Journal of Neuroimmune Pharmacology

, Volume 7, Issue 1, pp 187–201

Clozapine Protects Dopaminergic Neurons from Inflammation-Induced Damage by Inhibiting Microglial Overactivation

  • Xiaoming Hu
  • Hui Zhou
  • Dan Zhang
  • Sufen Yang
  • Li Qian
  • Hung-Ming Wu
  • Po-See Chen
  • Belinda Wilson
  • Hui-Ming Gao
  • Ru-band Lu
  • Jau-Shyong Hong
ORIGINAL ARTICLE

DOI: 10.1007/s11481-011-9309-0

Cite this article as:
Hu, X., Zhou, H., Zhang, D. et al. J Neuroimmune Pharmacol (2012) 7: 187. doi:10.1007/s11481-011-9309-0

Abstract

Increasing evidence suggests a possible involvement of neuroinflammation in some psychiatric disorders, and also pharmacological reports indicate that anti-inflammatory effects are associated with therapeutic actions of psychoactive drugs, such as anti-depressants and antipsychotics. The purpose of this study was to explore whether clozapine, a widely used antipsychotic drugs, displays anti-inflammatory and neuroprotective effects. Using primary cortical and mesencephalic neuron-glia cultures, we found that clozapine was protective against inflammation-related neurodegeneration induced by lipopolysaccharide (LPS). Pretreatment of cortical or mesencephalic neuron–glia cultures with clozapine (0.1 or 1 μM) for 24 h attenuated LPS-induced neurotoxicity. Clozapine also protected neurons against 1-methyl-4-phenylpyridinium+ (MPP+)-induced neurotoxicity, but only in cultures containing microglia, indicating an indispensable role of microglia in clozapine-afforded neuroprotection. Further observation revealed attenuated LPS-induced microglial activation in primary neuron-glia cultures and in HAPI microglial cell line with clozapine pretreatment. Clozapine ameliorated the production of microglia-derived superoxide and intracellular reactive oxygen species (ROS), as well as the production of nitric oxide and TNF-α following LPS. In addition, the protective effect of clozapine was not observed in neuron-glia cultures from mice lacking functional NADPH oxidase (PHOX), a key enzyme for superoxide production in immune cells. Further mechanistic studies demonstrated that clozapine pretreatment inhibited LPS-induced translocation of cytosolic subunit p47phox to the membrane in microglia, which was most likely through inhibiting the phosphoinositide 3-kinase (PI3K) pathway. Taken together, this study demonstrates that clozapine exerts neuroprotective effect via the attenuation of microglia activation through inhibition of PHOX-generated ROS production and suggests potential use of antipsychotic drugs for neuroprotection.

Keywords

Clozapine Microglia NADPH oxidase Neurodegeneration Neuroinflammation 

Copyright information

© Springer Science+Business Media, LLC (outside the USA)  2011

Authors and Affiliations

  • Xiaoming Hu
    • 1
    • 3
  • Hui Zhou
    • 1
  • Dan Zhang
    • 1
  • Sufen Yang
    • 1
  • Li Qian
    • 1
  • Hung-Ming Wu
    • 1
    • 2
  • Po-See Chen
    • 1
  • Belinda Wilson
    • 1
  • Hui-Ming Gao
    • 1
  • Ru-band Lu
    • 2
  • Jau-Shyong Hong
    • 1
  1. 1.Neuropharmacology Section, Laboratory of Toxicology and PharmacologyNational Institute of Environmental Health Sciences, NIHResearch Triangle ParkUSA
  2. 2.Institute of Behavioral Medicine and Department of Psychiatry, College of Medicine & HospitalNational Cheng-Kung UniversityTainanTaiwan
  3. 3.Department of Neurology and Pittsburgh Institute of Neurodegenerative DiseasesUniversity of Pittsburgh School of MedicinePittsburghUSA

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