WD17-1
PTP1B inhibition ameliorates blood-brain barrier damage induced by cerebral ischemia/reperfusion
PTP1B阻害は脳虚血再灌流に伴う血液脳関門障害を軽減する
Sun Meiling（孫 美玲）
Dept. Pharmacol., Grad. Sch. Pharm. Sci., Tohoku Univ.
Background: We recently reported that KY-226, a novel PTP1B inhibitor, could protect neurons from cerebral ischemic injury in mice. KY-226 restored the reduced Akt (protein kinase B) and eNOS phosphorylation (Ser1177) levels after ischemia/reperfusion (I/R) insult. Furthermore, KY-226 could restore the extracellular signal-regulated kinase (ERK) phosphorylation decreased by I/R damage. However, the mechanism of PTP1B function for neuroprotection remains unclear. Methods: We tested the effects of KY-226 on the BBB function in the transient middle cerebral artery occlusion (tMCAO) mice model. KY-226 (10 mg/kg, i.p.) was administered to ICR mice 30 min after tMCAO for 2 h. Wortmannin (i.c.v.) and U0126 (i.v.), specific inhibitors of PI3K and ERK respectively, were administered to mice 30 min before ischemia. At 24 h after reperfusion, the BBB integrity was assessed by leakage of evans blue method and the neurological deficits were measured. Protein levels of ZO-1 and occludin and mRNA level of ZO-1 were measured with biochemical analyses. Result&Discussion: KY-226 treatment could improve neurological deficits concomitant with prevention of BBB breakdown and remarkably attenuated the reduction in ZO-1 and occludin protein levels. Wortmannin and U0126 could inhibit the effects of KY-226 in I/R insult. Furthermore, KY-226 elevated ZO-1 mRNA levels after reperfusion. These results indicated that KY-226 protects BBB integrity by reserving ZO-1/occludin expression during ischemic injury. Our results provided novel insights into the mechanisms of KY-226 underlying its BBB protection and propose a novel therapeutic candidate, KY-226 against ischemic stroke. | | WD17-2
Reappearance of astricytic mGluR5 in the primary somatosensory cortex is a cause of neuropathic pain - reassembles of cortical networks -
S1アストロサイトのmGluR5再発現が神経障害性疼痛の原因である -大脳皮質ネットワークの再構築-
Danjo Yosuke（檀上 洋右）1，平山 幸歩1，繁冨 英治1，柴田 圭輔1，高梨 健太1，篠崎 陽一1，Kim Sun-Kwang2，鍋倉 淳一2，小泉 修一1
1Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan
2Division of Homeostatic Development, National Institute for Physiological Sciences, Okazaki, Japan.
Astrocytes play essential roles for the development and maturation of neural networks, but also have critical roles for the pathogenesis of neural disorders. Recently, we revealed that astrocytes in the primary somatosensory cortex (S1) have a responsible role for mechanical allodynia after partial sciatic nerve ligation (PSNL). In brief, PSNL generated Ca2+ excitation in S1 astrocytes, increased thrombospondin1 and synaptogenesis, thereby resulting in cross-wiring of nocuous and innocuous circuits. mGluR5 looked involved in the pathogenesis, but we still do not know whether astrocytic mGluR5 is crucial or not. Here, we show that reappearance of mGluR5 in S1 astrocytes is a cause of cortical rewiring and the pathogenesis.. Firstly, we made astrocyte-specific mGluR5 knockout mice (astro-mGluR5-KO) by crossing floxed-Grm5 with Glast-Cre mice. In the adult Wt, mGluR5 is almost absent but reappears in S1 after PSNL. Such mGluR5 increase was no longer observed in astro-mGluR5-KO. Due to insufficient Cre-recombination, the spinal astrocytes in astro-mGluR5-KO looked intact. Second, PSNL-induced mechanical allodynia was abolished in astro-mGluR5-KO mice, suggesting that upregulation of mGluR5 in S1 astrocytes should be required for mechanical allodynia. Contribution of spinal astrocytes could be negligible. Third, mechanisms underlying astrocytic mGluR5-mediated allodynia were; (1) increase in Ca2+ activity, (2) expression of synaptogenic molecules such as glypican4 and Hevin, (3) synaptogenesis, (4) persistent rewiring of incorrect S1 circuits. Hence, we conclude that astrocytic mGluR5 is a responsible molecule that triggers synaptogenesis in S1 cortex after PSNL, which is the causative event for the pathogenesis of neuropathic pain. |
