TRPC3/6/7 knockdown protects the brain from cerebral ischemia injury via astrocyte apoptosis inhibition and effects on NF-кB translocation

• Autores: Chen, Xiaoyun; Lu, Min; He, Xiju; Ma, Le; Birnbaumer, Lutz; Liao, Yanhong
• Año de publicación: 2017
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: Molecular Neurobiology. 2017, 57
• Materia: ENFERMEDADES CEREBROVASCULARES; ISQUEMIA ENCEFALICA; ACCIDENTE CEREBROVASCULAR; TRATAMIENTO MEDICO; PREVENCION Y CONTROL; APOPTOSIS
• Institución: Pontificia Universidad Católica Argentina

Fil: Chen, Xiaoyun. Huazhong University of Science and Technology. Tongji Medical College. Department of Anatomy; China
Fil: Chen, Xiaoyun. Huazhong University of Science and Technology. Tongji Medical College. Brain Research Institute; China
Fil: Lu, Min. Huazhong University of Science and Technology. Tongji Medical College. Department of Anatomy; China
Fil: Huazhong University of Science and Technology. Tongji Medical College. Brain Research Institute; China
Fil: He, Xiju. Huazhong University of Science and Technology. Tongji Medical College. Department of Anatomy; China
Fil: He, Xiju. Huazhong University of Science and Technology. Tongji Medical College. Brain Research Institute; China
Fil: Ma, Le. Huazhong University of Science and Technology. Tongji Medical College. Department of Anatomy; China
Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina
Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Birnbaumer, Lutz. Research Triangle Park. National Institute of Environmental Health Sciences. Neurobiology Laboratory; Estados Unidos
Fil: Liao, Yanhon. Huazhong University of Science and Technology. Tongji Medical College. Brain Research Institute; China
Fil: Liao, Yanhon. Huazhong University of Science and Technology. Tongji Medical College. Department of Anatomy; China
Abstract: Ischemia contributes significantly to morbidity and mortality associated with many common neurological diseases. Calcium overload is an important mechanism of cerebral ischemia and reperfusion (I/R) injury. Despite decades of intense research, an effective beneficial treatment of stroke remains limited; few therapeutic strategies exist to combat the consequences of cerebral ischemia. Traditionally, a “neurocentric” view has dominated research in this field. Evidence is now accumulating that glial cells, especially astrocytes, play an important role in the pathophysiology of cerebral ischemia. Here, we show that transient receptor potential (TRP)C3/6/7 knockout (KO) mice subjected to an I/R procedure demonstrate ameliorated brain injury (infract size), compared to wild-type (WT) control animals. This is accompanied by reduction of NF-кB phosphorylation and an increase in protein kinase B (AKT) phosphorylation in I/R-injured brain tissues in TRPC3/6/7 KO mice. Also, the expression of pro-apoptotic protein Bcl-2 associated X (Bax) is down-regulated and that of anti-apoptotic protein Bcl-2 is upregulated in TRPC3/6/7 mice. Astrocytes isolated from TRPC3/6/7 KO mice and subjected to oxygen/glucose deprivation and subsequent reoxygenation (OGD-R, mimicking in vivo I/R injury) also exhibit enhanced Bcl-2 expression, reduced Bax expression, enhanced AKT phosphorylation, and reduced NF-кB phosphorylation. Furthermore, apoptotic rates of TRPC3/6/7 KO astrocytes cultured in OGD-R conditions were reduced significantly compared to WT control. These findings suggest TRPC3/6/7 channels play a detrimental role in brain I/R injury. Deletion of these channels can interfere with the activation of NF-кB (pro-apoptotic), promote activation of AKT (anti-apoptotic), and ultimately, ameliorate brain damage via inhibition of astrocyte apoptosis after cerebral ischemia/reperfusion injury.