Apelin-13 is a novel endogenous ligand for an angiotensin-like orphan G-protein coupled receptor, and it may be neuroprotective against cerebral ischemia injury. However, the precise mechanisms of the effects of apelin-13 remain to be elucidated. To investigate the effects of apelin-13 on apoptosis and autophagy in models of cerebral ischemia/reperfusion injury, a rat model was established by middle cerebral artery occlusion. Apelin-13(50 μg/kg) was injected into the right ventricle as a treatment. In addition, an SH-SY5 Y cell model was established by oxygen-glucose deprivation/reperfusion, with cells first cultured in sugar-free medium with 95% N2 and 5% CO2 for 4 hours and then cultured in a normal environment with sugar-containing medium for 5 hours. This SH-SY5 Y cell model was treated with 10–7 M apelin-13 for 5 hours. Results showed that apelin-13 protected against cerebral ischemia/reperfusion injury. Apelin-13 treatment alleviated neuronal apoptosis by increasing the ratio of Bcl-2/Bax and significantly decreasing cleaved caspase-3 expression. In addition, apelin-13 significantly inhibited excessive autophagy by regulating the expression of LC3 B, p62, and Beclin1. Furthermore, the expression of Bcl-2 and the phosphatidylinositol-3-kinase(PI3 K)/Akt/mammalian target of rapamycin(mTOR) pathway was markedly increased. Both LY294002(20 μM) and rapamycin(500 nM), which are inhibitors of the PI3 K/Akt/mTOR pathway, significantly attenuated the inhibition of autophagy and apoptosis caused by apelin-13. In conclusion, the findings of the present study suggest that Bcl-2 upregulation and mTOR signaling pathway activation lead to the inhibition of apoptosis and excessive autophagy. These effects are involved in apelin-13-induced neuroprotection against cerebral ischemia/reperfusion injury, both in vivo and in vitro. The study was approved by the Animal Ethical and Welfare Committee of Jining Medical University, China(approval No. 2018-JS-001) in February 2018. 相似文献
Apoptosis is an important factor during the early stage of intracerebral hemorrhage.MiR-181 c plays a key regulatory role in apoptosis.However,whether miR-181 c is involved in apoptosis of prophase cells after intracerebral hemorrhage remains unclear.Therefore,in vitro and in vivo experiments were conducted to test this hypothesis.In vivo experiments:collagenase type VII was injected into the basal ganglia of adult Sprague-Dawley rats to establish an intracerebral hemorrhage model.MiR-181 c mimic or inhibitor was injected in situ 4 hours after intracerebral hemorrhage.Neurological functional defects(neurological severity scores)were assessed 1,7,and 14 days after model establishment.Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and western blot assay were conducted 14 days after model establishment.In vitro experiments:PC12 cells were cultured under oxygen-glucose deprivation,and hemins were added to simulate intracerebral hemorrhage in vitro.MiR-181 c mimic or inhibitor was added to regulate miR-181 c expression.3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,luciferase reporter system,and western blot assay were performed.Experimental results revealed differences in miR-181 c expression in brain tissues of both patients and rats with cerebral hemorrhage.In addition,in vitro experiments found that miR-181 c overexpression could upregulate the Bcl-2/Bax ratio to inhibit apoptosis,while inhibition of miR-181 c expression could reduce the Bcl-2/Bax ratio and aggravate apoptosis of cells.Regulation of apoptosis occurred through the phosphoinositide 3 kinase(PI3 K)/Akt pathway by targeting of phosphatase and tensin homolog deleted on chromosome ten(PTEN).Higher miR-181 c overexpression correlated with lower neurological severity scores,indicating better recovery of neurological function.In conclusion,miR-181 c affects the prognosis of intracerebral hemorrhage by regulating apoptosis,and these effects might be directly mediated and regulated by targeting of the PTEN\PI3 K/Akt pathway and Bcl-2/Bax ratio.Furthermore,these results indicated that miR-181 c played a neuroprotective role in intracerebral hemorrhage by regulating apoptosis of nerve cells,thus providing a potential target for the prevention and treatment of intracerebral hemorrhage.Testing of human serum was authorized by the Ethics Committee of China Medical University(No.2012-38-1)on February 20,2012.The protocol was registered with the Chinese Clinical Trial Registry(Registration No.ChiCTR-COC-17013559).The animal study was approved by the Institutional Animal Care and Use Committee of China Medical University(approval No.2017008)on March 8,2017. 相似文献
Multiple sclerosis(MS)is an inflammatory demyelinating disease of the central nervous system.The disability caused by inflammatory demyelination clinically dominates the early stages of relapsing-remitting MS and is reversible.Once there is considerable loss of axons,MS patients enter a secondary progressive stage.Disease-modifying drugs currently in use for MS suppress the immune system and reduce relapse rates but are not effective in the progressive stage.Various animal models of MS(mostly mouse and rat)have been established and proved useful in studying the disease process and response to therapy.The experimental autoimmune encephalomyelitis animal studies reviewed here showed that a chronic progressive disease can be induced by immunization with appropriate amounts of myelin oligodendrocyte glycoprotein together with mycobacterium tuberculosis and pertussis toxin in Freund's adjuvant.The clinical manifestations of autoimmune encephalomyelitis disease were prevented or reduced by treatment with certain pharmacological agents given prior to,at,or after peak disease,and the agents had protective effects as shown by inhibiting demyelination and damage to neurons,axons and oligodendrocytes.In the cuprizone-induced toxicity animal studies,the pharmacological agents tested were able to promote remyelination and increase the number of oligodendrocytes when administered therapeutically or prophylactically.A monoclonal IgM antibody protected axons in the spinal cord and preserved motor function in animals inoculated with Theiler's murine encephalomyelitis virus.In all these studies the pharmacological agents were administered singly.A combination therapy may be more effective,especially using agents that target neuroinflammation and neurodegeneration,as they may exert synergistic actions. 相似文献
