PPAR gamma activation protects the brain against microvascular dysfunction in sepsis

Abstract

Sepsis is a severe disorder characterized by systemic inflammatory responses in the presence of an infection and may progress to multiple organ dysfunction and death. Alterations in cerebral microcirculation fulfill a crucial role in the pathogenesis of severe sepsis, and include a decrease in capillary density and disturbances in leukocyte movement along capillaries. Nevertheless, the mechanisms involved in sepsis-associated cerebral microcirculatory alterations have so far not been defined. We investigated the effect of the peroxisome proliferator-activated receptor gamma (PPARγ) selective agonist rosiglitazone on leukocyte/endothelial cell interaction and functional capillary density in the brain in the cecal ligation and puncture (CLP) model of sepsis. Anti-inflammatory effects of rosiglitazone on the cerebral microcirculation were marked. Functional capillary density increased and leukocyte rolling and adhesion were decreased in animals submitted to CLP and treated with rosiglitazone. Our data provide evidence for involvement of PPARγ activation in leukocyte-endothelium interactions and alterations in capillary density. Improved cerebral perfusion in animals treated with rosiglitazone, suggests that PPARγ activation is protective against cerebral microvascular dysfunction in sepsis.

Role of Nitric Oxide Synthase in the Function of the Central Nervous System under Normal and Infectious Conditions

“…Our group and others have shown that eNOS is impaired during systemic infection, which leads to brain microcirculation dysfunction [46][47][48]. We showed that during different infectious diseases, there is a functional capillary rarefaction (Figure 3) that can be caused by the impairment of endothelial NO production by a reduction of eNOS activity or by reduced levels of the enzyme cofactor tetrahydrobiopterin-BH4 [49].…”

“…One mechanism of eNOS "uncoupling" from the reduction of NO production and ROS generation involves the oxidative degradation of the cofactor BH4 (tetrahydrobiopterin), especially by peroxynitrite (ONOO − ), which is produced in association with superoxide and nitric oxide. Several studies have shown that there is an increase in impaired eNOS-derived oxidative stress in brain tissue exposed to systemic infection, NO consumption and capillary dysfunction [46,47,52,53].…”

“…Cognitive decline is a major cause of disability in stroke survivors [69]. We have shown that microvascular impairment in malaria, sepsis, and Chagas' diseases may occur in response to other infectious agents [46][47][48]. Cerebral metabolism is dependent upon the glucose and oxygen that are delivered by blood, and it is clear that alterations in endothelial function can disrupt neuronal functions.…”

Effects of cococonut water and simvastatin in the treatment of sepsis and hemorrhagic shock in rats

“…Time points for analysis were chosen based on previous data 28 . The score consisted of analyzing the following parameters: 1-presence of piloerection, 2-altered respiration rate, 3-fecal alteration, 4-lacrimation/eyelid changes, 5-contraction of the abdomen, 6-lack of strength when grasping, 7-change in body temperature, 8-alert response (scape after touch), 9-exploration of the environment and 10-compromised locomotor activity.…”

Effects of Veronica officinalis extract in the kidney of rats with induced sepsis

“…Furthermore, sepsis is a syndrome resulting from the immune response initiated by an infectious process characterized by hemodynamic and metabolic changes that can lead to septic shock, multiple organ dysfunction and death [2].…”