Neurochemical Plasticity of the Carotid Body.

A striking feature of the carotid body (CB) is its remarkable degree of plasticity in a variety of neurotransmitter/modulator systems in response to environmental stimuli, particularly following hypoxic exposure of animals and during ascent to high altitude. Current evidence suggests that acetylcholine and adenosine triphosphate are two major excitatory neurotransmitter candidates in the hypoxic CB, and they may also be involved as co-transmitters in hypoxic signaling. Conversely, dopamine, histamine and nitric oxide have recently been considered inhibitory transmitters/modulators of hypoxic chemosensitivity. It has also been revealed that interactions between excitatory and inhibitory messenger molecules occur during hypoxia. On the other hand, alterations in purinergic neurotransmitter mechanisms have been implicated in ventilatory acclimatization to hypoxia. Chronic hypoxia also induces profound changes in other neurochemical systems within the CB such as the catecholaminergic, peptidergic and nitrergic, which in turn may contribute to increased ventilatory and chemoreceptor responsiveness to hypoxia at high altitude. Taken together, current data suggest that complex interactions among transmitters markedly influence hypoxia-induced transmitter release from the CB. In addition, the expression of a wide variety of growth factors, proinflammatory cytokines and their receptors have been identified in CB parenchymal cells in response to hypoxia and their upregulated expression could mediate the local inflammation and functional alteration of the CB under hypoxic conditions.

Stem Cell Niche in the Mammalian Carotid Body.

Accumulating evidence suggests that the mammalian carotid body (CB) constitutes a neurogenic center that contains a functionally active germinal niche. A variety of transcription factors is required for the generation of a precursor cell pool in the developing CB. Most of them are later silenced in their progeny, thus allowing for the maturation of the differentiated neurons. In the adult CB, neurotransmitters and vascular cytokines released by glomus cells upon exposure to chronic hypoxia act as paracrine signals that induce proliferation and differentiation of pluripotent stem cells, neuronal and vascular progenitors. Key proliferation markers such as Ki-67 and BrdU are widely used to evaluate the proliferative status of the CB parenchymal cells in the initial phase of this neurogenesis. During hypoxia sustentacular cells which are dormant cells in normoxic conditions can proliferate and differentiate into new glomus cells. However, more recent data have revealed that the majority of the newly formed glomus cells is derived from the glomus cell lineage itself. The mature glomus cells express numerous trophic and growth factors, and their corresponding receptors, which act on CB cell populations in autocrine or paracrine ways. Some of them initially serve as target-derived survival factors and then as signaling molecules in developing vascular targets. Morphofunctional insights into the cellular interactions in the CB stem cell microenvironment can be helpful in further understanding the therapeutic potential of the CB cell niche.

Mechanism of Cone Degeneration in Retinitis Pigmentosa.

Retinitis pigmentosa (RP) is a group of genetic disorders resulting in inherited blindness due to the degeneration of rod and cone photoreceptors. The various mechanisms underlying rod degeneration primarily rely on genetic mutations, leading to night blindness initially. Cones gradually degenerate after rods are almost eliminated, resulting in varying degrees of visual disability and blindness. The mechanism of cone degeneration remains unclear. An understanding of the mechanisms underlying cone degeneration in RP, a highly heterogeneous disease, is essential to develop novel treatments of RP. Herein, we review recent advancements in the five hypotheses of cone degeneration, including oxidative stress, trophic factors, metabolic stress, light damage, and inflammation activation. We also discuss the connection among these theories to provide a better understanding of secondary cone degeneration in RP. Five current mechanisms of cone degenerations in RP Interactions among different pathways are involved in RP.

Neuropathology of the Basal Ganglia in SNCA Transgenic Rat Model of Parkinson's Disease: Involvement of Parvalbuminergic Interneurons and Glial-Derived Neurotropic Factor.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein, encoded by the SNCA gene. The main neuropathological hallmark of PD is the degeneration of dopaminergic neurons leading to striatal dopamine depletion. Trophic support by a neurotrophin called glial-derived neurotrophic factor (GDNF) is also lacking in PD. We performed immunohistochemical studies to investigate neuropathological changes in the basal ganglia of a rat transgenic model of PD overexpressing alfa-synuclein. We observed that neuronal loss also occurs in the dorsolateral part of the striatum in the advanced stages of the disease. Moreover, along with the degeneration of the medium spiny projection neurons, we found a dramatic loss of parvalbumin interneurons. A marked decrease in GDNF, which is produced by parvalbumin interneurons, was observed in the striatum and in the substantia nigra of these animals. This confirmed the involvement of the striatum in the pathophysiology of PD and the importance of GDNF in maintaining the health of the substantia nigra.

