T0901317, an Agonist of Liver X Receptors, Attenuates Neuronal Apoptosis in Early Brain Injury after Subarachnoid Hemorrhage in Rats via Liver X Receptors/Interferon Regulatory Factor/P53 Upregulated Modulator of Apoptosis/Dynamin-1-Like Protein Pathway

Background and Purpose. T0901317, a liver X receptor (LXR) agonist, is widely used to explore the functions of LXRs. T0901317 exerts antiapoptotic effects in many central nervous system disease models. Our aim was to detect the role of T0901317 in neuronal apoptosis in early brain injury after subarachnoid hemorrhage. Methods. Subarachnoid hemorrhage (SAH) models of Sprague-Dawley rats were established with perforation method. T0901317 was injected intraperitoneally 1-hour post-SAH. GSK2033, an inhibitor of LXRs, and interferon regulatory factor (IRF-1) CRISPR activation were injected intracerebroventricularly to evaluate potential signaling pathway. The severity of SAH, neurobehavior test in both short- and long-term and apoptosis was measured with Western blot and immunofluorescence staining. Results. Expression of LXR-α and IRF-1 increased and peaked at 24 h post-SAH, while LXR-β remained unaffected in SAH+vehicle group compared with Sham group. Post-SAH T0901317 treatment attenuated neuronal impairments in both short- and long-term and decreased neuronal apoptosis, the expression of IRF-1, P53 upregulated modulator of apoptosis (PUMA), dynamin-1-like protein (Drp1), Bcl-2-associated X protein (Bax) and cleaved caspase-3, and increasing B-cell lymphoma 2 (Bcl-2) at 24 h from modeling. GSK2033 inhibited LXRs and reversed T0901317’s neuroprotective effects. IRF-1 CRISPR activation upregulated the expression of IRF-1 and abolished the treatment effects of T0901317. Conclusion. T0901317 attenuated neuronal apoptosis via LXRs/IRF-1/PUMA/Drp1 pathway in SAH rats.

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TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-κB pathways

Cell Death and Disease ◽

10.1038/s41419-020-03278-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yan Zhou ◽

Tao Tao ◽

Guangjie Liu ◽

Xuan Gao ◽

Yongyue Gao ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Therapeutic Target ◽

Cortical Neurons ◽

Neuronal Apoptosis ◽

Early Brain Injury ◽

Neurological Deficits ◽

Human Brain Tissue

AbstractNeuronal apoptosis has an important role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). TRAF3 was reported as a promising therapeutic target for stroke management, which covered several neuronal apoptosis signaling cascades. Hence, the present study is aimed to determine whether downregulation of TRAF3 could be neuroprotective in SAH-induced EBI. An in vivo SAH model in mice was established by endovascular perforation. Meanwhile, primary cultured cortical neurons of mice treated with oxygen hemoglobin were applied to mimic SAH in vitro. Our results demonstrated that TRAF3 protein expression increased and expressed in neurons both in vivo and in vitro SAH models. TRAF3 siRNA reversed neuronal loss and improved neurological deficits in SAH mice, and reduced cell death in SAH primary neurons. Mechanistically, we found that TRAF3 directly binds to TAK1 and potentiates phosphorylation and activation of TAK1, which further enhances the activation of NF-κB and MAPKs pathways to induce neuronal apoptosis. Importantly, TRAF3 expression was elevated following SAH in human brain tissue and was mainly expressed in neurons. Taken together, our study demonstrates that TRAF3 is an upstream regulator of MAPKs and NF-κB pathways in SAH-induced EBI via its interaction with and activation of TAK1. Furthermore, the TRAF3 may serve as a novel therapeutic target in SAH-induced EBI.

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Phosphodiesterase-4 inhibition confers a neuroprotective efficacy against early brain injury following experimental subarachnoid hemorrhage in rats by attenuating neuronal apoptosis through the SIRT1/Akt pathway

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2018.01.093 ◽

2018 ◽

Vol 99 ◽

pp. 947-955 ◽

Cited By ~ 9

Author(s):

Qun Li ◽

Yucong Peng ◽

Linfeng Fan ◽

Hangzhe Xu ◽

Pingyou He ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Neuronal Apoptosis ◽

Early Brain Injury ◽

Akt Pathway ◽

Phosphodiesterase 4 ◽

Experimental Subarachnoid Hemorrhage ◽

Neuroprotective Efficacy

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Apigenin attenuates oxidative stress and neuronal apoptosis in early brain injury following subarachnoid hemorrhage

Journal of Clinical Neuroscience ◽

10.1016/j.jocn.2017.03.003 ◽

2017 ◽

Vol 40 ◽

pp. 157-162 ◽

Cited By ~ 25

Author(s):

Yuwei Han ◽

Tingting Zhang ◽

Jingyuan Su ◽

Yuan Zhao ◽

Chenchen ◽

...

