apelin-13-peptide and Brain-Injuries

Early brain injury (EBI) has been considered as the major contributor to the neurological dysfunction and poor clinical outcomes of subarachnoid hemorrhage (SAH). Studies showed that apelin-13 exhibits a neuroprotective effect in brain damage induced by cerebral ischemia. However, it remains unclear whether apelin-13 could exhibit the protective functions following SAH. The present study aimed to validate the neuroprotective role of apelin-13 in SAH, and further investigated the underlying mechanisms.. We constructed SAH rat model and we found that apelin-13 significantly alleviated neurological disorder and brain edema, improved memory deficits in SAH rats. Apelin-13 treatment decreased contents of TNF-α and IL-1β in cerebral spinal fluid of SAH rat by using ELISA. Apelin-13 treatment promoted the expression of APJ and Bcl-2, and decreased the level of active caspase-3 and Bax in the temporal cortex after SAH by using western blot. Also, apelin-13 attenuated the cortical cell death and neuronal degeneration as shown by TUNEL, FJB and Nissl staining. However, ML221, an inhibitor of APJ, significantly reversed all the above neuroprotective effects of apelin-13. Moreover, a neuron-microglia co-culture system, which mimic SAH in vitro, confirmed the protective effect of apelin-13 on neurons and the inhibitory effect on inflammation through apoptosis-related proteins.. These data demonstrated that apelin-13 exhibit a neuroprotective role after SAH through inhibition of apoptosis in an APJ dependent manner.

Topics: Animals; Apoptosis; Brain Injuries; Inflammation; Intercellular Signaling Peptides and Proteins; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage

Apelin-13 can be expressed in brain tissue and exert neuroprotective effects. We attempted to determine whether serum apelin-13 is a prognostic biomarker for severe traumatic brain injury (sTBI).. Of 126 sTBI patients and 126 healthy controls, serum apelin-13 concentrations were quantified using ELISA. The trauma severity was assessed by Glasgow coma scale scores and Rotterdam computerized tomography scores. The relationship between serum apelin-13 concentrations and posttraumatic 30-day mortality was assessed using multivariate analysis.. Serum apelin-13 concentrations were significantly lower in patients than in controls. Serum apelin-13 concentrations of non-surviving and surviving patients within posttraumatic 30 days were strongly correlated with Glasgow coma scale scores and Rotterdam computerized tomography scores. Serum apelin-13 emerged as an independent predictor for 30-day mortality and overall survival. There was a significant discriminatory capability with respect to serum apelin-13 concentrations for the risk of 30-day death. Moreover, its prognostic predictive ability was similar to those of Glasgow coma scale scores and Rotterdam computerized tomography scores.. Declined serum apelin-13 concentrations, in substantial correlation with increasing severity, are independently associated with short-term mortality, hinting than serum apelin-13 might represent a useful prognostic biomarker for sTBI.

Topics: Brain Injuries; Brain Injuries, Traumatic; Glasgow Coma Scale; Humans; Intercellular Signaling Peptides and Proteins; Prognosis

Neuroinflammation and oxidative stress play important roles in early brain injury following subarachnoid hemorrhage (SAH). This study is the first to show that activation of apelin receptor (APJ) by apelin-13 could reduce endoplasmic reticulum (ER)-stress-associated inflammation and oxidative stress after SAH.. Apelin-13, apelin siRNA, APJ siRNA, and adenosine monophosphate-activated protein kinase (AMPK) inhibitor-dorsomorphin were used to investigate if the activation of APJ could provide neuroprotective effects after SAH. Brain water content, neurological functions, blood-brain barrier (BBB) integrity, and inflammatory molecules were evaluated at 24 h after SAH. Western blotting and immunofluorescence staining were applied to assess the expression of target proteins.. The results showed that endogenous apelin, APJ, and p-AMPK levels were significantly increased and peaked in the brain 24 h after SAH. In addition, administration of exogenous apelin-13 significantly alleviated neurological functions, attenuated brain edema, preserved BBB integrity, and also improved long-term spatial learning and memory abilities after SAH. The underlying mechanism of the neuroprotective effects of apelin-13 is that it suppresses microglia activation, prevents ER stress from overactivation, and reduces the levels of thioredoxin-interacting protein (TXNIP), NOD-like receptor pyrin domain-containing 3 protein (NLRP3), Bip, cleaved caspase-1, IL-1β, TNFα, myeloperoxidase (MPO), and reactive oxygen species (ROS). Furthermore, the use of APJ siRNA and dorsomorphin abolished the neuroprotective effects of apelin-13 on neuroinflammation and oxidative stress.. Exogenous apelin-13 binding to APJ attenuates early brain injury by reducing ER stress-mediated oxidative stress and neuroinflammation, which is at least partly mediated by the AMPK/TXNIP/NLRP3 signaling pathway.