The impact of trophic and immunomodulatory factors on oligodendrocyte maturation: Potential treatments for encephalopathy of prematurity.

Encephalopathy of prematurity (EoP) is a major cause of morbidity in preterm neonates, causing neurodevelopmental adversities that can lead to lifelong impairments. Preterm birth-related insults, such as cerebral oxygen fluctuations and perinatal inflammation, are believed to negatively impact brain development, leading to a range of brain abnormalities. Diffuse white matter injury is a major hallmark of EoP and characterized by widespread hypomyelination, the result of disturbances in oligodendrocyte lineage development. At present, there are no treatment options available, despite the enormous burden of EoP on patients, their families, and society. Over the years, research in the field of neonatal brain injury and other white matter pathologies has led to the identification of several promising trophic factors and cytokines that contribute to the survival and maturation of oligodendrocytes, and/or dampening neuroinflammation. In this review, we discuss the current literature on selected factors and their therapeutic potential to combat EoP, covering a wide range of in vitro, preclinical and clinical studies. Furthermore, we offer a future perspective on the translatability of these factors into clinical practice.

Neuroprotective Effect of Vascular Endothelial Growth Factor on Motoneurons of the Oculomotor System.

Vascular endothelial growth factor (VEGF) was initially characterized as a potent angiogenic factor based on its activity on the vascular system. However, it is now well established that VEGF also plays a crucial role as a neuroprotective factor in the nervous system. A deficit of VEGF has been related to motoneuronal degeneration, such as that occurring in amyotrophic lateral sclerosis (ALS). Strikingly, motoneurons of the oculomotor system show lesser vulnerability to neurodegeneration in ALS compared to other motoneurons. These motoneurons presented higher amounts of VEGF and its receptor Flk-1 than other brainstem pools. That higher VEGF level could be due to an enhanced retrograde input from their target muscles, but it can also be produced by the motoneurons themselves and act in an autocrine way. By contrast, VEGF's paracrine supply from the vicinity cells, such as glial cells, seems to represent a minor source of VEGF for brainstem motoneurons. In addition, ocular motoneurons experiment an increase in VEGF and Flk-1 level in response to axotomy, not observed in facial or hypoglossal motoneurons. Therefore, in this review, we summarize the differences in VEGF availability that could contribute to the higher resistance of extraocular motoneurons to injury and neurodegenerative diseases.

Therapeutic approaches of trophic factors in animal models and in patients with spinal cord injury.

Trophic factors are naturally produced by different tissues that participate in several functions such as the intercellular communication, in the development, stability, differentiation and regeneration at the cellular level. Specifically, in the case of spinal injuries, these factors can stimulate neuronal recovery. They are applied both in experimental models and in clinical trials in patients. The trophic factors analysed in this review include gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), growth hormone (GH), melatonin, oestrogens, the family of fibroblast growth factors (FGFs), the family of neurotrophins and the glial cell-derived neurotrophic factor (GDNF). There are some trophic (neurotrophic) factors that already been tested in patients with spinal cord injury (SCI), but only shown partial recovery effect. It is possible that, the administration of these trophic factors together with physical rehabilitation, act synergistically and, therefore, significantly improve the quality of life of patients with SCI.

The Role of Hormones and Trophic Factors as Components of Preservation Solutions in Protection of Renal Function before Transplantation: A Review of the Literature.

Transplantation is currently a routine method for treating end-stage organ failure. In recent years, there has been some progress in the development of an optimal composition of organ preservation solutions, improving the vital functions of the organ and allowing to extend its storage period until implantation into the recipient. Optimizations are mostly based on commercial solutions, routinely used to store grafts intended for transplantation. The paper reviews hormones with a potential nephroprotective effect, which were used to modify the composition of renal perfusion and preservation solutions. Their effectiveness as ingredients of preservation solutions was analysed based on a literature review. Hormones and trophic factors are innovative preservation solution supplements. They have a pleiotropic effect and affect normal renal function. The expression of receptors for melatonin, prolactin, thyrotropin, corticotropin, prostaglandin E1 and trophic factors was confirmed in the kidneys, which suggests that they are a promising therapeutic target for renal IR (ischemia-reperfusion) injury. They can have anti-inflammatory, antioxidant and anti-apoptotic effects, limiting IR injury.

