Angiotensin Receptor Type 2 Activation Induces Neuroprotection and Neurogenesis After Traumatic Brain Injury

Abstract

Angiotensin II receptor type 2 (AT 2 ) agonists have been shown to limit brain ischemic insult and to improve its outcome. The activation of AT 2 was also linked to induced neuronal proliferation and differentiation in vitro. In this study, we examined the therapeutic potential of AT 2 activation following traumatic brain injury (TBI) in mice, a brain pathology that displays ischemia-like secondary damages. The AT 2 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 ½ (ERK½), and the neurotrophins nerve growth factor and brain-derived neurotrophic factor; all were blocked by treatment with the AT 2 antagonist PD123319. Our results suggest that AT 2 activation after TBI promotes neuroprotection and neurogenesis, and may be a novel approach for the development of new drugs to treat victims of TBI.

Activation of Sphingosine 1-Phosphate Receptor 1 Enhances Hippocampus Neurogenesis in a Rat Model of Traumatic Brain Injury: An Involvement of MEK/Erk Signaling Pathway

“…The results implied that a potential association might exist between S1PR1 activation and MEK/Erk cascade phosphorylation in hippocampal neurogenesis after TBI. In addition to our findings, other studies have shown that the upregulated expression of pErk at 8 hours, 1 day, and even 14 days after CNS injury also played a positive role in hippocampal neurogenesis [31, 32, 37]. Accordingly, these evidences collectively provided an insight into the regulatory role of MEK/Erk signaling in neurogenesis after TBI.…”

“…In several previous studies, it was well acknowledged that MEK/Erk cascade was critical for the activation of transcription factors and genes to regulate NSCs proliferation and differentiation, as well as the maturation of NSCs-derived neuronal cells [18, 31, 32]. Recently, growing researches have demonstrated an involvement of MEK/Erk cascade in neurogenesis induced by diverse growth factors, such as neurotrophin-3 and vascular endothelial growth factor (VEGF) [33–35].…”

“…Particularly, Ge and his colleagues found that MEK/Erk pathway was required for the neuronal differentiation but not for the oligodentrocytic differentiation of NSCs induced by poly-L-ornithine in vitro [36]. Furthermore, MEK/Erk pathway has been reported to play protective roles for neurons survival in DG [17, 32] and also contribute to the antiapoptotic effect of S1PR1 on neurons in injured cortex after cerebral ischemia [19]. …”

Endogenous neurogenic cell response in the mature mammalian brain following traumatic injury

“…For example, post-TBI hypothermia treatment increases survival of newly generated neurons (Bregy et al, 2012). Intraventricular infusion of angiotensin receptor type 2 agonist (CGP42112A) for 3 days following a closed head injury induces cell proliferation in both the SVZ and DG, and increases the total number of new neurons in a dose-dependent manner (Umschweif et al, 2014). Post-TBI treatment with the P7C3 class of aminopropyl carbazole agents (P7C3-A20) 30min post LFPI for 7 days increases cell proliferation and survival of newly generated neurons in the SGZ (Blaya et al, 2014).…”

Strategies targeting endogenous neurogenic cell response to improve recovery following traumatic brain injury

“…Activation of AT2 increases the expression levels of BDNF and its receptors in neurons (Namsolleck et al, 2013). Activating AT2 via pharmacological agent CGP42112A in a closed head injury model in mice via intraventricular infusion for 3 days immediately following injury shows a dose dependent improvement in functional recovery accompanied by enhanced cell proliferation and generation of new neurons in the DG (Umschweif et al, 2014a & 2014b). …”