Received June 13, 2005; Accepted June 13, 2005. Author to whom all correspondence and reprint requests should be addressed: Russel J. Reiter, Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900 USA. E-mail: reiter@uthscsa.edu Melatonin and Parkinson’s Disease Juan C. Mayo, 1 Rosa M. Sainz, 1 Dun-Xian Tan, 2 Isaac Antolín, 1 Carmen Rodríguez, 1 and Russel J. Reiter 2 1 Departamento de Morfología y Biología Celular, School of Medicine, University of Oviedo, Oviedo, Spain; and 2 Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Endocrine, vol. 27, no. 2, 169–178, July 2005 0969–711X/05/27:169–178/$30.00 © 2005 by Humana Press Inc. All rights of any nature whatsoever reserved. 169 Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. It is characterized by a progressive loss of dopamine in the substantia nigra and striatum. However, over 70% of dopaminergic neuronal death occurs before the first symptoms appear, which makes either early diagnosis or effective treatments extremely difficult. Only symp- tomatic therapies have been used, including levodopa (L-dopa), to restore dopamine content; however, the use of L-dopa leads to some long-term pro-oxidant dam- age. In addition to a few specific mutations, oxidative stress and generation of free radicals from both mito- chondrial impairment and dopamine metabolism are considered to play critical roles in PD etiology. Thus, the use of antioxidants as an important co-treatment with traditional therapies for PD has been suggested. Melatonin, or N-acetyl-5-methoxy-tryptamine, an in- dole mainly produced in the pineal gland, has been shown to have potent endogenous antioxidant actions. Because neurodegenerative disorders are mainly caused by oxidative damage, melatonin has been tested suc- cessfully in both in vivo and in vitro models of PD. The present review provides an up-to-date account of the findings and mechanisms involved in neuroprotection of melatonin in PD. Key Words: Melatonin; Parkinson’s disease; antioxi- dant; oxidative damage; dopaminergic neurons; neuro- degeneration. Introduction First described by James Parkinson in 1817, Parkinson’s disease (PD) is the second most common neurodegenera- tive disease, affecting roughly 1.8% of people over 65 (1). PD is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) in the midbrain and a subsequent loss of dopamine. It is clinically manifested by defective motor function, a decline in cog- nitive function, and depression. Histologically, its features include the presence of Lewy bodies and cytoplasmic inclu- sions that are composed predominantly of fibrillar -sy- nuclein (2). Most biochemical studies suggest that, directly or indirectly, reactive oxygen/nitrogen species (ROS/RNS) are important mediators in the pathogenesis of PD. Given the difficulties in studying the molecular events that precede the onset of PD in patients, several in vivo and in vitro models have been developed. These models are pri- marily based on free-radical-generating toxins with a spe- cific target in the nigrostriatal system. Some of the dopa- minergic neuronal loss in PD has been postulated to be via apoptosis, given the morphological characteristics exhib- ited by what appear to be dying cells in postmortem brains of parkinsonism patients. Furthermore, in vivo experimen- tal models of PD strongly suggest a role for apoptosis in the pathology of this human disease. The initial original observations of PD patients reported that about 15% of PD patients had a family background of the disease. Since then, the role of genetic factors in PD has been the subject of intense research (3). To date, a few spe- cific mutations have been identified to be responsible for rare familial forms of the disease: -synuclein, parkin, UCH- L1, DJ-1, and PINK1 are genes found to be related to PD. As is the case in Alzheimer’s disease, these genetic defects seem to affect a common molecular pathway related to the ubiq- uitin–proteasome system (4) with the exception of PINK1, which is related to mitochondrial metabolism. Analysis of the products of these genes are beyond the scope of the pres- ent review and have been reviewed extensively elsewhere (3,4). Some (if not all) of these mutations are partially related to free-radical generation. Thus, in addition to its genetic basis, it is widely believed that oxidative stress and free radicals play a critical role in idiopathic PD etiology. A “Radical” View to PD In eukaryotic cells, reactive ROS/RNS are generated as part of the normal metabolism by the chemical reduction of oxygen by cellular oxidases, peroxidases, and mono- and dioxygenases, by exposure to ultraviolet light or other environmental agents and by incomplete reduction of oxy- gen to water in the mitochondrial respiratory chain (5).