Using Plants as a Source of Potential Therapeutics for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia with the numbers expected to increase dramatically as our society ages. There are no treatments to cure, prevent, or slow down the progression of the disease. Age is the single greatest risk factor for AD. However, to date, AD drug discovery efforts have generally not taken this fact into consideration. Multiple changes associated with brain aging, including neuroinflammation and oxidative stress, are important contributors to disease development and progression. Thus, due to the multifactorial nature of AD, the one target strategy to fight the disease needs to be replaced by a more general approach using pleiotropic compounds to deal with the complexity of the disease. In this perspectives piece, our alternative approach to AD drug development based on the biology of aging is described. Starting with plants or plant-derived natural products, we have used a battery of cell-based screening assays that reflect multiple, age-associated toxicity pathways to identify compounds that can target the aspects of aging that contribute to AD pathology. We have found that this combination of assays provides a replicable, cost- and time-effective screening approach that has to date yielded one compound in clinical trials for AD (NCT03838185) and several others that show significant promise.

Subregional differences in astrocytes underlie selective neurodegeneration or protection in Parkinson's disease models in culture.

Parkinson's disease (PD) is characterized by the selective degeneration of dopamine (DA) neurons of the substantia nigra pars compacta (SN), while the neighboring ventral tegmental area (VTA) is relatively spared. The mechanisms underlying this selectivity are not fully understood. Here, we demonstrate a vital role for subregional astrocytes in the protection of VTA DA neurons. We found that elimination of astrocytes in vitro exposes a novel vulnerability of presumably protected VTA DA neurons to the PD mimetic toxin MPP+ , as well as exacerbation of SN DA neuron vulnerability. Conversely, VTA astrocytes protected both VTA and SN DA neurons from MPP+ toxicity in a dose dependent manner, and this protection was mediated via a secreted molecule. RNAseq analysis of isolated VTA and SN astrocytes demonstrated a vast array of transcriptional differences between these two closely related populations demonstrating regional heterogeneity of midbrain astrocytes. We found that GDF15, a member of the TGFß superfamily which is expressed 230-fold higher in VTA astrocytes than SN, recapitulates neuroprotection of both rat midbrain and iPSC-derived DA neurons, whereas its knockdown conversely diminished this effect. Neuroprotection was likely mediated through the GRFAL receptor expressed on DA neurons. Together; these results suggest that subregional differences in astrocytes underlie the selective degeneration or protection of DA neurons in PD.

Regenerative medicine as a therapeutic option for fecal incontinence: a systematic review of preclinical and clinical studies.

BACKGROUND: Fecal incontinence is the uncontrollable loss of stool and has a prevalence of around 7-15%. This condition has serious implications for patients' quality of life. Current treatment options show unsatisfactory results. A novel treatment option is therefore needed. OBJECTIVE: This systematic review aims to perform a quality assessment and to give a critical overview of the current research available on regenerative medicine as a treatment for fecal incontinence. STUDY DESIGN: A systematic search strategy was applied in PubMed, Cochrane Library, EMBASE, MEDLINE, Web of Science, and Cinahl from inception until March of 2018. Studies were found relevant when the animals or patients in the studied group had objectively determined or induced fecal incontinence, and the intervention must have used any kind of cells, stem cells, or biocompatible material, with or without the use of trophic factors. Studies were screened on title and consecutively on abstract for relevance by 2 independent investigators. The risk of bias of preclinical studies was assessed using the SYstematic Review Centre for Laboratory animal Experimentation risk of bias tool for animal studies, and for clinical studies the Cochrane risk of bias tool for randomized trials was used. RESULTS: In all, 34 preclinical studies and 5 clinical studies were included. Animal species, type of anal sphincter injury, intervention, and outcome parameters were heterogenous. Therefore, a meta-analysis could not be performed. The overall risk of bias of the included studies was high. CONCLUSION: The efficacy of regenerative medicine to treat fecal incontinence could not be determined due to the high risk of bias and heterogenicity of the available preclinical and clinical studies. The findings of this systematic review may result in improved study design of future studies, which could help the translation of regenerative medicine to the clinic as an alternative to current treatments for fecal incontinence.

