Neurobehavioral effects of uremic toxin–indoxyl sulfate in the rat model

Abstract

Chronic kidney disease (CKD) is deemed to be a worldwide health concern connected with neurological manifestations. The etiology of central nervous system (CNS) disorders in CKD is still not fully understood, however particular attention is currently being paid to the impact of accumulated toxins. Indoxyl sulfate (IS) is one of the most potent uremic toxins. The purpose of the present study was to assess IS concentrations in the cerebellum, brainstem, cortex, hypothalamus, and striatum with hippocampus of rats chronically exposed to IS. To evaluate IS impact on neurochemical and behavioral alterations, we examined its influence on brain levels of norepinephrine, epinephrine, dopamine, serotonin and their metabolites, as well as changes in behavioral tests (open field test, elevated plus maze test, chimney test, T maze test, and splash test). Our results show the highest IS accumulation in the brainstem. IS leads to behavioral alterations involving apathetic behavior, increased stress sensitivity, and reduced locomotor and exploratory activity. Besides, IS contributes to the impairment of spatial memory and motor coordination. Furthermore, we observed reduced levels of norepinephrine, dopamine or serotonin, mainly in the brainstem. Our findings indicate that IS can be one of the crucial uremic factors responsible for altered mental status in CKD.

Indoxyl sulfate, a gut microbiome-derived uremic toxin, is associated with psychic anxiety and its functional magnetic resonance imaging-based neurologic signature

“…With respect to psychiatric disorders, IS has been associated with behavioral defects in preclinical models of anxiety and depression. The administration of IS into rodents’ drinking water results in increased concentrations of IS in the brain and increased blood–brain barrier permeability in an AHR-dependent manner, with accompanying increases in anxiety and cognitive deficits 31 , 32 . Monocolonization experiments with indole-producing Escherichia coli and isogenic mutants have shown that indole production by gut bacteria is sufficient to drive increases in anxiety- and depressive-like behavior in rats 33 .…”

Indoxyl sulfate, a gut microbiome-derived uremic toxin, is associated with psychic anxiety and its functional magnetic resonance imaging-based neurologic signature

“…Further, IS has been associated with behavioral defects in preclinical models of anxiety and depression. The administration of IS into rodents’ drinking water results in increased concentrations of IS in the brain and increased blood-brain barrier permeability in an AHR-dependent manner, with accompanying increases in anxiety and cognitive deficits (27,28). Monocolonization experiments with indole-producing Escherichia coli and isogenic mutants have shown that indole production by gut bacteria is sufficient to drive increases in anxiety- and depressive-like behavior in rats (29).…”

Indoxyl sulfate caused behavioral abnormality and neurodegeneration in mice with unilateral nephrectomy

“…Although current study revealed interesting findings, there were some limitations. In normal Albino Wistar rats, indoxyl sulfate (100 and 200 mg/kg) administration via drinking water for 28 days led to its increased accumulation in various brain regions and high dose of indoxyl sulfate (200 mg/kg) caused biochemical and behavioral alterations [ 56 ]. The same experimental conditions demonstrated higher plasma indoxyl sulfate concentrations in both two doses and the high dose treatment slightly impaired renal function [ 57 ].…”