Сепсис-ассоциированная энцефалопатия (обзор)

International studies demonstrate an annual increase in the frequency and impact of sepsis in intensive care units (ICU). Cerebral dysfunction, or so-called sepsis-associated encephalopathy (SAE), is one of the earliest signs of sepsis, as well as its common complication. Up to 70% of patients with sepsis have symptoms of encephalopathy [1, 2]. A direct link between the SAE and an increased mortality rate is a major concern; more than a half of sepsis survivors experience continuous memory and concentration impairment [3—5]. Diagnosis of the cerebral dysfunction in sepsis is often difficult because of lack of specific biomarkers and frequent prescription of sedatives to critically ill patients. Clinical manifestations of SAE are diverse, may vary from simple malaise and lack of concentration to deep coma. The literature discusses probable mechanisms of formation and development of septic encephalopathy, such as oxidative stress, inflammation, mitochondrial and endothelial dysfunction, increased permeability of the blood-brain barrier, impairment of macro- and microcirculation, changes in neirotransmission, activation of microglia. The lack of clear data and consensus about the etiology and mechanisms of SAE at present does not permit predicting its development and prescribing a specific therapy. The review discusses current understanding of the causes of septic encephalopathy, methods of diagnosis, the main clinical manifestations, key mediators, and pathophysiological mechanisms. A hypothesis is proposed that poses a contribution of aromatic microbial metabolites (AMM) of phenol and indole nature (products of bacterial biodegradation of tyrosine and tryptophan) to the development of brain dysfunction. The fields of exploratory studies, which might open perspectives in the diagnosis, as well as new approaches in the treatment of SAE are outlined.Результаты международных исследований указывают на ежегодный рост частоты и актуальности сепсиса в реанимационных отделениях. Одним из наиболее ранних признаков, а также частым осложнением сепсиса является дисфункция мозга или так называемая сепсис-ассоциированная энцефалопатия (SAE). До 70% больных с сепсисом имеют симптомы энцефалопатии [1, 2]. Особое беспокойство вызывает факт прямой связи SAE с повышенной летальностью, а среди выживших после сепсиса более половины имеют длительные когнитивные расстройства, нарушения памяти и концентрации внимания [3—5]. Диагностика дисфункции мозга при сепсисе часто затруднена из-за отсутствия специфических биомаркеров, а также в связи с частым применением седативных препаратов у критических больных. Клинические проявления SAE разнообразны, могут варьировать от простого недомогания и недостатка концентрации внимания до глубокой комы. В литературе обсуждаются предполагаемые механизмы формирования и развития септической энцефалопатии, такие как окислительный стресс, воспаление, митохондриальная и эндотелиальная дисфункция, увеличение проницаемости гематоэнцефалического барьера, нарушения макро- и микроциркуляции, изменение нейротрансмиссии, активация микроглии. Отсутствие четких данных и единого мнения о происхождении и механизмах SAE в настоящее время не позволяет прогнозировать ее развитие и проводить специальную терапию. В обзоре обсуждаются современные представления о причинах развития септической энцефалопатии, методах диагностики, рассмотрены основные клинические проявления, ключевые медиаторы, патофизиологические механизмы. Предложена гипотеза о роли ароматических микробных метаболитов (АММ) фенольной и индольной природы — продуктов бактериальной биодеградации тирозина и триптофана — в развитии дисфункции мозга, намечены направления поисковых исследований, открывающие перспективы в диагностике и новые подходы в лечении SAE