Keyword(s):

Oxidative Stress ◽

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Neuronal Apoptosis ◽

Early Brain Injury

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Abstract P783: Alpha 7 -Acetylcholine Receptor Signaling Reduces Neuronal Apoptosis After Subarachnoid Hemorrhage

Stroke ◽

10.1161/str.52.suppl_1.p783 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Ari Dienel ◽

Remya A Veettil ◽

Kanako Matsumura ◽

Peeyush Kumar T. ◽

Spiros Blackburn ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Acetylcholine Receptor ◽

Neuronal Apoptosis ◽

Neuronal Survival ◽

Memory Function ◽

Memory Deficits ◽

Long Term Memory ◽

Term Memory ◽

Receptor Knockout Mouse

Subarachnoid hemorrhage induces neuronal apoptosis which causes acute and long-term memory deficits. Ourhypothesis is that agonism of α7-acetylcholine receptors attenuates neuronal apoptosis and improves memorydeficits in SAH mice. Mice were randomly assigned into the experimental groups. One cohort was euthanizedone day after SAH to assess neuronal apoptosis and signaling pathways. A second cohort survived for 30 dayspost-SAH to test long-term memory function. Inhibitors and an α7-acetylcholine receptor knockout mouse wereused. Neurobehavioral performance was assessed on days 1-3, 5, 7, and 23-28. All outcomes were performedand all data was analyzed by a blinded investigator. The α7-acetylcholine receptor agonist prevented neuronalapoptosis and improved acute memory deficits caused by SAH via activation of the PI3K/Akt pathway in neurons.Agonism of the α7-acetylcholine receptor was beneficial in both male and female mice, although the protectionin females was significantly better than in male mice. α7-acetylcholine receptor agonism did not provide anybenefit in α7-acetylcholine receptor knockout mice subjected to SAH. Treatment with the α7-acetylcholinereceptor agonist for 3 days after SAH led to improved working memory one month after SAH suggesting thatacutely improving neuronal survival can have long-lasting benefits. The α7-acetylcholine receptor may be atherapeutic target for SAH which can promote neuronal survival acutely after SAH, but also confer long-lastingmemory benefits. The findings of this study support the α7-acetylcholine receptor as a treatment target whichmay attenuate the long-term memory deficits which SAH patients suffer from.

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Clinical complications and outcomes of angiographically negative subarachnoid hemorrhage

Neurology ◽

10.1212/wnl.0000000000007501 ◽

2019 ◽

Vol 92 (20) ◽

pp. e2385-e2394 ◽

Cited By ~ 2

Author(s):

Cody L. Nesvick ◽

Soliman Oushy ◽

Lorenzo Rinaldo ◽

Eelco F. Wijdicks ◽

Giuseppe Lanzino ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Confidence Interval ◽

Ventriculoperitoneal Shunt ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Tertiary Referral Center ◽

