SCCM Resource Library-07-HNSC Therapy Is More Neuroprotective Than Glibenclamide After Cardiac Arrest via Immunomodulation

Video Transcription

I'm Xiaofeng Jia, professor from University of Maryland and Johns Hopkins University. I do not have a conflict of interest to disclosure.  I would like to acknowledge funding support from NHL1s for this cardiorest research. I'm speaking on neurostem cell therapy is more neuroprotective than glabin-clamate after  cardiorest via immunomodulation. Cardiorest is a common but devastating disease. Every year, more than 350,000 cardiorest occurred outside of the hospital in the United States.  About 10% of these patients had a chance to survive to hospital discharge. Among these survivors, half of them suffered from cognitive deficit.  About 20% had to live with reduced quality of life. Among survivors of cardiorest, brain injury is a big impediment to functional recovery.  Neuroprotective intervention after cardiorest is really a challenge. We know targeted temperature management partially improved the neurological functional outcome,  but only works in one out of six patients. Almost no more therapeutic options solidly proven to be effective.  While we're looking at the literature, we know GBC has a protective effect in several brain disorders such as stroke, traumatic brain injury in animal models.  Neurostem cell therapy reduced hypoxia ischemic brain damage and brain loss in the chronic phase.  However, the effectiveness among these two interventions and the mechanisms underlying that remains unknown.  We aim to investigate and compare the effect of GBC and human neurostem cell treatments on neurological outcome and to explore the underlying therapeutic mechanism on the accurate  stage of brain injury in a rodent model of cardiorest. We are targeting the microglia and TLR4 and LRP3 signaling pathway.  24 Wistar rats was randomly assigned to three groups, GBC group, human neurostem cell group, and the control group.  All rats underwent eight minutes experimental asphyxia cardiorest model.  GBC, the loading dose was administrated at 10 minutes after return of spontaneous circulation and then repeated at 8, 16, and 24 hours for maintenance.  NSC was intranasal administrated at three hours after ROSC. The functional recovery was evaluated with neurological deficit scoring, which has been  well validated by our private studies. Previous study indicated that the best score is 80 and the worst score is zero.  And good outcome, MDS, is higher than 60, and bad outcome usually is lower than 60, and usually lack of spontaneously supportive.  So we also use immunofluorescence staining and western blot to check the cells and also compare the activation subtype and the polarization phenotype of microglia.  We also use this in-vitro technique to quantify and compare the expression and the cellular specification of the TLR4 and NLRP3 pathway-related protein in the brain.  Our results shows the MDS neurological recovery is the best in the NSC group and the second in the GBC group, which both has significantly better than the control group.  Microglia, we divided by four types. Type one is more resting microglia and type four is more activated.  So we can see from this figure, control group had more higher type, which is more active,  activated microglia, while HNC has more inactive morphology in microglia. So, which means neurostem cell therapy restored the maximum resting microglia and the minimum  the activated microglia.  Well, when we're looking at the anti-inflammatory polarization phenotype, which is marked with  CD206, we can see in the control, CD206 minimum is the least, while neurostem cell and the GBC had much higher CD206 positive cells, which means the anti-inflammatory polarization  phenotype was found higher in the HNSC treatment group. IBA, we can see that's a co-localization with microglia.  Our immunofluorescence study further showed the quantification of this protein, positive  TLR4, for example, NLRP3 and the Capsid1 and IL-1 beta. All them shows human neurostem cell has less positive compared to the middle GBC and the rest in control group.  Similarly, our western blot study demonstrated the expression of TLR4, NLRP3, inflammatory pathway-related proteins, which including NLRP3, TLR4, NF-CAPA beta, IL-1 beta, were  significantly suppressed by both treatment. And among them, many protein was showing even further suppressed by neurostem cell compared to GBC.  Thus, overall, we can conclude neurostem cell and the GBC therapy regulated brain microglia  activation and the neuroinflammatory response after cardiac arrest through the TLR4, NLRP3 signaling pathway, which automatically improved the neurological outcome.  Human NSC showed a better therapeutic effect than GBC in the process of inflammation regulation.  I would like to thank the outstanding work from our research team and collaborators.  Thank you for your attention. Bye-bye.

