Angiotensin-(1-7) improves cognitive function and reduces inflammation in mice following mild traumatic brain injury

Abstract

IntroductionTraumatic brain injury (TBI) is a leading cause of disability in the US. Angiotensin 1-7 (Ang-1-7), an endogenous peptide, acts at the G protein coupled MAS1 receptors (MASR) to inhibit inflammatory mediators and decrease reactive oxygen species within the CNS. Few studies have identified whether Ang-(1-7) decreases cognitive impairment following closed TBI. This study examined the therapeutic effect of Ang-(1-7) on secondary injury observed in a murine model of mild TBI (mTBI) in a closed skull, single injury model.Materials and methodsMale mice (n = 108) underwent a closed skull, controlled cortical impact injury. Two hours after injury, mice were administered either Ang-(1-7) (n = 12) or vehicle (n = 12), continuing through day 5 post-TBI, and tested for cognitive impairment on days 1–5 and 18. pTau, Tau, GFAP, and serum cytokines were measured at multiple time points. Animals were observed daily for cognition and motor coordination via novel object recognition. Brain sections were stained and evaluated for neuronal injury.ResultsAdministration of Ang-(1-7) daily for 5 days post-mTBI significantly increased cognitive function as compared to saline control-treated animals. Cortical and hippocampal structures showed less damage in the presence of Ang-(1-7), while Ang-(1-7) administration significantly changed the expression of pTau and GFAP in cortical and hippocampal regions as compared to control.DiscussionThese are among the first studies to demonstrate that sustained administration of Ang-(1-7) following a closed-skull, single impact mTBI significantly improves neurologic outcomes, potentially offering a novel therapeutic modality for the prevention of long-term CNS impairment following such injuries.

PNA6, a Lactosyl Analogue of Angiotensin-(1—7), Reverses Pain Induced in Murine Models of Inflammation, Metastatic Bone Disease, and Chemotherapy-Induced Peripheral Neuropathy

“…Ang-(1-7) at Mas receptors (MasR1) has been reported to prevent cognitive impairment in cardiovascular disease [20,21], reduce cognitive decline in Traumatic Brain Injury (TBI) [22], and attenuate cancer-induced bone pain (CIBP) [23]. However, Ang-(1-7) is degraded rapidly by enzymes and has a short half-life in vivo.…”

PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease

“…Our team has taken a novel approach to treating CIPN by taking advantage of our extensive experience with the G-protein linked Mas receptor and its agonist Ang-(1-7) to develop a platform of glycosylated Ang-(1-7) Mas receptor agonists including PNA5 and PNA6 that have outstanding brain penetration, enhanced bioavailability, decreased brain and peripheral inflammation, improved cerebral blood flow, and restored cognitive function in our preclinical vascular dementia and TBI animal models. Activation of Mas decreases ROS and brain inflammation, increases cerebral circulation, increases induction of neuroprotective cytokines, and inhibits hypoxia-inducing factor-1alpha (HIF-1alpha) [20][21][22][23]. However, Ang-(1-7) is degraded rapidly by enzymes and has a short half-life in vivo.…”

PNA5, A Novel Mas Receptor Agonist, Improves Neurovascular and Blood-Brain-Barrier Function in a Mouse Model of Vascular Cognitive Impairment and Dementia

“…The peptide PNA5 is a novel pleiotropic anti-inflammatory Angiotensin-(1-7) (Ang-1-7) peptide derivative acting at the Mas receptor that has outstanding brain penetration and enhanced bioavailability. PNA5 decreases brain and cerebrovascular inflammation and restores cognitive function in our preclinical VCID model [ 15 - 20 ], likely by reducing endothelial reactive oxygen species (ROS) generation, decreasing brain and circulating inflammatory cytokines, and circulating neurofilament light protein (NfL), a well-known biomarker for neurodegeneration [ 15 , 16 , 21 , 22 ]. Within the brain, the Mas receptor is expressed on neurons, glia, and vascular endothelial cells [ 23 ].…”