Abstract
Blood-brain barrier (BBB) impairment in systemic inflammation leads to neuroinflammation. Several factors including cytokines, chemokines and signal transduction molecules are implicated in BBB dysfunction in response to systemic inflammation. Here, we have adopted a novel in vivo technique; namely, cerebral open flow microperfusion (cOFM), to perform time-dependent cytokine analysis (TNF-alpha, IL-6 and IL-10) in the frontal cortex of the rat brain in response to a single peripheral administration of lipopolysaccharide (LPS). In parallel, we monitored BBB function using sodium fluorescein as low molecular weight reporter in the cOFM sample. In response to the systemic LPS administration, we observed a rapid increase of TNF-alpha in the serum and brain, which coincides with the BBB disruption. Brain IL-6 and IL-10 synthesis was delayed by approximately 1 h. Our data demonstrate that cOFM can be used to monitor changes in brain cytokine levels and BBB disruption in a rat sepsis model.
Highlights
Septic encephalopathy, a frequent complication of sepsis, is characterized by blood-brain barrier (BBB) disruption, leucocyte infiltration, up-regulation of aquaporin-4, activation of microglia, astrocytosis, and apoptotic cell death [1,2]
We demonstrated that BBB disruption due to cerebral open flow microperfusion (cOFM) probe implantation in the frontal cortex of rats is healed within 15 days of probe implantation
These analyses revealed that in response to LPS, the Naf concentration in the cOFM sample was higher than baseline after 2 h (Fig. 2)
Summary
A frequent complication of sepsis, is characterized by blood-brain barrier (BBB) disruption, leucocyte infiltration, up-regulation of aquaporin-4, activation of microglia, astrocytosis, and apoptotic cell death [1,2]. Clinical and experimental studies demonstrate that complement activation and the production of inflammatory cytokines could drive BBB disruption, leukocyte recruitment, neuroinflammation, and neuronal cell death [1]. In a variety of other neurological (inflammatory, infectious, neoplastic and neurodegenerative) diseases, BBB dysfunctions have been described [5]. Brain endothelial barrier disruption in neuroinflammation involves cytokines [6] and these signalling peptides diffuse into interstitial fluid [7] to provide signals to neighbouring cells. Neuropathological and imaging studies demonstrate that loss of BBB integrity precede neuronal damage in many conditions [8,9,10]. Early detection of compromised BBB function could potentially permit early diagnosis and allow testing interventions that will prevent irreversible brain damage
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