L‐3,4‐dihydroxyphenylalanine (L‐DOPA) reduces symptoms of Parkinson's disease (PD), but suffers from serious side effects on long‐term use. Melatonin (10–30 mg/kg, 6 doses at 10 hr intervals) was investigated to potentiate L‐DOPA therapeutic effects in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced parkinsonism in mice. Striatal tyrosine hydroxylase (TH) immunoreactivity, TH, and phosphorylated ser 40 TH (p‐TH) protein levels were assayed on 7th day. Nigral TH‐positive neurons stereology was conducted on serial sections 2.8 mm from bregma rostrally to 3.74 mm caudally. MPTP caused 39% and 58% decrease, respectively, in striatal fibers and TH protein levels, but 2.5‐fold increase in p‐TH levels. About 35% TH neurons were lost between 360 and 600 μm from 940 μm of the entire nigra analyzed, but no neurons were lost between 250 μm rostrally and 220 μm caudally. When L‐DOPA in small doses (5–8 mg/kg) failed to affect MPTP‐induced akinesia or catalepsy, co‐administration of melatonin with L‐DOPA attenuated these behaviors. Melatonin administration significantly attenuated MPTP‐induced loss in striatal TH fibers (82%), TH (62%) and p‐TH protein (100%) levels, and nigral neurons (87–100%). Melatonin failed to attenuate MPTP‐induced striatal dopamine depletion. L‐DOPA administration (5 mg/kg, once 40 min prior to sacrifice, p.o.) in MPTP‐ and melatonin‐treated mice caused significant increase in striatal dopamine (31%), as compared to L‐DOPA and MPTP‐treated mice. This was equivalent to 8 mg/kg L‐DOPA administration in parkinsonian mouse. Therefore, prolonged, effective use of L‐DOPA in PD with lesser side effects could be achieved by treating with 60% lower doses of L‐DOPA along with melatonin. 相似文献
Seven natural compounds, including new compounds hyperascyrins L-N (1-3) and four known compounds (4-7), were acquired from the aerial parts of Hypericum ascyron, that were all identified as methylated polycyclic polyprenylated acylphloroglucinol derivatives (mPPAPs). The structures of these compounds were established by NMR spectroscopy, experimental and calculated electronic circular dichroism (ECD) data. The neuroprotective activities and hepatoprotective activity of these compounds (10 µM) were evaluated. Compounds 1, 2 and 3 exhibited neuroprotection activity. Compounds 1 and 3 show hepatoprotective activity. 相似文献
Introduction: Ischemic stroke is becoming a primary cause of disability and death worldwide. To date, therapeutic options remain limited focusing on mechanical thrombolysis or administration of thrombolytic agents. However, these therapies do not promote neuroprotection and neuro-restoration of the ischemic area of the brain.
Areas covered: This review highlights the option of minimal invasive, intra-arterial, administration of biological agents for stroke therapy. The authors provide an update of all available studies, discuss issues that influence outcomes and describe future perspectives which aim to improve clinical outcomes. New therapeutic options based on cellular and molecular interactions following an ischemic brain event, will be highlighted.
Expert opinion: Intra-arterial administration of biological agents during trans-catheter thrombolysis or thrombectomy could limit neuronal cell death and facilitate regeneration or neurogenesis following ischemic brain injury. Despite the initial progress, further meticulous studies are needed in order to establish the clinical use of stem cell-induced neuroprotection and neuroregeneration. 相似文献
ObjectivesAneurysmal subarachnoid hemorrhage (SAH) continues to be a difficult cerebrovascular disease with limited pharmacologic treatment options. Cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) are leading causes of morbidity and mortality after SAH. Despite the advances in the understanding of its pathophysiology and tremendous efforts to date, nimodipine is currently the sole Food and Drug Administration–approved treatment for patients with SAH, with benefits that are marginal at best. The neuromodulation therapies are promising, especially those that target CV and DCI to improve functional outcomes. The aim of this review is therefore to summarize the available evidence for each type of neuromodulation for CV and DCI, with a special focus on its pathophysiological mechanisms, in addition to their clinical utility and drawbacks, which we hope will lead to future translational therapy options after SAH.Materials and MethodsWe conducted a comprehensive review of preclinical and clinical studies demonstrating the use of neuromodulation for SAH. The literature search was performed using PubMed, Embase, and ClinicalTrials.gov. A total of 21 articles published from 1992 to 2021 and eight clinical trials were chosen.ResultsThe studies reviewed provide a compelling demonstration that neuromodulation is a potentially useful strategy to target multiple mechanisms of DCI and thus to potentially improve functional outcomes from SAH. There are several types of neuromodulation that have been tested to treat CV and DCI, including the trigeminal/vagus/facial nerve stimulation, sphenopalatine ganglion and spinal cord stimulation, transcranial direct electrical stimulation, transcutaneous electrical neurostimulation, and electroacupuncture. Most of them are in the preclinical or early phases of clinical application; however, they show promising results.ConclusionsDCI has a complex pathogenesis, making the unique anatomical distribution and pleiotropic capabilities of various types of neuromodulation a promising field of study. We may be at the cusp of a breakthrough in the use of these techniques for the treatment of this stubbornly difficult disease. 相似文献