Statins prevent cognitive impairment after sepsis by reverting neuroinflammation, and microcirculatory/endothelial dysfunction.
Acute brain dysfunction is a frequent condition in sepsis patients and is associated with increased mortality and long-term neurocognitive consequences. Impaired memory and executive function are common findings in sepsis survivors. Although neuroinflammation and blood-brain barrier dysfunction have been associated with acute brain dysfunction and its consequences, no specific treatments are available that prevent cognitive impairment after sepsis. Experimental sepsis was induced in Swiss Webster mice by intraperitoneal injection of cecal material (5mg/kg, 500μL). Control groups (n=5/group each experiment) received 500μL of saline. Support therapy recover (saline 0.9%, 1mL and imipenem 30mg/kg) were applied (6, 24 and 48h post injection, n=5-10/group, each experiment), together or not with additive orally treatment with statins (atorvastatin/simvastatin 20mg/kg b.w.). Survival rate was monitored at 6, 24 and 48h. In a setting of experiments, animals were euthanized at 6 and 24h after induction for biochemical, immunohistochemistry and intravital analysis. Statins did not prevented mortality in septic mice, however survivors presented lower clinical score. At another setting of experiments, after 15days, mice survivors from fecal supernatant peritoneal sepsis presented cognitive dysfunction for contextual hippocampal and aversive amygdala-dependent memories, which was prevented by atorvastatin/simvastatin treatment. Systemic and brain tissue levels of proinflammatory cytokines/chemokines and activation of microglial were lower in septic mice treated with statins. Brain lipid peroxidation and myeloperoxidase levels were also reduced by statins treatment. Intravital examination of the brain vessels of septic animals revealed decreased functional capillary density and increased rolling and adhesion of leukocytes, and blood flow impairment, which were reversed by treatment with statins. In addition, treatment with statins restored the cholinergic vasodilator response due to sepsis. Taken together, these data demonstrated that statins reverse microvascular dysfunction and reduce neuroinflammation during sepsis, preventing the development of long-term cognitive decline.
Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
Patricia A
PA
Reis
Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
Pedro C B
PCB
Alexandre
Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
Joana C
JC
D'Avila
Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
Luciana D
LD
Siqueira
Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
Barbara
B
Antunes
Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
Vanessa
V
Estato
Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
Eduardo V
EV
Tibiriça
Department of Histopathology and Animal Models, Institut Pasteur, Paris, France.
Franck
F
Verdonk
Department of Histopathology and Animal Models, Institut Pasteur, Paris, France.
Tarek
T
Sharshar
Department of Histopathology and Animal Models, Institut Pasteur, Paris, France.
Fabrice
F
Chrétien
Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil; Faculdade de Medicina, Universidade Estácio de Sá, Brazil.
Hugo C
HC
Castro-Faria-Neto
Evandro Chagas National Institute of Infectious Diseases, Fiocruz, Rio de Janeiro, Brazil; D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil. Electronic address: fernando.bozza@ipec.fiocruz.br.
Fernando A
FA
Bozza
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000188:drug therapy / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008833:Microcirculation / Q000187:drug effects*; D018805:Sepsis / Q000150:complications / Q000188:drug therapy*
D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors
Cognition; Endothelium; Neuroinflammation; Sepsis; Statin