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Neurotrauma: The Crosstalk between Neurotrophins and Inflammation in the Acutely Injured Brain.

ABSTRACT: Traumatic brain injury (TBI) is a major cause of morbidity and mortality among young individuals worldwide. Understanding the pathophysiology of neurotrauma is crucial for the development of more effective therapeutic strategies. After the trauma occurs, immediate neurologic damage is produced by the traumatic forces; this primary injury triggers a secondary wave of biochemical cascades together with metabolic and cellular changes, called secondary neural injury. In the scenario of the acutely injured brain, the ongoing secondary injury results in ischemia and edema culminating in an uncontrollable increase in intracranial pressure. These areas of secondary injury progression, or areas of "traumatic penumbra", represent crucial targets for therapeutic interventions. Neurotrophins are a class of signaling molecules that promote survival and/or maintenance of neurons. They also stimulate axonal growth, synaptic plasticity, and neurotransmitter synthesis and release. Therefore, this review focuses on the role of neurotrophins in the acute post-injury response. Here, we discuss possible endogenous neuroprotective mechanisms of neurotrophins in the prevailing environment surrounding the injured areas, and highlight the crosstalk between neurotrophins and inflammation with focus on neurovascular unit cells, particularly pericytes. The perspective is that neurotrophins may represent promising targets for research on neuroprotective and neurorestorative processes in the short-term following TBI.

SUBMITTER: da Silva Meirelles L

PROVIDER: S-EPMC5454991 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Neurotrauma: The Crosstalk between Neurotrophins and Inflammation in the Acutely Injured Brain.

da Silva Meirelles Lindolfo L Simon Daniel D Regner Andrea A

International journal of molecular sciences 20170518 5

Traumatic brain injury (TBI) is a major cause of morbidity and mortality among young individuals worldwide. Understanding the pathophysiology of neurotrauma is crucial for the development of more effective therapeutic strategies. After the trauma occurs, immediate neurologic damage is produced by the traumatic forces; this primary injury triggers a secondary wave of biochemical cascades together with metabolic and cellular changes, called secondary neural injury. In the scenario of the acutely i ...[more]

PMID: 28524074

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Project description:ObjectivesHeart rate variability is controlled by the autonomic nervous system. After brain death, this autonomic control stops, and heart rate variability is significantly decreased. However, it is unknown if early changes in heart rate variability are predictive of progression to brain death. We hypothesized that in brain-injured children, lower heart rate variability is an early indicator of autonomic system failure, and it predicts progression to brain death. We additionally explored the association between heart rate variability and markers of brain dysfunction such as electroencephalogram and neurologic examination between brain-injured children who progressed to brain death and those who survived.DesignRetrospective case-control study.SettingPICU, single institution.PatientsChildren up to 18 years with a Glasgow Coma Scale score of less than 8 admitted between August of 2016 and December of 2017, who had electrocardiographic data available for heart rate variability analysis, were included.Exclusion criteriapatients who died of causes other than brain death. Twenty-three patients met inclusion criteria: six progressed to brain death (cases), and 17 survived (controls). Five-minute electrocardiogram segments were used to estimate heart rate variability in the time domain (SD of normal-normal intervals, root mean square successive differences), frequency domain (low frequency, high frequency, low frequency/high frequency ratio), Poincaré plots, and approximate entropy.InterventionsNone.Measurements and main resultsPatients who progressed to brain death exhibited significantly lower heart rate variability in the time domain, frequency domain, and Poincaré plots (p < 0.01). The odds of death increased with decreasing low frequency (odds ratio, 4.0; 95% CI, 1.2-13.6) and high frequency (odds ratio, 2.5; 95% CI, 1.2-5.4) heart rate variability power (p < 0.03). Heart rate variability was significantly lower in those with discontinuous or attenuated/featureless electroencephalogram versus those with slow/disorganized background (p < 0.03).ConclusionsThese results support the concept of autonomic system failure as an early indicator of impending brain death in brain-injured children. Furthermore, decreased heart rate variability is associated with markers of CNS dysfunction such as electroencephalogram abnormalities.

