Your browser doesn't support javascript.
loading
A Novel Na+-K+-Cl- Cotransporter 1 Inhibitor STS66* Reduces Brain Damage in Mice After Ischemic Stroke.
Huang, Huachen; Bhuiyan, Mohammad Iqbal H; Jiang, Tong; Song, Shanshan; Shankar, Sandhya; Taheri, Taraneh; Li, Eric; Schreppel, Philipp; Hintersteininger, Michael; Yang, Sung-Sen; Lin, Shih-Hua; Molyneaux, Bradley J; Zhang, Zhongling; Erker, Thomas; Sun, Dandan.
Afiliação
  • Huang H; From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
  • Bhuiyan MIH; Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
  • Jiang T; Department of Neurology, First Affiliate Hospital, Harbin Medical University, Heilongjiang, China (H.H., Z.Z.).
  • Song S; From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
  • Shankar S; Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
  • Taheri T; From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
  • Li E; Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
  • Schreppel P; From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
  • Hintersteininger M; Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
  • Yang SS; From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
  • Lin SH; Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
  • Molyneaux BJ; From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
  • Zhang Z; Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
  • Erker T; From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
  • Sun D; Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.
Stroke ; 50(4): 1021-1025, 2019 04.
Article em En | MEDLINE | ID: mdl-30862257
Background and Purpose- Inhibition of brain NKCC1 (Na+-K+-Cl- cotransporter 1) with bumetanide (BMT) is of interest in ischemic stroke therapy. However, its poor brain penetration limits the application. In this study, we investigated the efficacy of 2 novel NKCC1 inhibitors, a lipophilic BMT prodrug STS5 (2-(Dimethylamino)ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate;hydrochloride) and a novel NKCC1 inhibitor STS66 (3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide), on reducing ischemic brain injury. Methods- Large-vessel transient ischemic stroke in normotensive C57BL/6J mice was induced with 50-min occlusion of the middle cerebral artery and reperfusion. Focal, permanent ischemic stroke in angiotensin II (Ang II)-induced hypertensive C57BL/6J mice was induced by permanent occlusion of distal branches of middle cerebral artery. A total of 206 mice were randomly assigned to receive vehicle DMSO, BMT, STS5, or STS66. Results- Poststroke BMT, STS5, or STS66 treatment significantly decreased infarct volume and cerebral swelling by ≈40% to 50% in normotensive mice after transient middle cerebral artery occlusion, but STS66-treated mice displayed better survival and sensorimotor functional recovery. STS5 treatment increased the mortality. Ang II-induced hypertensive mice exhibited increased phosphorylatory activation of SPAK (Ste20-related proline alanine-rich kinase) and NKCC1, as well as worsened infarct and neurological deficit after permanent distal middle cerebral artery occlusion. Conclusions- The novel NKCC1 inhibitor STS66 is superior to BMT and STS5 in reducing ischemic infarction, swelling, and neurological deficits in large-vessel transient ischemic stroke, as well as in permanent focal ischemic stroke with hypertension comorbidity.
Assuntos
Palavras-chave
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Encéfalo / Isquemia Encefálica / Recuperação de Função Fisiológica / Acidente Vascular Cerebral / Inibidores de Simportadores de Cloreto de Sódio e Potássio / Membro 2 da Família 12 de Carreador de Soluto Limite: Animals Idioma: En Revista: Stroke Ano de publicação: 2019 Tipo de documento: Article País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Encéfalo / Isquemia Encefálica / Recuperação de Função Fisiológica / Acidente Vascular Cerebral / Inibidores de Simportadores de Cloreto de Sódio e Potássio / Membro 2 da Família 12 de Carreador de Soluto Limite: Animals Idioma: En Revista: Stroke Ano de publicação: 2019 Tipo de documento: Article País de publicação: Estados Unidos