Octreotide-mediated neurofunctional recovery in rats following traumatic brain injury. Role of H2S, Nrf2 and TNF-α

ABSTRACT Purpose: To explore the role and mechanisms of octreotide in neurofunctional recovery in the traumatic brain injury (TBI) model. Methods: Rats were subjected to midline incision followed by TBI in the prefrontal cortex region. After 72 hours, the behavioural and neurological deficits tests were performed, which included memory testing on Morris water maze for 5 days. Octreotide (15 and 30 mg/kg i.p.) was administered 30 minutes before subjecting to TBI, and its administration was continued for three days. Results: In TBI-subjected rats, administration of octreotide restored on day 4 escape latency time (ELT) and increased the time spent in the target quadrant (TSTQ) on day 5, suggesting the improvement in learning and memory. It also increased the expression of H2S, Nrf2, and cystathionine-γ-lyase (CSE) in the prefrontal cortex, without any significant effect on cystathionine-β-synthase. Octreotide also decreased the TNF-α levels and neurological severity score. However, co-administration of CSE inhibitor (D,L-propargylglycine) abolished octreotide-mediated neurofunctional recovery, decreased the levels of H2S and Nrf2 and increased the levels of TNF-α. Conclusions: Octreotide improved the neurological functions in TBI-subjected rats, which may be due to up-regulation of H2S biosynthetic enzyme (CSE), levels of H2S and Nrf2 and down-regulation of neuroinflammation.

Edaravone improves the post-traumatic brain injury dysfunction in learning and memory by modulating Nrf2/are signal pathway

OBJECTIVES: To investigate the molecular mechanism of edaravone (EDA) in improving the post-traumatic brain injury (TBI) dysfunction in learning and memory. METHODS: In vitro and in vivo TBI models were established using hydrogen peroxide (H2O2) treatment for hippocampal nerve stem cells (NSCs) and surgery for rats, followed by EDA treatment. WST 1 measurement, methylthiazol tetrazolium assay, and flow cytometry were performed to determine the activity, proliferation, and apoptosis of NSCs, and malondialdehyde (MDA), lactic dehydrogenase (LDH), and reactive oxygen species (ROS) detection kits were used to analyze the oxides in NSCs. RESULTS: Following EDA pretreatment, NSCs presented with promising resistance to H2O2-induced oxidative stress, whereas NSCs manifested significant increases in activity and proliferation and a decrease in apoptosis. Meanwhile, for NSCs, EDA pretreatment reduced the levels of MDA, LDH, and ROS, with a significant upregulation of Nrf2/antioxidant response element (ARE) signaling pathway, whereas for EDA-treated TBI rats, a significant reduction was observed in the trauma area and injury to the hippocampus, with improvement in memory and learning performance and upregulation of Nrf2/ARE signaling pathway. CONCLUSIONS: EDA, by regulating the activity of Nrf2/ARE signal pathway, can improve the TBI-induced injury to NSCs and learning and memory dysfunction in rats.

Comparison of half-molar sodium lactate and mannitol to treat brain edema in severe traumatic brain injury: A systematic review / 中华创伤杂志(英文版)

PURPOSE@#Hypertonic fluids such as mannitol and half-molar sodium lactate are given to treat intracranial hypertension in patients with severe traumatic brain injury (TBI). In this study, sodium lactate was compared to mannitol in patients with TBI to investigate the efficacy in reducing intracranial pressure (ICP).@*METHODS@#This study was a systematic review with literature research on articles published in any year in the databases of PubMed, ScienceDirect, Asian Journal of Neurosurgery, and Cochrane Central Register of Controlled Trials. The keywords were "half-molar sodium lactate", "mannitol", "cerebral edema or brain swelling", and "severe traumatic brain injury". The inclusion criteria were (1) studies published in English, (2) randomized control trials or retrospective/prospective studies on TBI patients, and (3) therapies including half-molar sodium lactate and mannitol and (4) sufficient data such as mean difference (MD) and risk ratio (RR). Data analysis was conducted using Review Manager 5.3.@*RESULTS@#From 1499 studies, a total of 8 studies were eligible. Mannitol group reduced ICP of 0.65 times (MD 0.65; p = 0.64) and improved cerebral perfusion pressure of 0.61 times (MD 0.61; p = 0.88), better than the half-molar group of sodium lactate. But the half-molar group of sodium lactate maintained the mean arterial pressure level of 0.86 times, better than the mannitol group (MD 0.86; p = 0.09).@*CONCLUSION@#Half-molar sodium lactate is as effective as mannitol in reducing ICP in the early phase of brain injury, superior over mannitol in an extended period. It is able to prevent intracranial hypertension and give better brain tissue perfusion as well as more stable hemodynamics. Blood osmolarity is a concern as it increases serum sodium.

