of cerebral ischemic neuronal damage. This paper presents our data on the involvement of cerebral SGLT in the exacerbation of cerebral ischemic neuronal damage.

  • Sodium-Glucose Transporter as a novel therapeutic target in disease.
    European journal of pharmacology, 2018
    Co-Authors: Yui Yamazaki, Shinichi Harada, Shogo Tokuyama
    Abstract:

    Glucose is the primary energy fuel of life. A Glucose Transporter, the Sodium-Glucose Transporter (SGLT), is receiving attention as a novel therapeutic target in disease. This review summarizes the physiological role of SGLT in cerebral ischemia, cancer, cardiac disease, and intestinal ischemia, which has encouraged analysis of SGLT function. In cerebral ischemia and cardiomyopathy, SGLT-1 is involved in worsening of the injury. In addition, SGLT-1 promotes the development of cancer. On the other hand, SGLT-1 has a protective effect against cardiac and intestinal ischemia. Interestingly, SGLT-1 expression levels are increased in some diseased tissue, such as in cerebral ischemia and cancer. This suggests that SGLT-1 may have an important role in many diseases. This review discusses the potential of SGLT as a target for novel therapeutic agents.

  • Sodium influx through cerebral Sodium-Glucose Transporter type 1 exacerbates the development of cerebral ischemic neuronal damage.
    European journal of pharmacology, 2017
    Co-Authors: Yui Yamazaki, Shinichi Harada, Tetsuyuki Wada, Shigeru Yoshida, Teruki Hagiwara, Shogo Tokuyama
    Abstract:

    Abstract We recently reported that cerebral Sodium-Glucose Transporter type 1 (SGLT-1) plays a role in exacerbation of cerebral ischemia. However, the mechanism by which cerebral SGLT-1 acts remains unclear. Here we demonstrated that Sodium influx through cerebral SGLT-1 exacerbates cerebral ischemic neuronal damage. SGLT-specific Sodium ion influx was induced using α-methyl-D-glucopyranoside (α-MG). Intracellular Sodium concentrations in primary cortical neurons were estimated using Sodium-binding benzofuran isophthalate fluorescence. SGLT-1 knockdown in primary cortical neurons and mice was achieved using SGLT-1 siRNA. The survival rates of primary cultured cortical neurons were assessed using biochemical assays 1 day after treatment. Middle cerebral artery occlusion (MCAO) was used to generate a focal cerebral ischemic model in SGLT-1 knockdown mice. The change in fasting blood Glucose levels, infarction development, and behavioral abnormalities were assessed 1 day after MCAO. Treatment with 200 mM α-MG induced a continuous increase in the intracellular Sodium concentration, and this increase was normalized after α-MG removal. Neuronal SGLT-1 knockdown had no effect on 100 µM H 2 O 2 -induced neuronal cell death; however, the knockdown prevented the neuronal cell death induced by 17.5 mM Glucose and the co-treatment of 100 µM H 2 O 2 /8.75 mM Glucose. Neuronal SGLT-1 knockdown also suppressed the cell death induced by α-MG alone and the co-treatment of 100 µM H 2 O 2 /0.01 mM α-MG. Our in vivo results showed that the exacerbation of cerebral ischemic neuronal damage induced by the intracerebroventricular administration of 5.0 µg α-MG/mouse was ameliorated in cerebral SGLT-1 knockdown mice. Thus, Sodium influx through cerebral SGLT-1 may exacerbate cerebral ischemia-induced neuronal damage.

  • Sodium transport through the cerebral Sodium-Glucose Transporter exacerbates neuron damage during cerebral ischaemia.
    The Journal of pharmacy and pharmacology, 2016
    Co-Authors: Yui Yamazaki, Shinichi Harada, Tetsuyuki Wada, Shigeru Yoshida, Shogo Tokuyama
    Abstract:

    Objectives We recently demonstrated that the cerebral Sodium-Glucose Transporter (SGLT) is involved in postischaemic hyperglycaemia-induced exacerbation of cerebral ischaemia. However, the associated SGLT-mediated mechanisms remain unclear. Thus, we examined the involvement of cerebral SGLT-induced excessive Sodium ion influx in the development of cerebral ischaemic neuronal damage. Methods [Na+]i was estimated according to Sodium-binding benzofuran isophthalate fluorescence. In the in vitro study, primary cortical neurons were prepared from fetuses of ddY mice. Primary cortical neurons were cultured for 5 days before each treatment with reagents, and these survival rates were assessed using biochemical assays. In in vivo study, a mouse model of focal ischaemia was generated using middle cerebral artery occlusion (MCAO). Key findings In these experiments, treatment with high concentrations of Glucose induced increment in [Na+]i, and this phenomenon was suppressed by the SGLT-specific inhibitor phlorizin. SGLT-specific Sodium ion influx was induced using a-methyl-D-glucopyranoside (a-MG) treatments, which led to significant concentration-dependent declines in neuronal survival rates and exacerbated hydrogen peroxide-induced neuronal cell death. Moreover, phlorizin ameliorated these effects. Finally, intracerebroventricular administration of a-MG exacerbated the development of neuronal damage induced by MCAO, and these effects were ameliorated by the administration of phlorizin. Conclusions Hence, excessive influx of Sodium ions into neuronal cells through cerebral SGLT may exacerbate the development of cerebral ischaemic neuronal damage.

Sanjay K Banerjee - One of the best experts on this subject based on the ideXlab platform.

Abhinav Kanwal - One of the best experts on this subject based on the ideXlab platform.

Siddamal Reddy Putapatri - One of the best experts on this subject based on the ideXlab platform.