Нейропротективное действие хлорида лития на модели остановки сердца у крыс

Lithium chloride, which is used for the treatment of bipolar disorders, has a neuroprotective effect in conditions associated with acute and chronic circulatory disorders.The purpose of the study: to investigate the efficacy of lithium chloride for the prevention of post-resuscitation death of hippocampal neurons during the post-resuscitation period.Material and methods. Cardiac arrest for 10 minutes was evoked in mature male rats by intrathoracic clumping of the vascular bundle of the heart, followed by resuscitation. 40 mg/kg or 20 mg/kg of 4,2% lithium chloride (LiCl) was injected intraperitoneally 1 hour before cardiac arrest, on the 1st and 2nd day after resuscitation (n=9). Untreated animals received equivalent doses of saline (n=9). Rats after a sham surgery served as a reference group (n=10). The number of viable neurons in the CA1 and CA3/CA4 fields of the hippocampus was estimated in slides stained with cresyl violet by day 6 or 7 postresuscitation. In a separate series of experiments, at the same terms, we studied the effect of lithium chloride on the protein content of GSK3β (glycogen synthase kinase) in brain tissue using Western-Blot analysis.Results. Histological assay showed that a 10-minute cardiac arrest resulted in a decrease in the number of viable neurons in the hippocampal CA1 field — by 37.5% (P0.001), in the CA3/CA4 field — by 12.9% (P0.05) vs. the reference group. Lithium treatment increased the number of viable neurons in resuscitated rats — in the CA1 field by 37% (P<0.01), in the CA3/CA4 field — by 11.5% (P0.1) vs. the untreated animals. It was found that lithium caused an increase in phosphorylated form of GSK3β: by 180% vs. the reference group (P[1]0.05), and by 150% vs. the untreated animals (P0.05).Conclusion. Lithium treatment leads to a pronounced neuroprotection in the neuronal populations of the hippocampus post-resuscitation. This effect may be due to an increase in the content of the phosphorylated form of GSK3β protein. The results indicate a high potential of lithium for the prevention and treatment of neurodegenerative disorders caused by a temporary arrest of blood circulation. Хлорид лития, используемый для коррекции биполярных расстройств, обладает нейропротективным эффектом при состояниях, связанных с острым и хроническим нарушением кровообращения в головном мозге. Цель исследования — оценить эффективность хлорида лития для предотвращения гибели высокочувствительных к гипоксии нейронов гиппокампа в постреанимационном периоде после временной остановки сердца. Материал и методы. Остановку сердца у взрослых крыс-самцов на 10 минут вызывали путем внутриторакального пережатия сосудистого пучка сердца с последующей реанимацией. 9-ти животным вводили раствор 4,2% LiCl за 1 час до остановки сердца (40 мг/кг в/б), на 1-е и на 2-е сутки после реанимации (20 мг/кг в/б, соответственно). 9 нелеченых животных в те же сроки получали эквивалентные дозы физиологического раствора хлорида натрия. Контролем служили ложноперированные крысы (n=10). Через 7 дней методом морфометрического анализа оценили число жизнеспособных нейронов в полях СА1 и СА3/СА4 гиппокампа на срезах, окрашенных крезиловым фиолетовым по Нисслю. В отдельной серии экспериментов с помощью Western-Blot анализа в эти же сроки исследовали влияние хлорида лития на содержание белка GSK3β (киназа гликогенсинтазы киназы-3) в ткани мозга. Результаты. При гистологическом исследовании установили, что 10-минутная остановка сердца приводит к снижению числа жизнеспособных нейронов в поле СА1 гиппокампа — на 37,5% (p0,001), в поле СА3/СА4 — на 12,9% (p0,05). Применение LiCl приводило к увеличению числа жизнеспособных нейронов гиппокампа у реанимированных крыс в поле СА1 на 37% (p0,01), в поле СА3/СА4 — на 11,5% (p0,1) по сравнению с нелечеными животными.  При исследовании белка GSK3β установили, что у реанимированных животных, получавших хлорид лития, содержание его фосфорилированной формы в ткани мозга было выше на 180% по сравнению с контролем (р0,05), и на 150% выше, чем у нелеченных животных (р0,05). Заключение. Введение хлорида лития в постреанимационном периоде приводило к выраженной нейропротекции в нейрональных популяциях гиппокампа. Этот эффект может быть обусловлен повышением содержания фосфорилированной формы белка GSK3β. Полученные результаты свидетельствуют о высоком потенциале лития для профилактики и лечения нейродегенеративных нарушений, вызванных временной остановкой кровообращения.

