Uremic Toxic Blood-Brain Barrier Disruption Mediated by AhR Activation Leads to Cognitive Impairment during Experimental Renal Dysfunction.

BACKGROUND: Uremic toxicity may play a role in the elevated risk of developing cognitive impairment found among patients with CKD. Some uremic toxins, like indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AhR), which is widely expressed in the central nervous system and which we previously identified as the receptor of indoxyl sulfate in endothelial cells. METHODS: To characterize involvement of uremic toxins in cerebral and neurobehavioral abnormalities in three rat models of CKD, we induced CKD in rats by an adenine-rich diet or by 5/6 nephrectomy; we also used AhR-/- knockout mice overloaded with indoxyl sulfate in drinking water. We assessed neurologic deficits by neurobehavioral tests and blood-brain barrier disruption by SPECT/CT imaging after injection of 99mTc-DTPA, an imaging marker of blood-brain barrier permeability. RESULTS: In CKD rats, we found cognitive impairment in the novel object recognition test, the object location task, and social memory tests and an increase of blood-brain barrier permeability associated with renal dysfunction. We found a significant correlation between 99mTc-DTPA content in brain and both the discrimination index in the novel object recognition test and indoxyl sulfate concentrations in serum. When we added indoxyl sulfate to the drinking water of rats fed an adenine-rich diet, we found an increase in indoxyl sulfate concentrations in serum associated with a stronger impairment in cognition and a higher permeability of the blood-brain barrier. In addition, non-CKD AhR-/- knockout mice were protected against indoxyl sulfate-induced blood-brain barrier disruption and cognitive impairment. CONCLUSIONS: AhR activation by indoxyl sulfate, a uremic toxin, leads to blood-brain barrier disruption associated with cognitive impairment in animal models of CKD.

Higher cerebrospinal fluid to plasma ratio of p-cresol sulfate and indoxyl sulfate in patients with Parkinson's disease.

BACKGROUND: In Parkinson's disease (PD), impairment of brain to blood barrier and/or blood-cerebrospinal fluid (CSF) barrier is described. It can increase the level of uremic toxins in CSF. So far, role of these compounds in neurological disorders has not been completely understood. However, a link has been observed between chronic kidney disease and neurological disorders. We measured the concentrations of uremic toxins (i.e. indoxyl sulfate (IS), p-cresol sulfate (pCS), symmetric dimethylarginine (SDMA), asymmetric dimethylarginine (ADMA), and trimethylamine N-oxide (TMAO)) in CSF and plasma, and correlated them with inflammation and oxidative stress biomarkers. METHODS: Plasma and CSF samples were collected from 27 volunteers (18 with PD and 9 controls). The level of toxins was determined using liquid chromatography coupled with tandem mass spectrometry. RESULTS: In PD, for IS and pCS, CSF-plasma ratio was higher. Concentration of pCS in CSF was higher in PD compared to controls. TMAO level was also higher in plasma of that group. Patients with motor fluctuations had higher level of uremic toxins in CSF, but not in plasma. CONCLUSIONS: The level of pCS and IS in CSF of PD is higher than expected, based on their blood level. It can influence pathogenesis and progression of PD.