Cystatin C prevents degeneration of rat nigral dopaminergic neurons: in vitro and in vivo studies

Lei Xu, Jiansong Sheng, Zhongshu Tang, Xuefei Wu, Yi Yu, Hong Guo, Yan Shen, Changfu Zhou, Luminita Paraoan, Jiawei Zhou

Research output: Contribution to journalArticle (journal)peer-review

57 Citations (Scopus)

Abstract

Destruction of nigrostriatal dopaminergic (DA) pathway triggers various persistent responses, such as inflammation and increased synthesis of neural growth factors, both in striatum and in substantia nigra. The pathological processes involved in such responses are poorly characterized and could contribute to secondary damage and/or regeneration in the central nervous system (CNS). Cystatin C was previously implicated in the process of neurodegeneration. However, its biological role during neurodegeneration is not understood and remains controversial. The present study identified an increased cystatin C mRNA level in the DA-depleted rat striatum, starting from the second week following a 6-OHDA-induced lesion. Immunohistochemical analysis confirmed the increase in cystatin C protein level in the striatum following DA depletion. Double-labeled fluorescence immunohistochemistry revealed that nigrostriatal neurons, astrocytes, and microglia contributed to the elevated level of cystatin C. Exposure to 6-hydroxydopamine, a DA-specific neurotoxin, resulted in DA neurons loss in the fetal mesencephalic cultures, an effect which could be partially reversed by treatment with cystatin C. Moreover, in vivo DA neurons survival study showed that administration of cystatin C in rats with 6-OHDA-induced lesion partially rescued the nigral DA neurons. The results indicate that the 6-OHDA lesioning induced a relatively slow but sustained up-regulation of cystatin C expression and suggest that the inhibitor may exert a neuroprotective action on DA neurons. The findings raise the possibility that cysteine proteinase inhibitors may be new candidates for neuroprotective treatment of Parkinson's disease. Cystatin C may be useful therapeutically in limiting neuropathy in Parkinson's disease.

Original languageEnglish
Pages (from-to)152-65
Number of pages14
JournalNeurobiology of Disease
Volume18
Issue number1
DOIs
Publication statusPublished - 1 Feb 2005

Keywords

  • Animals
  • Astrocytes/metabolism
  • Cell Survival/drug effects
  • Cells, Cultured
  • Cystatin C
  • Cystatins/metabolism
  • Cysteine Proteinase Inhibitors/pharmacology
  • Disease Models, Animal
  • Dopamine/metabolism
  • Female
  • Fluorescent Antibody Technique
  • Microglia/metabolism
  • Nerve Degeneration/drug therapy
  • Neurons/drug effects
  • Neuroprotective Agents/metabolism
  • Oxidopamine/antagonists & inhibitors
  • Parkinsonian Disorders/drug therapy
  • RNA, Messenger/drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Substantia Nigra/drug effects
  • Time Factors
  • Up-Regulation/drug effects

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