Brain Morphological Changes in COVID-19

The aim of the study was to identify the pathomorphology of brain damage in patients who died of COVID-19.Material and methods. Autopsy reports and autopsy brain material of 17 deceased patients with premortem confirmed COVID-19 infection were analyzed. Fatal cases in which COVID-19 was the major cause of death were included in the study. Five people were diagnosed with cerebral infarction. Organ samples were taken for histological examination during autopsy. Sections were stained with hematoxylin and eosin and by Nissl to assess brain histopathology. To study the vascular basal membranes the PAS reaction was used, to detect fibrin in vessels phosphotungstic acid-hematoxylin (PTAH) staining was used, to determine DNA in nuclei sections were stained according to Feulgen, to detect RNA in neuronal nuclei and cytoplasm sections were stained with methyl green-pyronin. Immunohistochemical study of a neuronal marker, nuclear protein NeuN, was performed to assess neuronal damage.Results. The signs of neuronal damage found in patients who died of COVID-19 included nonspecific changes of nerve cells (acute swelling, retrograde degeneration, karyolysis and cytolysis, ‘ghost' cells, neuronophagia and satellitosis) and signs of circulatory disorders (perivascular and pericellular edema, diapedesis, congested and engorged microvasculature).Conclusion. Brain histopathological data indicate damage to the central nervous system in COVID-19 patients. Ischemic stroke in patients with COVID-19 is mostly caused by a combination of hypoxia resulting from respiratory failure and individual risk factors, including cerebrovascular atherosclerosis and hypertension

Морфологические изменения головного мозга при COVID-19

The aim of the study was to identify the pathomorphology of brain damage in patients who died of COVID-19.Material and methods. Autopsy reports and autopsy brain material of 17 deceased patients with premortem confirmed COVID-19 infection were analyzed. Fatal cases in which COVID-19 was the major cause of death were included in the study. Five people were diagnosed with cerebral infarction. Organ samples were taken for histological examination during autopsy. Sections were stained with hematoxylin and eosin and by Nissl to assess brain histopathology. To study the vascular basal membranes the PAS reaction was used, to detect fibrin in vessels phosphotungstic acid-hematoxylin (PTAH) staining was used, to determine DNA in nuclei sections were stained according to Feulgen, to detect RNA in neuronal nuclei and cytoplasm sections were stained with methyl green-pyronin. Immunohistochemical study of a neuronal marker, nuclear protein NeuN, was performed to assess neuronal damage.Results. The signs of neuronal damage found in patients who died of COVID-19 included nonspecific changes of nerve cells (acute swelling, retrograde degeneration, karyolysis and cytolysis, ‘ghost' cells, neuronophagia and satellitosis) and signs of circulatory disorders (perivascular and pericellular edema, diapedesis, congested and engorged microvasculature).Conclusion. Brain histopathological data indicate damage to the central nervous system in COVID-19 patients. Ischemic stroke in patients with COVID-19 is mostly caused by a combination of hypoxia resulting from respiratory failure and individual risk factors, including cerebrovascular atherosclerosis and hypertension.Цель исследования — выявить морфологические признаки повреждения головного мозга умерших от COVID-19.Материал и методы. Провели анализ протоколов вскрытий и аутопсийного материала головного мозга 17 умерших пациентов с прижизненно подтвержденной инфекцией СOVID-19. В исследование включили случаи летального исхода, в которых COVID-19 явилась основной причиной смерти. У 5 человек диагностировали инфаркт головного мозга. Кусочки органов для гистологического исследования изымали в ходе патологоанатомического исследования. Для выявления морфологических изменений головного мозга срезы окрашивали гематоксилином и эозином и по методу Ниссля. Для исследования состояния базальных мембран сосудов применяли ШИК-реакцию, для выявления фибрина в сосудах использовали окраску гематоксилином Р.Т.А.Н. фосфовольфрамовым кислым, для выявления ДНК в ядрах срезы окрашивали по Фельгену, для выявления РНК в ядрах и цитоплазме нейронов срезы красили метиловым зеленым пиронином. Для оценки повреждения нейронов проводили иммуногистохимическое (ИГХ) исследование нейронального маркера — ядерного белка NeuN.  Результаты. Выявили признаки повреждения нейронов у умерших от COVID-19, заключающиеся в неспецифических изменениях нервных клеток (острое набухание, первичное раздражение, кариоцитолиз, клетки-тени, нейронофагия и саттелитоз) и признаках нарушения кровообращения (периваскулярный и перицеллюлярный отек, диапедезные кровоизлияния, стазы, полнокровие сосудов микроциркуляторного русла).Заключение. Морфологические изменения головного мозга свидетельствуют о повреждении центральной нервной системы у больных COVID-19. Ишемический инсульт у пациентов с COVID-19 во многом обусловлен сочетанием гипоксии, развивающейся вследствие дыхательной недостаточности, и существующих у больного факторов риска — атеросклероза артерий основания головного мозга и гипертонической болезни

Sepsis-Associated Encephalopathy (Review)

