A reassessment of the blood–brain barrier transport of large neutral amino acids during acute systemic inflammation in humans

Berg, Ronan M. G.; Taudorf, Sarah; Bailey, Damian Miles; Lundby, Carsten; Larsen, Fin Stolze; Møller, Kirsten

doi:10.1111/cpf.12463

Cited by 8 publications

(4 citation statements)

References 43 publications

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“…6 , 7 ). Arterial concentrations of phenylalanine were also increased after intravenous lipopolysaccharide (LPS) infusion in healthy volunteers 28 . The liver is the main site of phenylalanine metabolism; therefore, deterioration of liver function may reduce this metabolism, raising systemic phenylalanine levels.…”

Section: Discussionmentioning

confidence: 99%

Persistent hyperammonia and altered concentrations of urea cycle metabolites in a 5-day swine experiment of sepsis

Ferrario

Pastorelli

Brunelli

et al. 2021

Sci Rep

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We measured plasma and cerebrospinal fluid (CSF) metabolite concentrations in a 5-day porcine sepsis model of fecal peritonitis. The objectives were: (i) to verify whether the expected pathways that had emerged in previous studies pertain only to the early inflammatory response or persist for the subsequent days; (ii) to identify metabolic derangements that arise later; (iii) to verify whether CSF metabolite concentrations were altered and if these alterations were similar to those in the blood or delayed. We observed an early response to inflammation and cytokine storms with alterations in lipid and glucose metabolism. The arginine/asymmetric dimethylarginine (ADMA) and phenylalanine/tyrosine balances changed 24 h after resuscitation in plasma, and later in CSF. There was a rise in ammonia concentration, with altered concentrations of metabolites in the urea cycle. Whether persistent derangement of these pathways have a role not only on short-term outcomes but also on longer-term comorbidities, such as septic encephalopathy, should be addressed in further studies.

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Section: Discussionmentioning

confidence: 99%

Persistent hyperammonia and altered concentrations of urea cycle metabolites in a 5-day swine experiment of sepsis

Ferrario

Pastorelli

Brunelli

et al. 2021

Sci Rep

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“…Various studies have found abnormal levels of neurotransmitter precursors, including amino acids, in both the serum and cerebrospinal fluid of patients with SAD [11,12]. The significance of this is unclear but may suggest concurrently deranged levels of neurotransmitters in sepsis and abnormal neurotransmission, however it may also reflect protective mechanisms to detoxify phenylalanine levels [13].…”

Section: Neurotransmissionmentioning

confidence: 99%

Sepsis Associated Delirium

et al. 2020

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Sepsis is a potentially life-threatening condition caused by a systemic dysregulated host response to infection. The brain is particularly susceptible to the effects of sepsis with clinical manifestations ranging from mild confusion to a deep comatose state. Sepsis-associated delirium (SAD) is a cerebral manifestation commonly occurring in patients with sepsis and is thought to occur due to a combination of neuroinflammation and disturbances in cerebral perfusion, the blood brain barrier (BBB) and neurotransmission. The neurological impairment associated with SAD can persist for months or even longer, after the initial septic episode has subsided which may impair the rehabilitation potential of sepsis survivors. Early identification and treatment of the underlying sepsis is key in the management of SAD as once present it can be difficult to control. Through the regular use of validated screening tools for delirium, cases of SAD can be identified early; this allows potentially aggravating factors to be addressed promptly. The usefulness of biomarkers, neuroimaging and electroencephalopathy (EEG) in the diagnosis of SAD remains controversial. The Society of Critical Care Medicine (SCCM) guidelines advise against the use of medications to treat delirium unless distressing symptoms are present or it is hindering the patient’s ability to wean from organ support.

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“…Blood–brain barrier (BBB), formed by the tight junctions of endothelial cells, is a major barrier for drugs aiming to reach the central nervous system (CNS). − Most neuroprotective drugs have nutrition, repair, and protection functions to CNS, which are hindered by the BBB. Only small hydrophobic molecules with low molecular weight can cross it.…”

Section: Introductionmentioning

confidence: 99%

Proline-Loaded Chitosan Nanoparticles Penetrate the Blood–Brain Barrier to Confer Neuroprotection in Mice Cerebral Ischemia Injury

Gao,

Wang,

Kong

et al. 2023

ACS Appl. Polym. Mater.

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Proline, a nonessential amino acid, has been demonstrated to possess neuroprotective capabilities in the central nervous system (CNS). However, the mechanisms through which it impacts cerebral ischemia− reperfusion (I/R) injuries remain unclear. Our study observed a decrease in proline concentrations within the ischemic brain tissues of I/R mice. Supplementing proline protected against ischemic neuronal death, both in vivo and in vitro, suggesting its potential as a neuroprotectant. However, our data indicated that proline has a low permeability to the blood−brain barrier (BBB) in mice. Therefore, it is clinically infeasible to develop proline as a stroke therapy. To develop an approach to deliver proline into the injured brain, we engineered a method to transport proline to the injured brain. We prepared chitosan nanoparticles (NPs) loaded with proline utilizing the ion cross-linking method. Our findings demonstrated that the proline-loaded chitosan NPs efficiently passed through the BBB and delivered proline into the injured brain, thereby conferring neuroprotection. Further exploration revealed that proline upregulated the level of annexin A6 (ANX6)/β1 integrin, which, in turn, increased the phosphorylation of cell-survival-promoting kinase Akt. This sequence of events consequently promotes neuronal survival following I/R. In conclusion, our study has developed a neuroprotection approach by which low-BBBpermeable proline is delivered by chitosan NPs into the brain. Furthermore, this study suggests that the neuroprotective role of proline in I/R is mediated by the ANX6/β1 integrin/Akt signaling pathway.

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A reassessment of the blood–brain barrier transport of large neutral amino acids during acute systemic inflammation in humans

Cited by 8 publications

References 43 publications

Persistent hyperammonia and altered concentrations of urea cycle metabolites in a 5-day swine experiment of sepsis

Persistent hyperammonia and altered concentrations of urea cycle metabolites in a 5-day swine experiment of sepsis

Sepsis Associated Delirium

Proline-Loaded Chitosan Nanoparticles Penetrate the Blood–Brain Barrier to Confer Neuroprotection in Mice Cerebral Ischemia Injury

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