Dopamine Dynamics in the Amygdala Influence Emotional Changes in the Early Stage of Systemic Inflammatory Response Syndrome in Rats / La Dinámica de la Dopamina en la Amígdala Influye en los Cambios Emocionales en la Etapa Temprana del Síndrome de Respuesta Inflamatoria Sistémica en Ratas

SUMMARY: Systemic inflammatory response syndrome (SIRS) is a potentially fatal reaction to various forms of tissue damage and infections that cause damage to various organs. Furthermore, the brain is damaged earlier than other organs, resulting in diffuse brain dysfunction. The central clinical symptom of SIRS is delirium and emotional changes are involved in disease development. Although the amygdala is known to play a major role, the mechanisms underlying emotional changes in the early stages of SIRS have not been elucidated. Therefore, changes to dopamine levels in the amygdala were observed using an in vivo model of lipopolysaccharide (LPS)- induced SIRS to clarify the biochemical mechanisms activated in the early stages of SIRS. Extracellular dopamine was collected from the amygdala of free moving rats via microdialysis and then analyzed by high-performance liquid chromatography. In addition, emotional changes were assessed with the open field and sucrose preference tests. In the LPS group, dopamine release in the amygdala increased remarkably immediately after LPS administration, peaking at 120 min. Thereafter, dopamine release temporarily decreased, but then significantly increased again after 180 min. The present results suggest that diffuse brain dysfunction in the early stages of SIRS may involve altered dopamine levels in the amygdala.

El síndrome de respuesta inflamatoria sistémica (SRIS) es una reacción potencialmente fatal a diversas formas de daño tisular e infecciones que causan injuria a varios órganos. Además, el cerebro se daña antes que otros órganos, lo que provoca una disfunción cerebral difusa. El síntoma clínico central del SIRS es el delirio y los cambios emocionales están involucrados en el desarrollo de la enfermedad. Aunque se sabe que la amígdala desempeña un papel importante, no se han dilucidado los mecanismos que subyacen a los cambios emocionales en las primeras etapas del SRIS. Por lo tanto, en el estudio se provocaron cambios en los niveles de dopamina en la amígdala utilizando un modelo in vivo de SRIS inducido por lipopolisacáridos (LPS) para dilucidar los mecanismos bioquímicos activados en las primeras etapas del SRIS. La dopamina extracelular se recogió de la amígdala de ratas en movimiento libre mediante microdiálisis y luego se analizó mediante cromatografía líquida de alta resolución. Además, se evaluaron los cambios emocionales con las pruebas de campo abierto y de preferencia de sacarosa. En el grupo de LPS, la liberación de dopamina en la amígdala aumentó de manera notable inmediatamente después de la administración de LPS, alcanzando un máximo a los 120 minutos. A partir de entonces, la liberación de dopamina disminuyó temporalmente, pero luego volvió a aumentar significativamente después de 180 min. Los resultadosactuales sugieren que la disfunción cerebral difusa en las primeras etapas del SIRS puede implicar niveles alterados de dopamina en la amígdala.

Potential of piperine for neuroprotection in sepsis-associated encephalopathy.

AIMS: Sepsis-associated encephalopathy (SAE) is a common complication that increases mortality and leads to long-term cognitive impairment in sepsis survivors. However, no specific or effective therapy has been identified for this complication. Piperine is an alkaloid known for its anti-inflammatory, antioxidant, and neuroprotective properties, which are important characteristics for treatment of SAE. The objective of this study was to evaluate the neuroprotective effect of piperine on SAE in C57BL/6 mice that underwent cecum ligation and perforation surgery (CLP). MAIN METHODS: C57BL/6 male mice were randomly assigned to groups that underwent SHAM surgery or CLP. Mice in the CLP group were treated with piperine at doses of 20 or 40 mg/kg for short- (5 days) or long-term (10 days) periods after CLP. KEY FINDINGS: Our results revealed that untreated septic animals exhibited increased concentrations of IL-6, TNF, VEGF, MMP-9, TBARS, and NLRP3, and decreased levels of BDNF, sulfhydryl groups, and catalase in the short term. Additionally, the levels of carbonylated proteins and degenerated neuronal cells were increased at both time points. Furthermore, short-term and visuospatial memories were impaired. Piperine treatment reduced MMP-9 activity in the short term and decreased the levels of carbonylated proteins and degenerated neuronal cells in the long term. It also lowered IL-6 and TBARS levels at both time points evaluated. Moreover, piperine increased short-term catalase and long-term BDNF factor levels and improved memory at both time points. SIGNIFICANCE: In conclusion, our data demonstrate that piperine exerts a neuroprotective effect on SAE in animals that have undergone CLP.

P2X7 receptor contributes to long-term neuroinflammation and cognitive impairment in sepsis-surviving mice.

