{"doi":"10.1002/ctm2.1562","title":"Managing noradrenaline after traumatic brain injury","abstract":"Traumatic brain injury (TBI) affects roughly 55−74 million people per year worldwide and is a leading cause of death and disability in young adults. As such, TBI has profound and long-lasting effects on individuals, families and the healthcare system. Treatment is particularly challenging due to a complex interplay of causative factors, aetiology and management. A particularly dire manifestation of TBI is cerebral oedema, which increases the risk of death by 10-fold and the chances of disability in patients who survive the initial injury. Despite the fact that the treatment of TBI patients is a complex phenomenon, noradrenaline (NA) has been the drug of choice in trauma clinics to counteract hypotension and maintenance of cerebral perfusion pressure. NA's ability to constrict blood vessels results in increased vascular resistance, which helps to elevate blood pressure and maintain adequate perfusion to vital organs. Paradoxically, clinical evidence suggests a dramatic upregulation of NA in plasma and cerebral spinal fluid (CSF), immediately after brain injury.1, 2 The two possible sources of NA are the central brainstem noradrenergic nuclei and peripheral adrenal medulla via release into bloodstream. Plasma NA increases to very high concentrations after multiple types of injury and is a likely predominant source of post-traumatic NA. In a newly published study,3 we interrogated post-TBI cerebral oedema using the ‘Hit-and-Run’ mouse model. A substantial increase in brain water content was observed; initially in the ipsilateral hemisphere and subsequently in the contralateral hemisphere. Microdialysis of the extracellular fluid from the contralateral hemisphere showed that NA widely fluctuates and peaks at 2 hours post-injury. Concurrently, the glymphatic system which is the brain's waste clearance pathway involving the transport of CSF through the brain's perivascular space to facilitate the removal of solutes and excess fluids shuts down and fluid starts accumulating within the brain. This signifies that cerebral oedema is not a result of increased CSF influx, but rather of the ability of the injured brain to export the excess fluid. The major observation was that the pan-adrenergic blockage, based on the administration of a cocktail of α1, α2 and β receptor antagonists reduced or eliminated the acute oedema bilaterally. Remarkably, the pan-adrenergic receptor blockage also enhanced neurological functionality, as evidenced by improved performance in various behavioural assays, including the Morris water maze test. The study also delved into the role of cervical lymphatic drainage in TBI, revealing its impairment due to the excessive increase in NA. Pan-adrenergic blockage was found to improve, significantly, the function of cervical lymphatic vessels draining CSF and interstitial fluid out of central nervous system (CNS), as evidenced by increased lymph vessel contractility and enhanced velocity of lymph efflux. The impairment of the glymphatic/lymphatic system results not only in oedema but also leads to the accumulation of metabolic waste and cellular debris, which become ensnared within the brain's interstitial spaces (as illustrated in Figure 1). In turn, the entrapment of cellular debris initiates a vicious cycle of neuro-inflammation and neural tissue degeneration. Intriguingly, we visualised cellular debris being washed out of the post-traumatic brain via cervical lymphatic vessels using high-resolution two-photon microscopy after administering the cocktail of noradrenergic receptor blockers. This suggests that the efficacy of pan-adrenergic inhibitors extends beyond mere oedema reduction to facilitating the clearance of cellular debris and enhancing overall glymphatic/lymphatic function. In support of this finding, other studies have reported that ultraviolet irradiation of meningeal lymphatic vessels4 or physical ligation of cervical lymphatic vessels5 exacerbate cognitive impairment in murine Alzheimer models, highli","journal":"Clinical and Translational Medicine","year":2024,"id":455234,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9616,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":110045,"name":"Maiken Nedergaard","orcid":"0000-0001-6502-6031","position":1,"is_corresponding":false},{"id":857971,"name":"Rashad Hussain","orcid":"0000-0003-2830-9678","position":0,"is_corresponding":true}],"reference_count":16,"raw_metadata":null,"created_at":"2026-07-19T02:03:17.458329Z","pmid":"38279839","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}