Beta blockade in TBI: Dose-dependent reductions in BBB leukocyte mobilization and permeability in vivo

Lopez, Alfonso J; ElSaadani, Mohamed; Jacovides, Christina; George, Anastasia; Culkin, Matthew C; Ahmed, Syed; Kumar, Monisha A.; Kaplan, Lewis J.; Smith, Douglas H.; Pascual, José L.

doi:10.1097/ta.0000000000003537

Cited by 11 publications

(8 citation statements)

References 48 publications

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“…After TBI, the BBB is damaged, resulting in increased permeability and severe brain edema ( 31 – 33 ). Previous studies have demonstrated that the posttraumatic inflammation cascade promotes TBI-induced BBB disruption ( 10 ).…”

Section: Resultsmentioning

confidence: 99%

Targeting pyroptosis with nanoparticles to alleviate neuroinflammatory for preventing secondary damage following traumatic brain injury

Zhang,

Huang,

Hang

et al. 2024

Sci. Adv.

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Posttraumatic neuroinflammation is a key driver of secondary injury after traumatic brain injury (TBI). Pyroptosis, a proinflammatory form of programmed cell death, considerably activates strong neuroinflammation and amplifies the inflammatory response by releasing inflammatory contents. Therefore, treatments targeting pyroptosis may have beneficial effects on the treatment of secondary brain damage after TBI. Here, a cysteine-alanine-glutamine-lysine peptide–modified β-lactoglobulin (β-LG) nanoparticle was constructed to deliver disulfiram (DSF), C-β-LG/DSF, to inhibit pyroptosis and decrease neuroinflammation, thereby preventing TBI-induced secondary injury. In the post-TBI mice model, C-β-LG/DSF selectively targets the injured brain, increases DSF accumulation, and extends the time of the systemic circulation of DSF. C-β-LG/DSF can alleviate brain edema and inflammatory response, inhibit secondary brain injury, promote learning, and improve memory recovery in mice after trauma. Therefore, this study likely provided a potential approach for reducing the secondary spread of TBI.

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Section: Resultsmentioning

confidence: 99%

Targeting pyroptosis with nanoparticles to alleviate neuroinflammatory for preventing secondary damage following traumatic brain injury

Zhang,

Huang,

Hang

et al. 2024

Sci. Adv.

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“…Beta blockers may also modulate the post-TBI catecholamine surge which can also contribute to secondary cerebral injury through worsening cerebral hypertension and edema ( 24 ). It is also possible that lipid-soluble beta blockers could cross the blood-brain barrier and exert their effects directly on cerebral tissue and vasculature, preventing ischemia by decreasing vasoconstriction, though this mechanism is largely theoretical ( 24 , 25 ). Finally, beta blockers’ cardioprotective effects may be a driving benefit, by reducing the risk of subsequent myocardial infarction by decreasing stroke volume, heart rate, blood pressure, and myocardial oxygen demand ( 24 , 26 ).…”

Section: Discussionmentioning

confidence: 99%

Association of Early Beta-Blocker Exposure and Functional Outcomes in Critically Ill Patients With Moderate to Severe Traumatic Brain Injury: A Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study

Kelly-Hedrick,

Liu,

Temkin

et al. 2023

Critical Care Explorations

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OBJECTIVES: We aimed to 1) describe patterns of beta-blocker utilization among critically ill patients following moderate–severe traumatic brain injury (TBI) and 2) examine the association of early beta-blocker exposure with functional and clinical outcomes following injury. DESIGN: Retrospective cohort study. SETTING: ICUs at 18 level I, U.S. trauma centers in the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study. PATIENTS: Greater than or equal to 17 years enrolled in the TRACK-TBI study with moderate–severe TBI (Glasgow Coma Scale of <13) were admitted to the ICU after a blunt TBI. INTERVENTIONS: None. MEASUREMENTS: Primary exposure was a beta blocker during the first 7 days in the ICU, with a primary outcome of 6-month Glasgow Outcome Scale-Extended (GOSE). Secondary outcomes included: length of hospital stay, in-hospital mortality, 6-month and 12-month mortality, 12-month GOSE score, and 6-month and 12-month measures of disability, well-being, quality of life, and life satisfaction. MAIN RESULTS: Of the 450 eligible participants, 57 (13%) received early beta blockers (BB+ group). The BB+ group was on average older, more likely to be on a preinjury beta blocker, and more likely to have a history of hypertension. In the BB+ group, 34 participants (60%) received metoprolol only, 19 participants (33%) received propranolol only, 3 participants (5%) received both, and 1 participant (2%) received atenolol only. In multivariable regression, there was no difference in the odds of a higher GOSE score at 6 months between the BB+ group and BB– group (odds ratio = 0.86; 95% CI, 0.48–1.53). There was no association between BB exposure and secondary outcomes. CONCLUSIONS: About one-sixth of subjects in our study received early beta blockers, and within this group, dose, and timing of beta-blocker administration varied substantially. No significant differences in GOSE score at 6 months were demonstrated, although our ability to draw conclusions is limited by overall low total doses administered compared with prior studies.