Novel Evidence of the Increase in Angiogenic Factor Plasma Levels after Lineage-Negative Stem/Progenitor Cell Intracoronary Infusion in Patients with Acute Myocardial Infarction.

Cell therapy raises hope to reduce the harmful effects of acute myocardial ischemia. Stem and progenitor cells (SPCs) may be a valuable source of trophic factors. In this study, we assessed the plasma levels of selected trophic factors in patients undergoing application of autologous bone marrow (BM)-derived, lineage-negative (Lin-) stem/progenitor cells into the coronary artery in the acute phase of myocardial infarction. The study group consisted of 15 patients with acute myocardial infarction (AMI) who underwent percutaneous revascularization and, afterwards, Lin- stem/progenitor cell administration into the infarct-related artery. The control group consisted of 19 patients. BM Lin- cells were isolated using immunomagnetic methods. Peripheral blood was collected on day 0, 2, 4, and 7 and after the first and third month to assess the concentration of selected trophic factors using multiplex fluorescent bead-based immunoassays. We found in the Lin- group that several angiogenic trophic factors (vascular endothelial growth factor, Angiopoietin-1, basic fibroblast growth factor, platelet-derived growth factor-aa) plasma level significantly increased to the 4th day after myocardial infarction. In parallel, we noticed a tendency where the plasma levels of the brain-derived neurotrophic factor were increased in the Lin- group. The obtained results suggest that the administered SPCs may be a valuable source of angiogenic trophic factors for damaged myocardium, although this observation requires further in-depth studies.

A journey into the retina: Müller glia commanding survival and death.

Müller glial cells (MGCs) are known to participate actively in retinal development and to contribute to homoeostasis through many intracellular mechanisms. As there are no homologous cells in other neuronal tissues, it is certain that retinal health depends on MGCs. These macroglial cells are located at the centre of the columnar subunit and have a great ability to interact with neurons, astrocytes, microglia and endothelial cells in order to modulate different events. Several investigations have focused their attention on the role of MGCs in diabetic retinopathy, a progressive pathology where several insults coexist. As expected, data suggest that MGCs display different responses according to the severity of the stimulus, and therefore trigger distinct events throughout the course of the disease. Here, we describe physiological functions of MGCs and their participation in inflammation, gliosis, synthesis and secretion of trophic and antioxidant factors in the diabetic retina. We invite the reader to consider the protective/deleterious role of MGCs in the early and late stages of the disease. In the light of the results, we open up the discussion around and ask the question: Is it possible that the modulation of a single cell type could improve or even re-establish retinal function after an injury?

Delayed and repeated intranasal delivery of bone marrow stromal cells increases regeneration and functional recovery after ischemic stroke in mice.

BACKGROUND: Stroke is a leading cause of death and disability worldwide, yet there are limited treatments available. Intranasal administration is a novel non-invasive strategy to deliver cell therapy into the brain. Cells delivered via the intranasal route can migrate from the nasal mucosa to the ischemic infarct and show acute neuroprotection as well as functional benefits. However, there is little information about the regenerative effects of this transplantation method in the delayed phase of stroke. We hypothesized that repeated intranasal deliveries of bone marrow stromal cells (BMSCs) would be feasible and could enhance delayed neurovascular repair and functional recovery after ischemic stroke. RESULTS: Reverse transcription polymerase chain reaction and immunocytochemistry were performed to analyze the expression of regenerative factors including SDF-1α, CXCR4, VEGF and FAK in BMSCs. Ischemic stroke targeting the somatosensory cortex was induced in adult C57BL/6 mice by permanently occluding the right middle cerebral artery and temporarily occluding both common carotid arteries. Hypoxic preconditioned (HP) BMSCs (HP-BMSCs) with increased expression of surviving factors HIF-1α and Bcl-xl (1 × 106 cells/100 µl per mouse) or cell media were administered intranasally at 3, 4, 5, and 6 days after stroke. Mice received daily BrdU (50 mg/kg) injections until sacrifice. BMSCs were prelabeled with Hoechst 33342 and detected within the peri-infarct area 6 and 24 h after transplantation. In immunohistochemical staining, significant increases in NeuN/BrdU and Glut-1/BrdU double positive cells were seen in stroke mice received HP-BMSCs compared to those received regular BMSCs. HP-BMSC transplantation significantly increased local cerebral blood flow and improved performance in the adhesive removal test. CONCLUSIONS: This study suggests that delayed and repeated intranasal deliveries of HP-treated BMSCs is an effective treatment to encourage regeneration after stroke.