Video Summary

In this video, Dr. Xiaofeng Jia from the University of Maryland and Johns Hopkins University discusses the effectiveness of neurostem cell therapy compared to glabin-clamate (GBC) in improving neurological outcomes after cardiorest, a common and devastating condition. Cardiorest often leads to cognitive deficits and reduced quality of life for survivors. While targeted temperature management has shown some improvement, there is a lack of effective therapeutic options. Dr. Jia's research aims to explore the effects of GBC and neurostem cell treatments on neurological outcomes and investigate the underlying mechanisms. Their findings suggest that neurostem cell therapy is more effective in regulating inflammation and improving neurological outcomes through the TLR4, NLRP3 signaling pathway compared to GBC.

Asset Subtitle

Resuscitation, Neuroscience, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Xiaofeng Jia

Introduction/Hypothesis: Cardiac arrest (CA) is a common but devastating disease, and neuroprotective therapy for brain injury after CA is a persistent difficulty in clinical practice. Neuroinflammation has been a focus for multiple potential therapies, including neural stem cell (NSCs) transplantation and glibenclamide (GBC) therapy. However, the underlying mechanism of immunoregulation remains unclear, and there is a lack of comparative evaluation between these two different interventions.

Methods: 24 Wistar rats were randomly assigned to three groups (Control, GBC, and hNSCs, N = 8/group). After 8 minutes of asphyxial CA, GBC was injected intraperitoneally or human (hNSCs) were administrated intranasally in the treatment groups. Neurological deficit scores (NDS) were performed at 24, 48, and 72h post return of spontaneous circulation (ROSC). Immunofluorescence was used to track the hNSCs, and the activation subtype and polarization phenotype of microglia were compared between

groups. The expression, quantification, and cellular specificity of the TLR4 â„ NLRP3 pathway-related proteins in the injured brain were compared between groups.

Results: The aggregate analysis of NDS shows a significant improvement in hNSCs or GBC group compared to the Control group (hNSCs VS. Control: Pï¼œ0.01, GBC VS. Control: Pï¼œ0.05), and NSCs treatment showed a superior neuroprotective effect compared to the GBC group (hNSCs VS. GBC: Pï¼œ0.01). Analysis of microglia revealed that more inactive morphology (NSCs VS. GBC: 56.1% Â± 4.4% VS. 35.6% Â± 5.7%, P = 0.017) and more anti-inflammatory polarization phenotype hNSCs (CD206+ cells, hNSCs VS. GBC: 43.0% Â± 7.1% VS. 38.9% Â± 8.9%, P = 0.012) were found in the hNSCs treatment group. Quantitative analysis of immune-fluorescence and Western blot demonstrated the expression of the TLR4 / NLRP3 inflammatory pathway-related proteins (TLR4, NFÎºB, NLRP3, caspase-1, and IL-1Î²) were suppressed by both treatments.

Conclusions: NSC and GBC therapy regulated brain microglial activation and the neuroinflammatory response after CA through the TLR4/NLRP3 signaling pathway and ultimately improved neurological function. In addition, hNSCs showed a better therapeutic effect than GBC in the process of inflammation regulation. This work was partially supported by NIH R01NS110387 and R01HL118084 (both to X JIA).

Meta Tag

Content Type Presentation

Knowledge Area Resuscitation

Knowledge Area Neuroscience

Knowledge Level Advanced

Membership Level Select

Tag Asphyxia

Tag Cardiac Arrest

Year 2021

Keywords

neurostem cell therapy

glabin-clamate (GBC)

neurological outcomes

cardiorest

TLR4, NLRP3 signaling pathway

	Society of Critical Care Medicine 500 Midway Drive Mount Prospect, IL 60056 USA Phone: +1 847 827-6888 Fax: +1 847 439-7226 Email: support@sccm.org	Contact Us About SCCM Newsroom Advertising & Sponsorship DONATE	MySCCM LearnICU Patients & Families Surviving Sepsis Campaign Critical Care Societies Collaborative	GET OUR NEWSLETTER
© Society of Critical Care Medicine. All rights reserved. \| Privacy Statement \| Terms & Conditions The Society of Critical Care Medicine, SCCM, and Critical Care Congress are registered trademarks of the Society of Critical Care Medicine.