Introduction: Sepsis is defined as a multifactorial debilitating condition with high risks of death. The intense inflammatory response causes deleterious effects on the brain, a condition called sepsis-associated encephalopathy. Neuroinflammation or pathogen recognition are able to stress cells, resulting in ATP (Adenosine Triphosphate) release and P2X7 receptor activation, which is abundantly expressed in the brain. The P2X7 receptor contributes to chronic neurodegenerative and neuroinflammatory diseases; however, its function in long-term neurological impairment caused by sepsis remains unclear. Therefore, we sought to evaluate the effects of P2X7 receptor activation in neuroinflammatory and behavioral changes in sepsis-surviving mice. Methods: Sepsis was induced in wild-type (WT), P2X7-/-, and BBG (Brilliant Blue G)-treated mice by cecal ligation and perforation (CLP). On the thirteenth day after the surgery, the cognitive function of mice was assessed using the novel recognition object and Water T-maze tests. Acetylcholinesterase (AChE) activity, microglial and astrocytic activation markers, and cytokine production were also evaluated. Results: Initially, we observed that both WT and P2X7-/- sepsis-surviving mice showed memory impairment 13 days after surgery, once they did not differentiate between novel and familiar objects. Both groups of animals presented increased AChE activity in the hippocampus and cerebral cortex. However, the absence of P2X7 prevented partly this increase in the cerebral cortex. Likewise, P2X7 absence decreased ionized calcium-binding protein 1 (Iba-1) and glial fibrillary acidic protein (GFAP) upregulation in the cerebral cortex of sepsis-surviving animals. There was an increase in GFAP protein levels in the cerebral cortex but not in the hippocampus of both WT and P2X7-/- sepsis-surviving animals. Pharmacological inhibition or genetic deletion of P2X7 receptor attenuated the production of Interleukin-1ß (IL-1ß), Tumor necrosis factor-α (TNF-α), and Interleukin-10 (IL-10). Conclusion: The modulation of the P2X7 receptor in sepsis-surviving animals may reduce neuroinflammation and prevent cognitive impairment due to sepsis-associated encephalopathy, being considered an important therapeutic target.

The Many Faces of Astrocytes in the Septic Brain.

Sepsis is a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. Surviving patients have cognitive and memory damage that started during sepsis. These neurologic damages have been associated with increased BBB permeability and microglial activation. However, a few discrete studies have seen over the years pointing to the potential role of astrocytes in the pathophysiology of neurological damage after sepsis. The purpose of this article is to review information on the potential role of astrocytes during sepsis, as well as to provoke further studies in this area. These published articles show astrocytic activation after sepsis; they also evidence the release of inflammatory mediators by these cells. In this sense, the role of astrocytes should be better elucidated during sepsis progression.

Biomarkers for sepsis: more than just fever and leukocytosis-a narrative review.

A biomarker describes a measurable indicator of a patient's clinical condition that can be measured accurately and reproducibly. Biomarkers offer utility for diagnosis, prognosis, early disease recognition, risk stratification, appropriate treatment (theranostics), and trial enrichment for patients with sepsis or suspected sepsis. In this narrative review, we aim to answer the question, "Do biomarkers in patients with sepsis or septic shock predict mortality, multiple organ dysfunction syndrome (MODS), or organ dysfunction?" We also discuss the role of pro- and anti-inflammatory biomarkers and biomarkers associated with intestinal permeability, endothelial injury, organ dysfunction, blood-brain barrier (BBB) breakdown, brain injury, and short and long-term mortality. For sepsis, a range of biomarkers is identified, including fluid phase pattern recognition molecules (PRMs), complement system, cytokines, chemokines, damage-associated molecular patterns (DAMPs), non-coding RNAs, miRNAs, cell membrane receptors, cell proteins, metabolites, and soluble receptors. We also provide an overview of immune response biomarkers that can help identify or differentiate between systemic inflammatory response syndrome (SIRS), sepsis, septic shock, and sepsis-associated encephalopathy. However, significant work is needed to identify the optimal combinations of biomarkers that can augment diagnosis, treatment, and good patient outcomes.

Neuroinflammation in Sepsis: Molecular Pathways of Microglia Activation.

Frequently underestimated, encephalopathy or delirium are common neurological manifestations associated with sepsis. Brain dysfunction occurs in up to 80% of cases and is directly associated with increased mortality and long-term neurocognitive consequences. Although the central nervous system (CNS) has been classically viewed as an immune-privileged system, neuroinflammation is emerging as a central mechanism of brain dysfunction in sepsis. Microglial cells are major players in this setting. Here, we aimed to discuss the current knowledge on how the brain is affected by peripheral immune activation in sepsis and the role of microglia in these processes. This review focused on the molecular pathways of microglial activity in sepsis, its regulatory mechanisms, and their interaction with other CNS cells, especially with neuronal cells and circuits.