International studies demonstrate an annual increase in the frequency and impact of sepsis in intensive care units (ICU). Cerebral dysfunction, or so-called sepsis-associated encephalopathy (SAE), is one of the earliest signs of sepsis, as well as its common complication. Up to 70% of patients with sepsis have symptoms of encephalopathy [1, 2]. A direct link between the SAE and an increased mortality rate is a major concern; more than a half of sepsis survivors experience continuous memory and concentration impairment [3—5]. Diagnosis of the cerebral dysfunction in sepsis is often difficult because of lack of specific biomarkers and frequent prescription of sedatives to critically ill patients. Clinical manifestations of SAE are diverse, may vary from simple malaise and lack of concentration to deep coma. The literature discusses probable mechanisms of formation and development of septic encephalopathy, such as oxidative stress, inflammation, mitochondrial and endothelial dysfunction, increased permeability of the blood-brain barrier, impairment of macro- and microcirculation, changes in neirotransmission, activation of microglia. The lack of clear data and consensus about the etiology and mechanisms of SAE at present does not permit predicting its development and prescribing a specific therapy. The review discusses current understanding of the causes of septic encephalopathy, methods of diagnosis, the main clinical manifestations, key mediators, and pathophysiological mechanisms. A hypothesis is proposed that poses a contribution of aromatic microbial metabolites (AMM) of phenol and indole nature (products of bacterial biodegradation of tyrosine and tryptophan) to the development of brain dysfunction. The fields of exploratory studies, which might open perspectives in the diagnosis, as well as new approaches in the treatment of SAE are outlined

Neuroprotective Effect of Lithium Chloride in Rat Model of Cardiac Arrest

Lithium chloride, which is used for the treatment of bipolar disorders, has a neuroprotective effect in conditions associated with acute and chronic circulatory disorders.The purpose of the study: to investigate the efficacy of lithium chloride for the prevention of post-resuscitation death of hippocampal neurons during the post-resuscitation period.Material and methods. Cardiac arrest for 10 minutes was evoked in mature male rats by intrathoracic clumping of the vascular bundle of the heart, followed by resuscitation. 40 mg/kg or 20 mg/kg of 4,2% lithium chloride (LiCl) was injected intraperitoneally 1 hour before cardiac arrest, on the 1st and 2nd day after resuscitation (n=9). Untreated animals received equivalent doses of saline (n=9). Rats after a sham surgery served as a reference group (n=10). The number of viable neurons in the CA1 and CA3/CA4 fields of the hippocampus was estimated in slides stained with cresyl violet by day 6 or 7 postresuscitation. In a separate series of experiments, at the same terms, we studied the effect of lithium chloride on the protein content of GSK3β (glycogen synthase kinase) in brain tissue using Western-Blot analysis.Results. Histological assay showed that a 10-minute cardiac arrest resulted in a decrease in the number of viable neurons in the hippocampal CA1 field — by 37.5% (P0.001), in the CA3/CA4 field — by 12.9% (P0.05) vs. the reference group. Lithium treatment increased the number of viable neurons in resuscitated rats — in the CA1 field by 37% (P<0.01), in the CA3/CA4 field — by 11.5% (P0.1) vs. the untreated animals. It was found that lithium caused an increase in phosphorylated form of GSK3β: by 180% vs. the reference group (P[1]0.05), and by 150% vs. the untreated animals (P0.05).Conclusion. Lithium treatment leads to a pronounced neuroprotection in the neuronal populations of the hippocampus post-resuscitation. This effect may be due to an increase in the content of the phosphorylated form of GSK3β protein. The results indicate a high potential of lithium for the prevention and treatment of neurodegenerative disorders caused by a temporary arrest of blood circulation

Prognostic Value and Therapeutic Potential of Brain-Derived Neurotrophic Factor (BDNF) in Brain Injuries (Review)

Neurotrophins are proteins that play an important role in the nervous system functioning by regulating cell proliferation, differentiation, processes of neuronal survival and death, and by participating in the mechanisms of neuronal plasticity. The brain-derived neurotrophic factor (BDNF) is one of the most well-described representatives of the neurotrophin family, which has received close attention over recent years. It is considered one of the key mediators of neuronal survival and recovery, and a drop of the BDNF level is considered a common mechanism underlying the development of various neurodegenerative diseases. The review discusses changes in BDNF levels in ischemic and traumatic brain damage, the prospects of its use in the clinical practice as a marker of brain dysfunction, as well as the possibility of its use for the treatment of post-ischemic encephalopathies