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

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Increasing evidence suggests a possible involvement of neuroinflammation in some psychiatric disorders, and also pharmacological reports indicate that antiinflammatory 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 neuronglia 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 p47 phox 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.

Original languageEnglish
Pages (from-to)187-201
Number of pages15
JournalJournal of Neuroimmune Pharmacology
Volume7
Issue number1
DOIs
Publication statusPublished - 2012 Mar 1

Fingerprint

Clozapine
Dopaminergic Neurons
Inflammation
Microglia
Lipopolysaccharides
Neuroglia
Antipsychotic Agents
Neurons
Neuroprotective Agents
Superoxides
Reactive Oxygen Species
Anti-Inflammatory Agents
1-Methyl-4-phenylpyridinium
1-Phosphatidylinositol 4-Kinase
NADPH Oxidase
Psychotropic Drugs
Psychiatry
Nitric Oxide
Observation
Pharmacology

All Science Journal Classification (ASJC) codes

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

Cite this

Hu, Xiaoming ; Zhou, Hui ; Zhang, Dan ; Yang, Sufen ; Qian, Li ; Wu, Hung Ming ; Chen, Po-See ; Wilson, Belinda ; Gao, Hui Ming ; Lu, Ru-Band ; Hong, Jau Shyong. / Clozapine protects dopaminergic neurons from inflammation-induced damage by inhibiting microglial overactivation. In: Journal of Neuroimmune Pharmacology. 2012 ; Vol. 7, No. 1. pp. 187-201.
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Clozapine protects dopaminergic neurons from inflammation-induced damage by inhibiting microglial overactivation. / Hu, Xiaoming; Zhou, Hui; Zhang, Dan; Yang, Sufen; Qian, Li; Wu, Hung Ming; Chen, Po-See; Wilson, Belinda; Gao, Hui Ming; Lu, Ru-Band; Hong, Jau Shyong.

In: Journal of Neuroimmune Pharmacology, Vol. 7, No. 1, 01.03.2012, p. 187-201.

Research output: Contribution to journalArticle

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AU - Chen, Po-See

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