What animal models can tell us about long-term cognitive dysfunction following sepsis: A systematic review.

Survivors of sepsis often develop long-term cognitive impairments. This review aimed at exploring the results of the behavioral tools and tests which have been used to evaluate cognitive dysfunction in different animal models of sepsis. Two independent investigators searched for sepsis- and cognition-related keywords. 6323 publications were found, of which 355 were selected based on their title, and 226 of these were chosen based on manuscript review. LPS was used to induce sepsis in 171 studies, while CLP was used in 55 studies. Inhibitory avoidance was the most widely used method for assessing aversive memory, followed by fear conditioning and continuous multi-trial inhibitory avoidance. With regard to non-aversive memory, most studies used the water maze, open-field, object recognition, Y-maze, plus maze, and radial maze tests. Both CLP and LPS models of sepsis were effective in inducing short- and long-term behavioral impairment. Our findings help elucidate the mechanisms involved in the pathophysiology of sepsis-induced cognitive changes, as well as the available methods and tests used to study this in animal models.

Septic encephalopathy: does inflammation drive the brain crazy?

Sepsis and the multiorgan dysfunction syndrome are among the most common reasons for admission to an intensive care unit, and are a leading cause of death. During sepsis, the central nervous system (CNS) is one of the first organs affected, and this is clinically manifested as sepsis-associated encephalopathy (SAE). It is postulated that the common final pathway that leads to SAE symptoms is the deregulation of neurotransmitters, mainly acetylcholine. Thus, it is supposed that inflammation can affect neurotransmitters, which is associated with SAE development. In this review, we will cover the current evidence (or lack thereof) for the mechanisms by which systemic inflammation interferes with the metabolism of major CNS neurotransmitters, trying to explain how systemic inflammation drives the brain crazy.

Morphometric investigation of neurons in the hippocampal CA1, CA3 areas and dentate gyrus in a rat model of sepsis / Investigación morfométrica de neuronas en las áreas hipocampales CA1, CA3 y giro dentado en un modelo de sepsis en rata

Approximately, half of the patients with progressive sepsis develop encephalopathy, but there is scarce knowledge onto question that how the sepsis associated encephalopathy contributes brain dysfunction. Hippocampus is one of the most vulnerable regions during experimental sepsis. In the present study, effects of sepsis on the neuronal density and morphology in CA1, CA3 and DG areas were investigated in a rat model of intraperitoneal sepsis. Twenty-four Wistar rats were divided into three different groups: faecal peritonitis group, sham-operated and un-operated control groups. Pyramidal neuron volume density was significantly higher in CA1 area of the faecal peritonitis group compared to both un-operated (p<0.05) and sham-operated (p<0.05) groups. Pyramidal neuron volume density was also significantly higher in CA3 area of the faecal peritonitis group compared to both un-operated (p<0.05) and sham-operated (p<0.05) groups. Mean nuclear diameter of pyramidal neurons in CA1 area of the faecal peritonitis group was significantly lower (p<0.05) compared to un-operated control group. Dark, shrunken neurons were frequently observed and neuroglial cells appeared to be prevalent in the faecal peritonitis group compared to control groups. These results collectively suggest that intraperitoneal sepsis does not initiate cell death in the early stages of sepsis, although morphological signs of neurodegeneration start to appear.

Aproximadamente, la mitad de los pacientes con sepsis progresiva desarrollan encefalopatía, pero hay escaso conocimiento en cuestión de como la sepsis asociada con encefalopatía contribuye a la disfunción cerebral. El hipocampo es una de las regiones más vulnerables durante la sepsis experimental. En el presente estudio, fueron analizados los efectos de la sepsis sobre la densidad neuronal y la morfología en las áreas CA1, CA3 y giro dentado en un modelo de sepsis intraperitoneal en rata. Veinticuatro ratas Wistar se dividieron en tres grupos diferentes: grupo de peritonitis fecal, operación simulada y control no operado. La densidad del volúmen piramidal fue significativamente mayor en el área CA1 del grupo con peritonitis fecal en comparación con los grupos no operados (p<0,05) y la operación simulada (p<0,05). La densidad de volumen de las neuronas piramidales fue significativamente mayor en el área CA3 del grupo peritonitis fecal en comparación con los no operado (p<0,05) y la operación simulada (p<0,05). El diámetro promedio nuclear de las neuronas piramidales en la zona CA1 del grupo de peritonitis fecal fue significativamente menor (p<0,05) en comparación con el grupo de control no operado. Las neuronas fueron observadas con frecuencia reducidas y las células neurogliales parecen ser frecuentes en el grupo de peritonitis fecal en comparación con grupos de control. Estos resultados en conjunto sugieren que la sepsis intraperitoneal no inicia la muerte celular en las primeras etapas de la sepsis, aunque los signos morfológicos de la neurodegeneración empiezan a aparecer.