Abstract

Objective The objective of this scoping review is to understand the extent and type of evidence in relation to the use of glucagon-like peptide-1 receptor agonists (GLP-1RA) for neuroprotection in aneurysmal subarachnoid haemorrhage (aSAH).

Introduction The individual and societal costs of aSAH remain high. Effective neuroprotection would reduce morbidity and mortality but there are uncertainties around both established and emerging therapies. GLP-1RA show promise as neuroprotective drugs in other forms of acute and chronic brain injury and could be repurposed for aSAH.

Inclusion criteria Animal and human studies of the use of GLP-1RA for aSAH will be included. Key exclusions are traumatic or non-aneurysmal subarachnoid haemorrhage, or the use of multi-agonist drugs.

Methods Searches were conducted in Embase (Ovid), Medline (Ovid), Cochrane Central Register of Controlled Trials (Wiley) and the World Health Organisation’s International Clinical Trials Registry Platform on 13th June 2025 with no limits applied. Screening and data extraction was performed by two independent reviewers.

Results After de-duplication 593 records were screened, 50 selected for full text review and 5 included in this review. GLP-1R were shown to be highly expressed in neurones and microvascular endothelial cells after aSAH. Administration of GLP-1RAs to rats affected by aSAH improved functional recovery. Furthermore, aSAH was reported to increase cerebral hemisphere oedema, blood-brain barrier permeability, cell death and inflammation, all of which were reversed by GLP-1RA treatment. Murine studies highlight potential mechanisms for these beneficial effects including inhibition of ferroptosis, downregulation of apoptosis, and upregulation of SIRT1 pathways. A human observational studies shows a correlation between higher SIRT1 levels and better neurological outcomes.

Conclusion The limited available evidence suggests a potential neuroprotective role for GLP-1RAs after aSAH. There is a need for extensive further research to determine the efficacy and safety of GLP1-RAs for neuroprotection in aSAH.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Protocols

https://www.medrxiv.org/content/10.1101/2024.12.04.24318321v1.full.pdf

Funding Statement

This study was supported by a BHF Intermediate Basic Science Research Fellowship (FS/IBSRF/21/25060) to SM. The funder played no role in this review.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This is a scoping review and all source data (retrieved papers) were publicly available before initiation of the study. References provided in manuscript.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

All data included in the present study are available in the references papers and summarised in the manuscript.

AbbreviationsAktActivation of protein kinase BAMPKAMP-activated protein kinaseaSAHAneurysmal subarachnoid haemorrhageBaxBcl-2-like protein 4BBBBlood brain barrierBcl-2B-cell lymphoma 2 proteinBcl-xlB-cell lymphoma extra large proteinCOX-2Cyclo-oxygenase 2DCIDelayed cerebral ischaemiaEBIEarly brain injuryFSP1Ferroptosis suppressor protein 1GLP-1Glucagon-like peptide-1GLP-1RGlucagon-like peptide-1 receptorGLP-1RAGlucagon-like peptide-1 receptor agonistGPX4Glutathione peroxidase 4HO-1Haem oxygenase 1IL-1βInterleukin 1-betaIL-6Interleukin 6ICTRPInternational Clinical Trials Registry PlatformiNOSInducible nitric oxide synthaseJBIJoanna Briggs InstituteMMP9Matrix metalloproteinase 9mRSModified Rankin ScaleNF-κBNuclear factor kappa-light-chain-enhancer of activated B cellsNrf2Nuclear factor erythroid 2-related factor 2PI3KPhosphoinositide 3-kinasePRISMAPreferred reporting items for systematic review and meta-analysesPROSPEROProspective register of systematic reviewssiRNASmall interfering ribonucleic acidSIRT1Sirtuin 1TNFαTumour necrosis factor alphaTNFβTumour necrosis factor beta