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Pharmaceutical Research

, Volume 24, Issue 4, pp 662–671 | Cite as

Involvement of Indoxyl Sulfate in Renal and Central Nervous System Toxicities During Cisplatin-induced Acute Renal Failure

  • Kazufumi Iwata
  • Hiroshi Watanabe
  • Takafumi Morisaki
  • Takanobu Matsuzaki
  • Takafumi Ohmura
  • Akinobu Hamada
  • Hideyuki Saito
Research Paper

Purpose

The purpose of the present study was to explore the involvement of indoxyl sulfate (IS) in nephrotoxicity and central nervous system (CNS) toxicity in cisplatin (CDDP)-treated rats.

Materials and Methods

Renal function was evaluated by serum creatinine and BUN levels. The IS levels in the serum, brain and kidney was monitored by high-performance liquid chromatography method. Body weight and rectal temperature were monitored. Real-time PCR analysis was performed to examine rPer2 mRNA expression.

Results

Renal function deteriorated in a time-dependent manner after administration of CDDP. The concentration of IS in the serum, brain and kidney markedly increased 24–84 h after commencement of CDDP treatment. The observed increase in the levels of serum creatinine, BUN and IS was suppressed by concomitant administration of AST-120. Rectal temperature was significantly lowered 72–92  h after CDDP-treatment, which was partially restored by coadministration of AST-120. Moreover, the amplitude of rectal temperature rhythms was disrupted by treatment with CDDP. Circadian rhythm of rPer2 mRNA expression, a clock gene, in suprachiasmatic nucleus (SCN) and kidney was disturbed in CDDP-treated rats.

Conclusions

An increase in the IS level and the associated disturbance to the circadian rhythm are involved in the renal and CNS toxicities in CDDP-treatment.

Key words

acute renal failure AST-120 cisplatin indoxyl sulfate Per2 

Abbreviations

IS

indoxyl sulfate

ARF

acute renal failure

CRF

chronic renal failure

SCN

suprachiasmatic nucleus

CNS

central nervous system

ZT

zeitgeber time

Per2

period 2

SCr

serum creatinine

Notes

Acknowledgments

This work was supported, in part, by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan.

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Kazufumi Iwata
    • 1
  • Hiroshi Watanabe
    • 1
  • Takafumi Morisaki
    • 1
  • Takanobu Matsuzaki
    • 1
  • Takafumi Ohmura
    • 1
  • Akinobu Hamada
    • 1
  • Hideyuki Saito
    • 1
  1. 1.Department of PharmacyKumamoto University HospitalKumamotoJapan

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