p-Cresol Sulfate Caused Behavior Disorders and Neurodegeneration in Mice with Unilateral Nephrectomy Involving Oxidative Stress and Neuroinflammation.

Abstract

Protein-bound uremic toxins, such as p-cresol sulfate (PCS), can be accumulated with declined renal function and aging and is closely linked with central nervous system (CNS) diseases. In the periphery, PCS has effects on oxidative stress and inflammation. Since oxidative stress and inflammation have substantial roles in the pathogenesis of neurological disorders, the CNS effects of PCS were investigated in unilateral nephrectomized C57/BL/6 mice. Unlike intact mice, unilateral nephrectomized mice showed increased circulating levels of PCS after exogenous administration. Upon PCS exposure, the unilateral nephrectomized mice developed depression-like, anxiety-like, and cognitive impairment behaviors with brain PCS accumulation in comparison with the nephrectomy-only group. In the prefrontal cortical tissues, neuronal cell survival and neurogenesis were impaired along with increased apoptosis, oxidative stress, and neuroinflammation. Circulating brain-derived neurotrophic factors (BDNF) and serotonin were decreased in association with increased corticosterone and repressor element-1 silencing transcription factor (REST), regulators involved in neurological disorders. On the contrary, these PCS-induced changes were alleviated by uremic toxin absorbent AST-120. Taken together, PCS administration in mice with nephrectomy contributed to neurological disorders with increased oxidative stress and neuroinflammation, which were alleviated by PCS chelation. It is suggested that PCS may be a therapeutic target for chronic kidney disease-associated CNS diseases.

• Authors: Chiao-Yin Sun, Jian-Ri Li, Ya-Yu Wang, Shih-Yi Lin, Yen-Chuan Ou, Cheng-Jui Lin, Jiaan-Der Wang, Su-Lan Liao, Chun-Jung Chen
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 18 (Sep 12 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32932690 (Publication Type: Journal Article)

Chemical References

• Brain-Derived Neurotrophic Factor
• Cresols
• Oxides
• RE1-silencing transcription factor
• Repressor Proteins
• Sulfuric Acid Esters
• Toxins, Biological
• Serotonin
• 4-cresol sulfate
• Carbon
• AST 120
• Corticosterone

Topics

• Animals
• Brain-Derived Neurotrophic Factor (metabolism)
• Carbon (pharmacology)
• Cell Survival (drug effects)
• Corticosterone (metabolism)
• Cresols (pharmacology)
• Inflammation (chemically induced, metabolism)
• Kidney (drug effects, metabolism, pathology)
• Male
• Mental Disorders (chemically induced, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Nephrectomy (methods)
• Neurodegenerative Diseases (chemically induced, metabolism, pathology)
• Neurons (drug effects, metabolism, pathology)
• Oxidative Stress (drug effects)
• Oxides (pharmacology)
• Repressor Proteins (metabolism)
• Serotonin (metabolism)
• Sulfuric Acid Esters (pharmacology)
• Toxins, Biological (pharmacology)
• Uremia (chemically induced, metabolism, pathology)