Allogeneic MSCs and Recycled Autologous Chondrons Mixed in a One-Stage Cartilage Cell Transplantion: A First-in-Man Trial in 35 Patients.

MSCs are known as multipotent mesenchymal stem cells that have been found capable of differentiating into various lineages including cartilage. However, recent studies suggest MSCs are pericytes that stimulate tissue repair through trophic signaling. Aimed at articular cartilage repair in a one-stage cell transplantation, this study provides first clinical evidence that MSCs stimulate autologous cartilage repair in the knee without engrafting in the host tissue. A phase I (first-in-man) clinical trial studied the one-stage application of allogeneic MSCs mixed with 10% or 20% recycled defect derived autologous chondrons for the treatment of cartilage defects in 35 patients. No treatment-related serious adverse events were found and statistically significant improvement in clinical outcome shown. Magnetic resonance imaging and second-look arthroscopies showed consistent newly formed cartilage tissue. A biopsy taken from the center of the repair tissue was found to have hyaline-like features with a high concentration of proteoglycans and type II collagen. DNA short tandem repeat analysis delivered unique proof that the regenerated tissue contained patient-DNA only. These findings support the hypothesis that allogeneic MSCs stimulate a regenerative host response. This first-in-man trial supports a paradigm shift in which MSCs are applied as augmentations or "signaling cells" rather than differentiating stem cells and opens doors for other applications. Stem Cells 2017;35:1984-1993.

Disease Modification for Parkinson's Disease: Axonal Regeneration and Trophic Factors.

Disease modification and structural neuroprotection have been the holy grail for Parkinson's disease (PD) experimental therapeutics. Theoretically, there are a number of ways to implement such therapeutics, but to date all have failed. This review examines the potential of axonal regeneration and trophic factor delivery for the nigrostriatal system as 2 such approaches that historically have initiated much excitement. However, we conclude this discussion with the following question: has science passed these approaches by? © 2018 International Parkinson and Movement Disorder Society.

Proteasome-Rich PaCS as an Oncofetal UPS Structure Handling Cytosolic Polyubiquitinated Proteins. In Vivo Occurrence, in Vitro Induction, and Biological Role.

In this article, we outline and discuss available information on the cellular site and mechanism of proteasome interaction with cytosolic polyubiquitinated proteins and heat-shock molecules. The particulate cytoplasmic structure (PaCS) formed by barrel-like particles, closely reproducing in vivo the high-resolution structure of 26S proteasome as isolated in vitro, has been detected in a variety of fetal and neoplastic cells, from living tissue or cultured cell lines. Specific trophic factors and interleukins were found to induce PaCS during in vitro differentiation of dendritic, natural killer (NK), or megakaryoblastic cells, apparently through activation of the MAPK-ERK pathway. Direct interaction of CagA bacterial oncoprotein with proteasome was shown inside the PaCSs of a Helicobacter pylori-infected gastric epithelium, a finding suggesting a role for PaCS in CagA-mediated gastric carcinogenesis. PaCS dissolution and autophagy were seen after withdrawal of inducing factors. PaCS-filled cell blebs and ectosomes were found in some cells and may represent a potential intercellular discharge and transport system of polyubiquitinated antigenic proteins. PaCS differs substantially from the inclusion bodies, sequestosomes, and aggresomes reported in proteinopathies like Huntington or Parkinson diseases, which usually lack PaCS. The latter seems more linked to conditions of increased cell proliferation/differentiation, implying an increased functional demand to the ubiquitin⁻proteasome system.

NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats.

