Matrix Metalloproteinase-2 and Metalloproteinase-9 Activities are Associated with Blood–Brain Barrier Dysfunction in an Animal Model of Severe Sepsis

Abstract

There is no description on the mechanisms associated with blood-brain barrier (BBB) disruption during sepsis development. Thus, we here determined changes in permeability of the BBB in an animal model of severe sepsis and the role of matrix metalloproteinase (MMP)-2 and MMP-9 in the dysfunction of the BBB. Sepsis was induced in Wistar rats by cecal ligation and perforation. BBB permeability was assessed using the Evans blue dye method. The content of MMP-2 and MMP-9 in the cerebral microvessels was determined by western blot. The activity of MMP-2 and MMP-9 was determined using zymography. An inhibitor of MMP-2 and MMP-9 or specific inhibitors of MMP-2 or MMP-9 were administered to define the role of MMPs on BBB permeability, brain inflammatory response, and sepsis-induced cognitive alterations. The increase of BBB permeability is time-related to the increase of MMP-9 and MMP-2 in the microvessels, both in cortex and hippocampus. Using an MMP-2 and MMP-9 inhibitor, or specific MMP-2 or MMP-9 inhibitors, the increase in the permeability of the BBB was reversed. This was associated with lower brain levels of interleukin (IL)-6 and lower oxidative damage. In contrast, only the inhibition of both MMP-9 and MMP-2 was able to improve acute cognitive alterations associated with sepsis. In conclusion, MMP-2 and MMP-9 activation seems to be a major step in BBB dysfunction, but BBB dysfunction seems not to be associated with acute cognitive dysfunction during sepsis development.

CD40-CD40 Ligand Pathway Is a Major Component of Acute Neuroinflammation and Contributes to Long-term Cognitive Dysfunction after Sepsis

“…We had demonstrated previously that the control of acute inflammation was associated with improved long-term outcome in the CLP model of sepsis (45)(46)(47). Here we demonstrated that the downregulation of CD40 signaling was able to improve long-term cognitive function in sepsis survivor rats.…”

Betaine prevents homocysteine-induced memory impairment via matrix metalloproteinase-9 in the frontal cortex

“…Interestingly, previous reports have demonstrated that the dysfunction of the BBB followed the development of diseases is temporally related to the increase in MMP-9 [54,55]. It is also intriguing that specific MMP-9 inhibitors ameliorate BBB dysfunction and inflammatory responses [54]. Therefore, we examined whether the changes in MMP-9 activity after Hcy injection induce memory impairments.…”

“…These findings suggest that HHcy increases oxidative stress, which results in enhanced levels of MMP-9 that are associated with the loss of memory. Interestingly, previous reports have demonstrated that the dysfunction of the BBB followed the development of diseases is temporally related to the increase in MMP-9 [54,55]. It is also intriguing that specific MMP-9 inhibitors ameliorate BBB dysfunction and inflammatory responses [54].…”

Septic encephalopathy: does inflammation drive the brain crazy?

“…26 In addition, BBB dysfunction induced by metalloproteinase (MMP) activation was also associated with brain inflammation and cognitive impairment in an animal model of sepsis. 55 This is supported by the fact that MMP-9 content was associated with delirium in the general ICU patient. 44 It is supposed that systemic inflammation can lead to neuronal or glial damage; however, at least in experimental endotoxemia in humans, there is no correlation between acute systemic inflammation and plasma levels of brain specific proteins (S-100b, neuronal enolase [NSE], glial fibrillary acidic protein [GFAP]) nor deterioration of cognitive function.…”