Hydroxysafflor yellow A acutely attenuates blood-brain barrier permeability, oxidative stress, inflammation and apoptosis in traumatic brain injury in rats1

Abstract Purpose: To investigate the therapeutic benefits of Hydroxysafflor yellow A (HSYA) on blood-brain barrier (BBB) vulnerability after traumatic brain injury (TBI) and identify its potential action of mechanisms on TBIinduced injuries. Methods: The rat TBI model was performed by using a controlled cortical impact device. The BBB permeability induced by TBI was measured through Evans Blue dye superflux and western blotting or polymerase chain reaction (PCR) for tight junctional proteins (TJPs). The post-TBI changes in oxidative stress markers, inflammatory response and neuron apoptosis in brain tissue were also tested. Results: Herein, the results showed that HSYA acutely attenuated BBB permeability via increasing the production of the TJPs, including occludin, claudin-1 and zonula occludens protein 24 h after TBI. Additionally, HSYA could suppress the secretion of proinflammatory factors, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α (IL-1β, IL-6, and TNF-α), and also concurrently down-regulate the expression of inflammation-related Toll-like receptor 4/nuclear factor kappa-B (TLR4/NF-kB) protein. These HSYA challenged changes were accompanied by the decreased TBI induced oxidative stress markers and inhibited the expression of apoptosis proteins Bax, caspase-3 and caspase-9. Conclusions: Taken together, all findings suggested that HSYA (30 mg/kg) are against TBI through improving the integrity in BBB, which are associated with the antioxidant, anti-inflammation and antiapoptosis via the probable mechanism of down-regulation of the TLR4/NF-kB pathway, and its in-detail protective mechanisms are under study.

Traumatic brain injury pharmacological treatment: recommendations / Tratamento farmacológico do traumatismo cranioencefálico: recomendações

ABSTRACT This article presents the recommendations on the pharmacological treatment employed in traumatic brain injury (TBI) at the outpatient clinic of the Cognitive Rehabilitation after TBI Service of the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil. A systematic assessment of the consensus reached in other countries, and of articles on TBI available in the PUBMED and LILACS medical databases, was carried out. We offer recommendations of pharmacological treatments in patients after TBI with different symptoms.

RESUMO Este artigo apresenta as recomendações sobre o tratamento farmacológico empregado para o traumatismo cranioencefálico (TCE) em pacientes ambulatoriais de Reabilitação Cognitiva pós-TCEno Serviço do HCFMUSP Foi realizada uma avaliação sistemática dos consensos publicados em outros países e dos artigos sobre TCE disponíveis nas bases de periódicos médicos como PUBMED e LILACS. Recomendamos tratamentos farmacológicos em pacientes pós-TCE com diferentes sintomas.

Critical Analysis of Sedation and Analgesia in Severe Head Trauma / Análise crítica da sedação e analgesia no traumatismo craniano grave

Introduction Head injury is a direct determinant of morbidity, disability, and mortality in the young population. Sedatives and analgesics are commonly used in patients with brain injury to retrieve an ICP, CMRO2, and CBF, preserving the cerebral regulation system and self-avoiding hypotension. Objective The objective of this paper is to review on this topic, linking themain drugs, side effects, costs, anxiolytic properties, anticonvulsants, and correlating them with complacency and brain metabolism. Methods We perform a literature review using PubMed database, MEDLINE, EMBASE, Science Direct, The Cochrane Database, Google Scholar, and Clinical trials.We selected papers from the period between 1958 and 2014, which totaled 254 papers. Of these, we selected 129 papers based on keywords, inclusion, and exclusion criteria. Evidence Review The volume of the brain decreases due to dislocation of the CBV out of the skull. The main sedatives and analgesics are propofol, midazolam, etomidate, ketamine, barbiturates, dexedetomedina, morphine, fentanyl, alfentanil, sulfenatil, and remifentanil. We hereby discuss the algorithm for a fast intubation sequence and the algorithm for intracranial hypertension treatment regarding the systematic sedation therapy. A range of sedatives and analgesic agents are available for sedation. Each class has its own positive and negative effects on neurotrauma patients. Conclusions The correct analysis of sedation and analgesia in neurotrauma, rapid sequence intubation, and management ofmedications in intracranial hypertension can lead to an ideal management of brain injury.

Introdução Traumatismo Craniano (TCE) é determinante direto na morbidade, incapacidade e mortalidade na população jovem. Sedativos e analgésicos são comumente usados em pacientes com lesão cerebral com o objetivo de recuperar PIC, CMRO2 e FBC, preservando o sistema de autorregulação cerebral, evitando hipotensão. Objetivo O objetivo deste trabalho é fazer uma revisão sobre este tema, correlacionando as principais drogas, efeitos colaterais, custos, propriedades ansiolíticas, anticonvulsivantes, correlacionando com complacência e metabolismo cerebral. Métodos Revisão da literatura utilizando base de dados PubMed, MEDLINE, EMBASE, Science Direct, The Cochrane Detabase, Google Scholar, ensaios clínicos. Os trabalhos selecionados de 1958 a 2014. Somou-se 254 trabalhos. Foram selecionados 129, através de palavras-chave, inclusão e critérios de exclusão. Evidência Revisão O volume do cérebro é reduzido devido o deslocamento do volume cerebral. Os principais sedativos e analgésicos são: propofol, midazolam, etomidato, cetamina, barbitúricos, a dexmedetomidina, morfina, fentanil, alfentanil, sulfato, remifentanil. Discute-se algoritmo para a sequência rápida de intubação e algoritmo para tratamento de hipertensão intracraniana. Uma série de sedativos e analgésicos agentes estão disponíveis para sedação. Cada classe tem seu próprio efeitos positivos e negativos em pacientes no neurotrauma. Conclusões e Relevância O presente trabalho contribui com a análise correta da sedação e analgesia em neurotrauma, sequência rápida de intubação e administração de medicamentos para analgesia e sedação em hipertensão intracraniana, e um ideal manejo na lesão cerebral.