Topics: AMP-Activated Protein Kinases; Animals; Apelin Receptors; Brain Injuries; Cell Cycle Proteins; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Intercellular Signaling Peptides and Proteins; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Protein Binding; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage

Apelin, an endogenous ligand for the orphan G-protein-coupled receptor APJ, possesses anti-apoptotic and neuroprotective properties. It has been shown to be a protective factor for different types of central nervous system insults, such as ischemia and traumatic brain injury. Here, we investigated the effects of apelin-13 on early brain injury (EBI) following subarachnoid hemorrhage (SAH), and the underlying molecular mechanisms involved. Apelin-13 was delivered to rats via intracerebroventricular administration. Neurological scores, brain water content and neuronal apoptosis were measured 24 h after SAH. The PI3K/Akt inhibitor LY294002 or GLP-1R siRNA were injected into the lateral cerebral ventricle before induction of SAH. Changes in the expression of p-Akt, GLP-1R and apoptosis-associated proteins (Bax, Bcl-2, cleaved caspase-3) were then investigated. Results showed that the levels of GLP-1R in neurons increased significantly, reaching a peak at 24 h after the induction of SAH. Treatment with apelin-13 improved neurological deficits, as well as alleviated brain edema and apoptotic cell death. Apelin-13 was also able to increase the levels of p-Akt, GLP-1R and Bcl-2, while inhibiting the expression levels of Bax and cleaved caspase-3. The anti-apoptotic and neuroprotective effects of apelin-13 were partially reversed by addition of LY294002 or GLP-1R siRNA. These results provide evidence that apelin-13 attenuates EBI following SAH via suppressing neuronal apoptosis, and that this effect may act partially via the activation of the GLP-1R/PI3K/Akt signaling pathway.

Topics: Animals; Apoptosis; Brain; Brain Injuries; Glucagon-Like Peptide-1 Receptor; Intercellular Signaling Peptides and Proteins; Male; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; Subarachnoid Hemorrhage

Neuronal apoptosis plays important roles in the early brain injury after subarachnoid hemorrhage (SAH). This study first showed that inhibition of activating transcription factor 6 (ATF6) by apelin-13 could reduce endoplasmic reticulum (ER)-stress-mediated apoptosis and blood-brain-barrier (BBB) disruption after SAH. We chose apelin-13, ATF6 and CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) siRNAs to verify the hypothesis. Brain water content, neurological behavior and Evans Blue (EB) were assessed at 24 h after SAH. Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) were applied to evaluate the expression of targets in both protein and mRNA levels. Neuronal apoptosis was assessed with Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) and caspase-3 staining. The results showed that the levels of ATF6, and its downstream protein, CHOP were upregulated and reached the peak at 24 h after SAH. ATF6 was highly expressed in neurons. The administration of apelin-13 could significantly reduce the mRNA and protein levels of ATF6, and its downstream targets, CHOP and caspase-3, but increase the Bcl-2/Bax ratio, Claudin-5, Occludin and ZO-1. What's more, the administration of apelin-13 could reduce brain edema, ameliorate BBB disruption and improve neurological functions. However, the CHOP siRNA could significantly reverse the pro-apoptotic effect induced by the increased ATF6 level after SAH. Apelin-13 could exert its neuroprotective effects via suppression of ATF6/CHOP arm of ER-stress-response pathway in the early brain injury after SAH.

Topics: Activating Transcription Factor 6; Animals; Apoptosis; Blood-Brain Barrier; Brain Edema; Brain Injuries; Disease Models, Animal; Intercellular Signaling Peptides and Proteins; Male; Neurons; Neuroprotective Agents; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Subarachnoid Hemorrhage; Time Factors; Transcription Factor CHOP

The adipocytokine apelin is a peptide, Apelin and its receptor are abundantly expressed in the nervous and cardiovascular systems. Previous studies had found apelin-13 reduces brain injuries and postischemic cerebral edema through blocking programmed cell death, Apelin-13 is also able to inhibit glucose deprivation induced cardiomyocyte autophagy in a concentration dependent fashion. To observe the effect of Apelin-13 on the brain injury induced by traumatic brain injury (TBI), and explore the effect of Apelin-13 on autophagy in TBI, We performed The neurological test, and the numbers of TBI-induced neural cell death were also counted by propidium iodide labeling. At last, the autophagy associated proteins LC3, Beclin-1, Bcl-2, p62 were also assessed with western-blotting. Compared with saline vehicle groups, the neural cell death, lesion volume, and neural dysfunction were attenuated by apelin-13 after TBI. In additionally, Apelin-13 also reversed TBI induced downregulation of LC3, Beclin-1, Bcl-2, p62 expression, compared with saline vehicle groups, at 24 and 48 h post TBI. Apelin-13 attenuates TBI induced brain damage by suppressing autophagy. All these results revealed that Apelin-13 suppressed autophagy. The autophagy may be involved in the mechanism of Apelin-13 rescue the subsequent damaged neuron in TBI.

Topics: Animals; Autophagy; Behavior, Animal; Brain Injuries; Cell Count; Cerebral Cortex; Hippocampus; Intercellular Signaling Peptides and Proteins; Male; Maze Learning; Mice; Movement Disorders