TY - JOUR
T1 - Angiotensin Receptor Type 2 Activation Induces Neuroprotection and Neurogenesis After Traumatic Brain Injury
AU - Umschweif, Gali
AU - Liraz-Zaltsman, Sigal
AU - Shabashov, Dalia
AU - Alexandrovich, Alexander
AU - Trembovler, Victoria
AU - Horowitz, Michal
AU - Shohami, Esther
N1 - Funding Information: This study was supported, in part, by grants (to ES) from the Brettler Foundation at the School of Pharmacy, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF).
PY - 2014/7
Y1 - 2014/7
N2 - Angiotensin II receptor type 2 (AT2) agonists have been shown to limit brain ischemic insult and to improve its outcome. The activation of AT2 was also linked to induced neuronal proliferation and differentiation in vitro. In this study, we examined the therapeutic potential of AT2 activation following traumatic brain injury (TBI) in mice, a brain pathology that displays ischemia-like secondary damages. The AT2 agonist CGP42112A was continuously infused immediately after closed head injury (CHI) for 3 days. We have followed the functional recovery of the injured mice for 35 days post-CHI, and evaluated cognitive function, lesion volume, molecular signaling, and neurogenesis at different time points after the impact. We found dose-dependent improvement in functional recovery and cognitive performance after CGP42112A treatment that was accompanied by reduced lesion volume and induced neurogenesis in the neurogenic niches of the brain and also in the injury region. At the cellular/molecular level, CGP42112A induced early activation of neuroprotective kinases protein kinase B (Akt) and extracellular-regulated kinases 1/2 (ERK1/2), and the neurotrophins nerve growth factor and brain-derived neurotrophic factor; all were blocked by treatment with the AT2 antagonist PD123319. Our results suggest that AT2 activation after TBI promotes neuroprotection and neurogenesis, and may be a novel approach for the development of new drugs to treat victims of TBI.
AB - Angiotensin II receptor type 2 (AT2) agonists have been shown to limit brain ischemic insult and to improve its outcome. The activation of AT2 was also linked to induced neuronal proliferation and differentiation in vitro. In this study, we examined the therapeutic potential of AT2 activation following traumatic brain injury (TBI) in mice, a brain pathology that displays ischemia-like secondary damages. The AT2 agonist CGP42112A was continuously infused immediately after closed head injury (CHI) for 3 days. We have followed the functional recovery of the injured mice for 35 days post-CHI, and evaluated cognitive function, lesion volume, molecular signaling, and neurogenesis at different time points after the impact. We found dose-dependent improvement in functional recovery and cognitive performance after CGP42112A treatment that was accompanied by reduced lesion volume and induced neurogenesis in the neurogenic niches of the brain and also in the injury region. At the cellular/molecular level, CGP42112A induced early activation of neuroprotective kinases protein kinase B (Akt) and extracellular-regulated kinases 1/2 (ERK1/2), and the neurotrophins nerve growth factor and brain-derived neurotrophic factor; all were blocked by treatment with the AT2 antagonist PD123319. Our results suggest that AT2 activation after TBI promotes neuroprotection and neurogenesis, and may be a novel approach for the development of new drugs to treat victims of TBI.
KW - CGP42112A
KW - Traumatic brain injury
KW - angiotensin receptor type 2
KW - neurogenesis
KW - neuroprotection
KW - neurotrophins
UR - http://www.scopus.com/inward/record.url?scp=84905587383&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s13311-014-0286-x
DO - https://doi.org/10.1007/s13311-014-0286-x
M3 - مقالة
C2 - 24957202
SN - 1933-7213
VL - 11
SP - 665
EP - 678
JO - Neurotherapeutics
JF - Neurotherapeutics
IS - 3
ER -