Project description:BACKGROUND:In acutely injured lungs, massively recruited polymorphonuclear neutrophils (PMNs) secrete abnormally neutrophil elastase (NE). Active NE creates a localized proteolytic environment where various host molecules are degraded leading to impairment of tissue homeostasis. Among the hallmarks of neutrophil-rich pathologies is a disrupted epithelium characterized by the loss of cell-cell adhesion and integrity. Epithelial-cadherin (E-cad) represents one of the most important intercellular junction proteins. E-cad exhibits various functions including its role in maintenance of tissue integrity. While much interest has focused on the expression and role of E-cad in different physio- and physiopathological states, proteolytic degradation of this structural molecule and ensuing potential consequences on host lung tissue injury are not completely understood. METHODS:NE capacity to cleave E-cad was determined in cell-free and lung epithelial cell culture systems. The impact of such cleavage on epithelial monolayer integrity was then investigated. Using mice deficient in NE in a clinically relevant experimental model of acute pneumonia, we examined whether degraded E-cad is associated with lung inflammation and injury and whether NE contributes to E-cad cleavage. Finally, we checked for the presence of both degraded E-cad and NE in bronchoalveolar lavage samples obtained from patients with exacerbated COPD, a clinical manifestation characterised by a neutrophilic inflammatory response. RESULTS:We show that NE is capable of degrading E-cad in vitro and in cultured cells. NE-mediated degradation of E-cad was accompanied with loss of epithelial monolayer integrity. Our in vivo findings provide evidence that NE contributes to E-cad cleavage that is concomitant with lung inflammation and injury. Importantly, we observed that the presence of degraded E-cad coincided with the detection of NE in diseased human lungs. CONCLUSIONS:Active NE has the capacity to cleave E-cad and interfere with its cell-cell adhesion function. These data suggest a mechanism by which unchecked NE participates potentially to the pathogenesis of neutrophil-rich lung inflammatory and tissue-destructive diseases.

Project description:BackgroundPresently, there is no effective treatment for the lethal muscle wasting disease Duchenne muscular dystrophy (DMD). Here we show that increased sphingosine-1-phoshate (S1P) through direct injection or via the administration of the small molecule 2-acetyl-4(5)-tetrahydroxybutyl imidazole (THI), an S1P lyase inhibitor, has beneficial effects in acutely injured dystrophic muscles of mdx mice.MethodsWe treated mdx mice with and without acute injury and characterized the histopathological and functional effects of increasing S1P levels. We also tested exogenous and direct administration of S1P on mdx muscles to examine the molecular pathways under which S1P promotes regeneration in dystrophic muscles.ResultsShort-term treatment with THI significantly increased muscle fiber size and extensor digitorum longus (EDL) muscle specific force in acutely injured mdx limb muscles. In addition, the accumulation of fibrosis and fat deposition, hallmarks of DMD pathology and impaired muscle regeneration, were lower in the injured muscles of THI-treated mdx mice. Furthermore, increased muscle force was observed in uninjured EDL muscles with a longer-term treatment of THI. Such regenerative effects were linked to the response of myogenic cells, since intramuscular injection of S1P increased the number of Myf5nlacz/+ positive myogenic cells and newly regenerated myofibers in injured mdx muscles. Intramuscular injection of biotinylated-S1P localized to muscle fibers, including newly regenerated fibers, which also stained positive for S1P receptor 1 (S1PR1). Importantly, plasma membrane and perinuclear localization of phosphorylated S1PR1 was observed in regenerating muscle fibers of mdx muscles. Intramuscular increases of S1P levels, S1PR1 and phosphorylated ribosomal protein S6 (P-rpS6), and elevated EDL muscle specific force, suggest S1P promoted the upregulation of anabolic pathways that mediate skeletal muscle mass and function.ConclusionsThese data show that S1P is beneficial for muscle regeneration and functional gain in dystrophic mice, and that THI, or other pharmacological agents that raise S1P levels systemically, may be developed into an effective treatment for improving muscle function and reducing the pathology of DMD.

Dataset Information

Neurotrauma: The Crosstalk between Neurotrophins and Inflammation in the Acutely Injured Brain.

Publications

Neurotrauma: The Crosstalk between Neurotrophins and Inflammation in the Acutely Injured Brain.

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