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“…It has been shown that TBI patients experience sympathetic hyperactivity, causing a catecholamine surge [213][214][215][216][217][218]. This surge causes secondary insults, which manifest as posttraumatic hyperthermia [216,218], increased inflammation and leukocyte migration [219,220], impaired cerebral homeostasis and perfusion [217], and cardiovascular dysfunction [216], and has been associated with increased mortality [221]. In light of such evidence, the use of beta-blockers to alleviate secondary damage caused by TBI gained interest.…”

Section: Beta-blockersmentioning

confidence: 99%

Dysregulated brain-gut axis in the setting of traumatic brain injury: review of mechanisms and anti-inflammatory pharmacotherapies

El Baassiri,

Raouf,

Badin

et al. 2024

J Neuroinflammation

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Traumatic brain injury (TBI) is a chronic and debilitating disease, associated with a high risk of psychiatric and neurodegenerative diseases. Despite significant advancements in improving outcomes, the lack of effective treatments underscore the urgent need for innovative therapeutic strategies. The brain-gut axis has emerged as a crucial bidirectional pathway connecting the brain and the gastrointestinal (GI) system through an intricate network of neuronal, hormonal, and immunological pathways. Four main pathways are primarily implicated in this crosstalk, including the systemic immune system, autonomic and enteric nervous systems, neuroendocrine system, and microbiome. TBI induces profound changes in the gut, initiating an unrestrained vicious cycle that exacerbates brain injury through the brain-gut axis. Alterations in the gut include mucosal damage associated with the malabsorption of nutrients/electrolytes, disintegration of the intestinal barrier, increased infiltration of systemic immune cells, dysmotility, dysbiosis, enteroendocrine cell (EEC) dysfunction and disruption in the enteric nervous system (ENS) and autonomic nervous system (ANS). Collectively, these changes further contribute to brain neuroinflammation and neurodegeneration via the gut-brain axis. In this review article, we elucidate the roles of various anti-inflammatory pharmacotherapies capable of attenuating the dysregulated inflammatory response along the brain-gut axis in TBI. These agents include hormones such as serotonin, ghrelin, and progesterone, ANS regulators such as beta-blockers, lipid-lowering drugs like statins, and intestinal flora modulators such as probiotics and antibiotics. They attenuate neuroinflammation by targeting distinct inflammatory pathways in both the brain and the gut post-TBI. These therapeutic agents exhibit promising potential in mitigating inflammation along the brain-gut axis and enhancing neurocognitive outcomes for TBI patients.

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Beta blockade in TBI: Dose-dependent reductions in BBB leukocyte mobilization and permeability in vivo

Abstract: Beta blockade in severe traumatic brain injury has shown improvements in survival and recovery after injury. This paper demonstrates in a series of in vivo and ex vivo experiments a potential mechanism for this benefit using a live rodent TBI model.

Cited by 11 publications

References 48 publications

Targeting pyroptosis with nanoparticles to alleviate neuroinflammatory for preventing secondary damage following traumatic brain injury

Targeting pyroptosis with nanoparticles to alleviate neuroinflammatory for preventing secondary damage following traumatic brain injury

Association of Early Beta-Blocker Exposure and Functional Outcomes in Critically Ill Patients With Moderate to Severe Traumatic Brain Injury: A Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study

Dysregulated brain-gut axis in the setting of traumatic brain injury: review of mechanisms and anti-inflammatory pharmacotherapies

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