Update in the management of severe traumatic brain injury

Traumatic brain injury is the main cause of death and disability in the young population, which presumes a large number of years of potential life lost and a great economic impact. Vital and functional outcomes after suffering a traumatic brain injury depend both on the severity of the initial biomechanical impact (primary injury) and on the presence and the severity of systemic or intracranial insults that magnify and/or produce new brain injuries, the so-called secondary injuries. Currently, no treatment in effective in improving functional recovery, except for usual medical care. Therefore, the main purpose of the care provided to a patient with severe cranial trauma is based on preventing and treating secondary brain injuries by maintaining an adequate cerebral perfusion and oxygenation. Increased intracranial pressure is associated with mortality and with unfavorable functional outcomes is patients with severe traumatic brain injury. The main clinical practice guidelines recommend using a number of staggered therapeutic measures. However, although these measures seem to be efficient in reducing intracranial pressure, this effect is not often translated into clinical improvement. This review describes the essential principles of the management of patients with severe traumatic brain injury in intensive care units.

Uso de morfina peridural em pacientes com disautonomia após traumatismo craniencefálico / Use of peridural morphine in patients with posttraumatic autonomic disturbances

Introdução: A disautonomia ou hiperatividade simpática paroxística (HSP) pode ocorrer em até um terço dos pacientes vítimas de trauma de crânio grave, entretanto ainda é uma entidade sem tratamento estabelecido. O uso de morfina intravenosa é descrito para o tratamento da HSP, sendo observada melhora principalmente na diminuição das frequências respiratória e cardíaca. Partindo desses preceitos, este estudo analisa os efeitos da morfina peridural nos pacientes com HSP. Pacientes e métodos: Foram avaliados três pacientes (dois masculino e um feminino), com idade média de 20,6 anos, vítimas de trauma de crânio grave, que apresentaram durante a evolução quadro clínico sugestivo de disautonomia. Os dados coletados incluíram detalhes do trauma, parâmetros fisiológicos, medicações utilizadas e evolução dos sintomas. Nesses pacientes, foi realizada infusão de morfina 4-6 mg/d no espaço peridural, em nível torácico, com média de 25,6 dias. Resultados: Dois pacientes tinham sinais radiológicos de lesão axonal difusa e um paciente tinha um volumoso hematoma extradural que foi operado. Os principais sintomas encontrados nos três pacientes foram sudorese, taquicardia, hipertermia e posturas distônicas. Em dois pacientes a hipertonia era global e em um paciente a postura distônica predominava no hemicorpo esquerdo. Após a passagem do cateter epidural com infusão de morfina, foi observada, já na primeira semana, melhora dos sintomas da hiperatividade simpática e da hipertonia nos grupos musculares envolvidos. Conclusão: O uso de morfina peridural pode ser uma alternativa de tratamento nos pacientes com HSP refratários ao tratamento clínico.

Introduction: The dysautonomia sympathetic hyperactivity or sympathetic storm syndrome (SSS) can occur in one third of patients with severe brain trauma, however, is still an entity without established treatment. The use of intravenous morphine is described for the treatment of SSS, and noted improvement mainly to lower frequencies of breathing and heartbeat. In this study we examine the effects of epidural morphine in patients with SSS. Patients and methods: We evaluated 3 patients (2 male, 1 female), with an average age of 20.6 years, victims of severe head trauma that presented SSS in hospital stay. The data collected included details of trauma, of physiology, medications used and symptoms. In these patients, infusion of morphine was realized 4 to 6 mg/d in the epidural space in the dorsal level with an average of 25.6 days. Results: Two patients had tomographic signs of diffuse axonal injury and one patient had a large acute epidural hematoma underwent to surgery. The main symptoms found in three patients, were dysautonomia, sweating, tachycardia, hyperthermia and postures distonics. In two patients, the stiffness was comprehensive and in one patient in the distonic posture in left side. After the procedure of the epidural catheter implant with infusion of morphine was found in the first week an improvement of symptoms of hyperactivity sympathetic. Conclusion: The use of epidural morphine can be an alternative treatment for sympathetic hyperactivity in patients with SSS.