BackgroundUremic 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.MethodsTo 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.ResultsIn 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.ConclusionsAhR activation by indoxyl sulfate, a uremic toxin, leads to blood-brain barrier disruption associated with cognitive impairment in animal models of CKD.

Over 75% of depressed patients suffer from painful symptoms predicting a greater severity and a less favorable outcome of depression. Imaging, anatomical and functional studies have demonstrated the existence of common brain structures, neuronal pathways and neurotransmitters in depression and pain. In particular, the ascending serotonergic and noradrenergic pathways originating from the raphe nuclei and the locus coeruleus; respectively, send projections to the limbic system. Such pathways control many of the psychological functions that are disturbed in depression and in the perception of pain. On the other hand, the descending pathways, from monoaminergic nuclei to the spinal cord, are specifically implicated in the inhibition of nociception providing rationale for the use of serotonin (5-HT) and/or norepinephrine (NE) reuptake inhibitors (SSRIs, NRIs, SNRIs), in the relief of pain. Compelling evidence suggests that dopamine (DA) is also involved in the pathophysiology and treatment of depression. Indeed, recent insights have demonstrated a central role for DA in analgesia through an action at both the spinal and suprasinal levels including brain regions such as the periaqueductal grey (PAG), the thalamus, the basal ganglia and the limbic system. In this context, dopaminergic antidepressants (i.e., containing dopaminergic activity), such as bupropion, nomifensine and more recently triple reuptake inhibitors (TRIs), might represent new promising therapeutic tools in the treatment of painful symptoms with depression. Nevertheless, whether the addition of the dopaminergic component produces more robust effects than single- or dual-acting agents, has yet to be demonstrated. This article reviews the main pathways regulating pain transmission in relation with the monoaminergic systems. It then focuses on the current knowledge regarding the in vivo pharmacological properties and mechanism of action of monoaminergic antidepressants including SSRIs, NRIs, SNRIs and TRIs. Finally, a synthesis of the preclinical studies supporting the efficacy of these antidepressants in analgesia is also addressed in order to highlight the relative contribution of 5-HT, NE and DA to nociception.

Limited information is available regarding the cellular mechanisms of oxaliplatin-induced painful neuropathy during exposure of patients to this drug. We therefore determined oxidative stress in cultured cells and evaluated its occurrence in C57BL/6 mice. Using both cultured neuroblastoma (SH-SY5Y) and macrophage (RAW 264.7) cell lines and also brain tissues of oxaliplatin-treated mice, we investigated whether oxaliplatin (OXA) induces oxidative stress and apoptosis. Cultured cells were treated with 2–200 µM OXA for 24 h. The effects of pharmacological inhibitors of oxidative stress or inflammation (N-acetyl cysteine, ibuprofen, acetaminophen) were also tested. Inhibitors were added 30 min before OXA treatment and then in combination with OXA for 24 h. In SH-SY5Y cells, OXA caused a significant dose-dependent decrease in viability, a large increase in ROS and NO production, lipid peroxidation and mitochondrial impairment as assessed by a drop in mitochondrial membrane potential, which are deleterious for the cell. An increase in levels of negatively charged phospholipids such as cardiolipin but also phosphatidylserine and phosphatidylinositol, was also observed. Additionally, OXA caused concentration-dependent P2X7 receptor activation, increased chromatin condensation and caspase-3 activation associated with TNF-α and IL-6 release. The majority of these toxic effects were equally observed in Raw 264.7 which also presented high levels of PGE2. Pretreatment of SH-SY5Y cells with pharmacological inhibitors significantly reduced or blocked all the neurotoxic OXA effects. In OXA-treated mice (28 mg/kg cumulated dose) significant cold hyperalgesia and oxidative stress in the tested brain areas were shown. Our study suggests that targeting P2X7 receptor activation and mitochondrial impairment might be a potential therapeutic strategy against OXA-induced neuropathic pain.