Abstract. It has been known for many years that immune system alterations occur with Parkinson's disease (PD). Changes in lymphocyte populations in cerebrospinal fluid and blood, immunoglobulin synthesis, and cytokine and acute phase protein production have been observed in patients with PD. Hence, there is evidence for inflammation. In this report we demonstrate that cyclic exercise over months results in a significant increase in the rise of plasma anti-inflammatory signal molecules, such as interleukin-10 and adrenocortico- tropin. Additionally, endogenous plasma morphine levels increase with the duration of the cyclic exercise protocol. Morphine is identified and quantified by high performance liquid chromatography coupled to electrochemical detection and nano electro-spray ionization double quadrupole orthogonal acceleration time of flight mass spectrometry. Proinflammatory cytokine, i.e., interleukin-1, interleukin-6, plasma levels did not increase. These results matched with those reported previously, demonstrating enhanced motor skills and mood elevation with this cyclic exercise protocol, suggest that this protocol induces the formation of anti- inflammatory signal molecules, which appear to be associated with alleviation of some of the clinical characteristics of PD. Introduction Idiopathic Parkinson's disease is a degenerative disorder of the central nervous system. Several pathogenic mechanisms have been proposed that lead to degeneration of dopamin- ergic neurons. These mechanisms encompass variables such as metabolic or toxic factors, oxidative stress and mito- chondrial dysfunction (1). The primary anatomical features central to PD patients include: a diminished number of myelinized dopaminergic cells in the substantia nigra (SN) and in related brain stem nuclei, a decrease in the dopamine content in nigrostriatal and mesolimbic pathways, the presence of Lewy bodies, and the deposition of neuromelanin (2,3). The perturbation of several neurotransmitters and neuropeptides has been reported in PD, indicating a more complicated and widespread pathology. The role of immune and vascular mechanisms in neurodegenerative diseases such as PD is, similarly, an important area of investigation (1,4). Death or injury to neurons in PD leads to the presence of many pro-inflammatory cytokine molecules, as well (1). This process resembles classic inflammation, but with minimal or no participation of macrophages and lymphocytes from blood (1). In the present report, we determine the plasma level of pro-and anti-inflammatory cytokines as well as signal mole- cules most often associated with stress, i.e., adrenocortico- tropin (ACTH) at baseline (group 1). We also measure these levels subsequent to the introduction of a 12 week cyclic exercise regime at week 4 (group 2), week 8 (group 3) and week 12 (group 4). We demonstrate that anti-inflammatory signal molecules significantly appear in the plasma months after initiating and sustaining this cyclic exercise protocol. These results are correlated with a previous study, which found that cyclic exercise in Parkinson's patients produced improvement in motor function and attitude (Rymer M, et al, Puijo Symposium, Kuopio, Finland, 2001). Materials and methods The participants were recruited from a private neurology practice in Kansas City, MO. The participants were all previously diagnosed and under treatment for Parkinson's disease. Their disease was staged at the beginning of the trial by an independent neurologist using the Hoehn and Yahr Scale (5). During their baseline testing in our program, the participants were evaluated with the standard scale, the Uniform Parkinson's Disease Rating Scale (UPDRS). They were all moderate to severely ill, average age 78 years, average time since diagnosis was around 8 years, 14 males, 5 females. The protocol described was reviewed and passed by the IRB at Saint Luke's Hospital in Kansas City, MO. Blood samples INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 12: 485-492, 2003 485 Cyclic exercise induces anti-inflammatory signal molecule increases in the plasma of Parkinson's patients PATRICK CADET 1 , WEI ZHU 1 , KIRK MANTIONE 1 , MARILYN RYMER 2 , IRVING DARDIK 3 , STAN REISMAN 4 , SEAN HAGBERG 3 and GEORGE B. STEFANO 1 1 Neuroscience Research Institute, State University of New York at Old Westbury, Old Westbury, NY; 2 Saint Luke's Hospital, Kansas City, MO; 3 Dardik Institute, Califon, NJ; 4 The Department of Biomedical Engineering, New Jersey Institute of Technology, NJ, USA Received June 2, 2003; Accepted July 11, 2003 _________________________________________ Correspondence to: Dr George B. Stefano, Neuroscience Research Institute, State University of New York at Old Westbury, P.O. Box 210, Old Westbury, NY 11568, USA E-mail: gstefano@sunynri.org Key words: inflammation, neurodegeneration, immune system, nitric oxide, exercise, Parkinson's disease