Enhancing neurogenesis may be a powerful stroke therapy. Here, we tested in a rat model of ischemic stroke the beneficial effects of NSI-189, an orally active, new molecular entity (mol. wt. 366) with enhanced neurogenic activity, and indicated as an anti-depressant drug in a clinical trial (Fava et al., , Molecular Psychiatry, DOI: 10.1038/mp.2015.178) and being tested in a Phase 2 efficacy trial (ClinicalTrials.gov, , ClinicalTrials.gov Identifier: NCT02695472) for treatment of major depression. Oral administration of NSI-189 in adult Sprague-Dawley rats starting at 6 hr after middle cerebral artery occlusion, and daily thereafter over the next 12 weeks resulted in significant amelioration of stroke-induced motor and neurological deficits, which was maintained up to 24 weeks post-stroke. Histopathological assessment of stroke brains from NSI-189-treated animals revealed significant increments in neurite outgrowth as evidenced by MAP2 immunoreactivity that was prominently detected in the hippocampus and partially in the cortex. These results suggest NSI-189 actively stimulated remodeling of the stroke brain. Parallel in vitro studies further probed this remodeling process and demonstrated that oxygen glucose deprivation and reperfusion (OGD/R) initiated typical cell death processes, which were reversed by NSI-189 treatment characterized by significant attenuation of OGD/R-mediated hippocampal cell death and increased Ki67 and MAP2 expression, coupled with upregulation of neurogenic factors such as BDNF and SCF. These findings support the use of oral NSI-189 as a therapeutic agent well beyond the initial 6-hr time window to accelerate and enhance the overall functional improvement in the initial 6 months post stroke.

Bone marrow-derived mesenchymal stromal cells regress aortic aneurysm via the NF-kB, Smad3 and Akt signaling pathways.

BACKGROUND AIMS: We have confirmed that aortic aneurysm (AA) can be regressed by the administration of bone marrow-derived mesenchymal stromal cells (BM-MSCs). We investigated the kinetics of signaling pathways in AA following treatment with BM-MSCs. METHODS: Angiotensin II-infused apolipoprotein E-deficient mice were treated by intravenous injection of 1 × 106 BM-MSCs in 0.2 mL saline (BM-MSCs group, n = 5) or 0.2 mL saline (saline group, n = 5). Mice were sacrificed 2 weeks after injection and subjected to measurements of the incidence of AA and levels of phosphorylated proteins. Levels of proteins in conditioned media of BM-MSCs were also measured. RESULTS: The incidence of AA in the BM-MSCs group was reduced (BM-MSC 40% versus saline 100%, P <0.05). Levels of pNF-kB and pSTAT1 were reduced (pNF-kB: 0.28 versus 0.45 unit/mL, P <0.05, pSTAT1: 0.16 versus 0.34, P <0.05), whereas levels of pAkt and pSmad3 were elevated (pAkt: 0.13 versus 0.07, P <0.01, pSmad3: 1.07 versus 0.47, P <0.05) in the BM-MSCs group. The levels of pNF-kB, pAkt, and pSmad3 were correlated with aortic diameters. Trophic factors including IGFPB-3, NRF, Activin A and PDGF-AA were secreted from BM-MSCs (IGFBP-3: 35.2 pg/mL, NRF: 3.1 pg/mL, Activin A: 3.1 pg/mL, PDGF-AA: 0.45 pg/mL). CONCLUSIONS: Our findings suggested that the therapeutic mechanism of BM-MSC-mediated AA regression could contribute to regulation of the NF-kB, Smad3 and Akt signaling pathways. In addition, paracrine actions by factors including NRF, IGFBP-3, Activin A and PDGF-AA might have affected these signaling pathways.

Kidney-brain axis inflammatory cross-talk: from bench to bedside.

Epidemiologic data suggest that individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing neuropsychiatric disorders, cognitive impairment, and dementia. This risk is generally explained by the high prevalence of both symptomatic and subclinical ischemic cerebrovascular lesions. However, other potential mechanisms, including cytokine/chemokine release, production of reactive oxygen species (ROS), circulating and local formation of trophic factors and of renin-angiotensin system (RAS) molecules, could also be involved, especially in the absence of obvious cerebrovascular disease. In this review, we discuss experimental and clinical evidence for the role of these mechanisms in kidney-brain cross-talk. In addition, we hypothesize potential pathways for the interactions between kidney and brain and their pathophysiological role in neuropsychiatric and cognitive changes found in patients with CKD. Understanding the pathophysiologic interactions between renal impairment and brain function is important in order to minimize the risk for future cognitive impairment and to develop new strategies for innovative pharmacological treatment.