%0 Journal Article
%T Transcriptional Factor NF- B as a Target for Therapy in Parkinson's Disease
%A Patrick M. Flood
%A Li Qian
%A Lynda J. Peterson
%A Feng Zhang
%A Jing-Shan Shi
%A Hui-Ming Gao
%A Jau-Shyong Hong
%J Parkinson's Disease
%D 2011
%I Hindawi Publishing Corporation
%R 10.4061/2011/216298
%X Parkinson's disease (PD) is a neurodegenerative condition characterized by chronic inflammation. Nuclear factor B (NF- B) is a family of inducible transcription factors that are expressed in a wide variety of cells and tissues, including microglia, astrocytes, and neurons, and the classical NF- B pathway plays a key role in the activation and regulation of inflammatory mediator production during inflammation. Activation of the classical NF- B pathway is mediated through the activity of the IKK kinase complex, which consists of a heterotrimer of IKK , IKK , and IKK subunits. Targeting NF- B has been proposed as an approach to the treatment of acute and chronic inflammatory conditions, and the use of inhibitors specific for either IKK or IKK has now been found to inhibit neurodegeneration of TH+ DA-producing neurons in murine and primate models of Parkinson's disease. These studies suggest that targeting the classical pathway of NF- B through the inhibition of the IKK complex can serve as a useful therapeutic approach to the treatment of PD. 1. Introduction Parkinson's disease (PD) is a progressive degenerative disorder of the central nervous system (CNS) that leads to impairment of motor skills and speech, as well as other functions. While the disease mechanisms that ultimately cause PD are still unclear, it is believed that the progressive nature of PD is characterized by chronic inflammation-induced neurodegeneration of dopamine-producing neurons within the substantia nigra (SN) and striatum [1¨C4]. It is now well documented that microglial activation results in the loss of dopaminergic neurons (DA-neurons). The premise of microglia activation in PD has been supported by analysis of postmortem brains from PD patients, which provides clear evidence of microglia activation in the SN. In the brains of patients with PD, large numbers of human leukocyte antigen (HLA-DR) and CD11b-positive reactive microglia were found in the SN, a region in which the degeneration of DA-neurons was most prominent [5¨C8]. In addition, levels of proinflammatory mediators, including TNF¦Á, IL-1¦Â, IL-6, and eicosanoids are elevated in the brains and peripheral blood mononuclear cells (PBMCs) of patients with PD [6, 7]. Nitrite in the cerebrospinal fluid as well as increased expression of inducible nitric oxide synthase (iNOS) within the SN have been found in PD patients [9, 10]. All of these findings lend strong support to the association of inflammation and PD. Many of these inflammatory mediators have been demonstrated to have strong neurotoxic effects on DA-neurons [1, 11¨C14],
%U http://www.hindawi.com/journals/pd/2011/216298/