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Urocortin Modulates Inflammatory Response and Neurotoxicity Induced by Microglial Activation¹

Mei-Jen Wang^2,3,*, Shinn-Zong Lin^2,*, Jon-Son Kuo^2,, Hsin-Yi Huang^*,, Shih-Fang Tzeng^*, Chia-Hsin Liao^*,, Der-Cherng Chen and Wu-Fu Chen^¶

^* Neuro-Medical Scientific Center, Buddhist Tzu-Chi General Hospital, Tzu-Chi College of Technology, Department of Neurosurgery, Buddhist Tzu-Chi General Hospital, Institute of Pharmacology and Toxicology, Institute of Medical Sciences, Buddhist Tzu-Chi University, and ^¶ Department of Neurosurgery, Chang-Gung Memorial Hospital-Kaohsiung Medical Center, and Chang Gung University College of Medicine, Taiwan, Republic of China

Microglia are the major inflammatory cells in the brain. Recent studies have highlighted the reciprocal roles of other brain cells in modulating the microglial inflammatory responses. Urocortin (UCN) is a member of the corticotropin-releasing hormone (CRH) family of neuropeptides that function to regulate stress responses. In the present study, we demonstrated that expression of UCN in rat substantia nigra was found to be localized principally to dopaminergic neurons. In cell culture models, the CRH receptors were expressed in microglia, and CRHR expression was up-regulated by treatment with LPS. Thus, it might be proposed that UCN regulates cellular communication between dopaminergic neurons and microglia. We show that femtomolar concentrations of UCN could inhibit LPS-induced TNF- production in cultured microglia. Investigation of the underlying signaling pathway that mediated the anti-inflammatory effect of UCN the involved PI3K/Akt and glycogen synthase kinase-3 pathway, but not cAMP pathway. Furthermore, UCN protected dopaminergic neurons against LPS-induced neurotoxicity by inhibiting microglial activation in LPS-treated mesencephalic neuron-glia cultures. These results suggest that endogenous UCN and its receptors might be involved in a complex network of paracrine interaction between dopaminergic neurons and glia.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant 94-2314-B-303-004 from the National Science Council, Taiwan, China.

² M.-J.W., S.-Z.L., and J.-S.K. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Mei-Jen Wang, Neuro-Medical Scientific Center, Buddhist Tzu-Chi General Hospital, Hualien 970, Taiwan, Republic of China. E-mail address: mjwang{at}tzuchi.com.tw

⁴ Abbreviations used in this paper: UCN, urocortin; CRH, corticotropin-releasing hormone; CRHR, CRH receptor; GSK, glycogen synthase kinase; TH, tyrosine hydroxylase; DA, dopamine; SN, substantia nigra; ddATP, 2',5'-dideoxyadenosine; eIF, eukaryotic initiation factor; BP1, binding protein 1.

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