Short And Long Term ◽

Csf Diversion

ObjectiveTo define the in-hospital course, complications, short- and long-term functional outcomes of patients with angiographically negative subarachnoid hemorrhage (anSAH), particularly those with aneurysmal-pattern anSAH (aanSAH).MethodsRetrospective cohort study of patients with aneurysmal subarachnoid hemorrhage (aSAH), aanSAH, and perimesencephalic-pattern anSAH (panSAH) treated at a single tertiary referral center between January 2006 and April 2018. Ninety-nine patients with anSAH (33 aanSAH and 66 panSAH) and 464 patients with aSAH were included in this study. Outcomes included symptomatic hydrocephalus requiring CSF drainage, need for ventriculoperitoneal shunt, radiographic vasospasm, delayed cerebral ischemia (DCI), radiographic infarction, disability level within 1 year of ictus, and at last clinical follow-up as defined by the modified Rankin Scale.ResultsPatients with aanSAH and panSAH had similar rates of DCI and radiologic infarction, and patients with aanSAH had significantly lower rates compared to aSAH (p ≤ 0.018). Patients with aanSAH were more likely than those with panSAH to require temporary CSF diversion and ventriculoperitoneal shunt (p ≤ 0.03), with similar rates to those seen in aSAH. Only one patient with anSAH died in the hospital. Compared to those with aSAH, patients with aanSAH were significantly less likely to have a poor functional outcome within 1 year of ictus (odds ratio 0.26, 95% confidence interval 0.090–0.75) and at last follow-up (hazard ratio 0.30, 95% confidence interval 0.19–0.49, p = 0.002).ConclusionsDCI is very uncommon in anSAH, but patients with aanSAH have a similar need for short- and long-term CSF diversion to patients with aSAH. Nevertheless, patients with aanSAH have significantly better short- and long-term outcomes.

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Upregulation of Interferon Regulatory Factor 6 Promotes Neuronal Apoptosis After Traumatic Brain Injury in Adult Rats

Cellular and Molecular Neurobiology ◽

10.1007/s10571-015-0217-3 ◽

2015 ◽

Vol 36 (1) ◽

pp. 27-36 ◽

Cited By ~ 12

Author(s):

Yuchang Lin ◽

Dezhi Xu ◽

Xiaohong Li ◽

Chun Liu ◽

Xia Liu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Neuronal Apoptosis ◽

Interferon Regulatory Factor ◽

Regulatory Factor ◽

Adult Rats ◽

Interferon Regulatory Factor 6

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Intranasal wnt-3a alleviates neuronal apoptosis in early brain injury post subarachnoid hemorrhage via the regulation of wnt target PPAN mediated by the moonlighting role of aldolase C

Neurochemistry International ◽

10.1016/j.neuint.2019.104656 ◽

2020 ◽

Vol 134 ◽

pp. 104656 ◽

Cited By ~ 2

Author(s):

Wu Ruan ◽

Junwen Hu ◽

Hang Zhou ◽

Yin Li ◽

Chaoran Xu ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Neuronal Apoptosis ◽

Early Brain Injury ◽

Aldolase C

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New Mechanisms and Targets of Subarachnoid Hemorrhage: A Focus on Mitochondria

Current Neuropharmacology ◽

10.2174/1570159x19666211101103646 ◽

2021 ◽

Vol 19 ◽

Author(s):

Zeyu Zhang ◽

Anke Zhang ◽

Yibo Liu ◽

Xiaoming Hu ◽

Yuanjian Fang ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Mitochondrial Dynamics ◽

Delayed Cerebral Ischemia ◽

Early Brain Injury ◽

Adverse Outcomes ◽

Heavy Burden ◽

Poor Outcomes ◽

Spontaneous Subarachnoid Hemorrhage ◽

Membrane Organelle

: Spontaneous subarachnoid hemorrhage (SAH) accounts for 5-10% of all strokes, and is a subtype of hemorrhagic stroke that places a heavy burden on health care. Despite great progress in surgical clipping and endovascular treatment for ruptured aneurysms, cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) threaten the long-term outcomes of patients with SAH. Moreover, there are limited drugs available to reduce the risk of DCI and adverse outcomes in SAH patients. New insight suggests that early brain injury (EBI), which occurs within 72 h after the onset of SAH, may lay the foundation for further DCI development and poor outcomes. The mechanisms of EBI mainly include excitotoxicity, oxidative stress, neuroinflammation, blood-brain barrier (BBB) destruction, and cellular death. Mitochondria are a double-membrane organelle, and they play an important role in energy production, cell growth, differentiation, apoptosis, and survival. Mitochondrial dysfunction, which can lead to mitochondrial membrane potential (ΔΨm) collapse, overproduction of reactive oxygen species (ROS), release of apoptogenic proteins, disorders of mitochondrial dynamics, and activation of mitochondria-related inflammation, is considered a novel mechanism of EBI related to DCI as well as post-SAH outcomes. In addition, mitophagy is activated after SAH. In this review, we discuss the latest perspectives on the role of mitochondria in EBI and DCI after SAH. We emphasize the potential of mitochondria as therapeutic targets, and summarize the promising therapeutic strategies targeting mitochondria for SAH.

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