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

Intestinal ischemia and reperfusion injury (IRI) can lead to multiple organ dysfunction,\r\nincluding the central nervous system (CNS), where a neuroinflammatory response may\r\ndevelop. Hyaluronan, a glycosaminoglycan component of the extracellular matrix, has\r\nbeen shown to modulate enteric neuronal and immune function during in vivo IRI in the\r\nrat small intestine. The aim of this study was to investigate the potential involvement of\r\nhyaluronan in the alterations induced by in vivo intestinal IRI in the rat hippocampus and\r\nstriatum. Mesenteric ischemia was induced in anesthetized adult male rats for 60 min,\r\nfollowed by 24 h of reperfusion. Injured (IRI group), sham-operated (SHAM group), and\r\nnon-injured (CTR group) animals were treated with the hyaluronan synthesis inhibitor\r\n4-methylumbelliferone (4-MU; 25 mg/kg). In the hippocampus and striatum of the IRI\r\ngroup, levels of both hyaluronan and neurocan, a proteoglycan primarily found in the\r\ncentral nervous system extracellular matrix, as well as the hyaluronan synthesizing enzyme\r\nHas2, were significantly downregulated compared to the CTR and SHAM groups. These\r\nchanges were associated with alterations in the TLR4-NFκB-pIκB pathway, with the effects\r\nbeing more prominent in the hippocampus than in the striatum. Increased levels of IL6,\r\nco-localizing with the microglial marker S100β, were observed in both regions and were\r\nattenuated by 4-MU only in the hippocampus. Overall, these findings suggest that intestinal IRI may disrupt extracellular matrix homeostasis and induce hyaluronan-mediated\r\nenhancement of local proinflammatory signaling, primarily involving IL6 and microglial\r\ncells, mainly in the hippocampus. Such changes may contribute to the development of\r\ncognitive deficits and memory dysfunction associated with intestinal IRI.