Intestinal Ischemia/Reperfusion Injury Influences Hyaluronan Homeostasis in the Rat Brain

Intestinal ischemia and reperfusion injury (IRI) can lead to multiple organ dysfunction,
including the central nervous system (CNS), where a neuroinflammatory response may
develop. Hyaluronan, a glycosaminoglycan component of the extracellular matrix, has
been shown to modulate enteric neuronal and immune function during in vivo IRI in the
rat small intestine. The aim of this study was to investigate the potential involvement of
hyaluronan in the alterations induced by in vivo intestinal IRI in the rat hippocampus and
striatum. Mesenteric ischemia was induced in anesthetized adult male rats for 60 min,
followed by 24 h of reperfusion. Injured (IRI group), sham-operated (SHAM group), and
non-injured (CTR group) animals were treated with the hyaluronan synthesis inhibitor
4-methylumbelliferone (4-MU; 25 mg/kg). In the hippocampus and striatum of the IRI
group, levels of both hyaluronan and neurocan, a proteoglycan primarily found in the
central nervous system extracellular matrix, as well as the hyaluronan synthesizing enzyme
Has2, were significantly downregulated compared to the CTR and SHAM groups. These
changes were associated with alterations in the TLR4-NFκB-pIκB pathway, with the effects
being more prominent in the hippocampus than in the striatum. Increased levels of IL6,
co-localizing with the microglial marker S100β, were observed in both regions and were
attenuated by 4-MU only in the hippocampus. Overall, these findings suggest that intestinal IRI may disrupt extracellular matrix homeostasis and induce hyaluronan-mediated
enhancement of local proinflammatory signaling, primarily involving IL6 and microglial
cells, mainly in the hippocampus. Such changes may contribute to the development of
cognitive deficits and memory dysfunction associated with intestinal IRI.