Journal of Neuroimmune Pharmacology

, Volume 7, Issue 1, pp 187–201 | Cite as

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 HongEmail author


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.


Clozapine Microglia NADPH oxidase Neurodegeneration Neuroinflammation 



We would like to thank Anthony Lockhart for assistance with animal colony management and maintenance of the timed pregnant mice. This research was supported by the Intramural Research Program of the National Institute of Health, the National Institute of Environmental Health Sciences.

Conflict of interest

The authors declare that they have nocompeting interests or conflicts of interest.


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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
    Email author
  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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