Changes in cytokines and neurotrophins in Parkinson’s disease

  • T. Nagatsu
  • M. Mogi
  • H. Ichinose
  • A. Togari
Conference paper


Degeneration of the dopamine (DA) neurons of the substantia nigra pars compacta and the resulting loss of nerve terminals accompanied by DA deficiency in the striatum are responsible for most of the movement disturbances called parkinsonism, observed in Parkinson’s disease (PD). One hypothesis of the cause of degeneration of the nigrostriatal DA neurons is that PD is caused by programmed cell death (apoptosis) due to increased levels of cytokines and/or decreased ones of neurotrophins. We and other workers found markedly increased levels of cytokines, such as tumor necrosis factor (TNF)-a, interleukin (IL)-1ß, IL-2, IL-4, IL-6, transforming growth factor (TFG)-a, TGF-131, and TGF-ß2, and decreased ones of neurotrophins, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), in the nigrostriatal DA regions and ventricular and lumbar cerebrospinal fluid of PD patients. Furthermore, the levels of TNF-a receptor Rl (TNF-R1, p55), bc1-2, soluble Fas (sFas), and the activities of caspase-1 and caspase-3 were also elevated in the nigrostriatal DA regions in PD. In experimental animal models of PD, IL-lß level was increased and NGF one decreased in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mice, and TNF-a level was increased in the substantia nigra and striatum of the 6-hydroxydopamine (6OHDA)-injected side of hemiparkinsonian rats. L-DOPA alone or together with 6OHDA does not increase the level of TNF-a in the brain in vivo. Increased levels of proinflammatory cytokines, cytokine receptors and caspase activities, and reduced levels of neurotrophins in the nigrostriatal region in PD patients, and in MPTP- and 6OHDA-produced parkinsonian animals suggest increased immune reactivity and programmed cell death (apoptosis) of neuronal and/or glial cells. These data indicate the presence of such proapoptotic environment in the substantia nigra in PD that may induce increased vulnerability of neuronal or glial cells towards a variety of neurotoxic factors. The probable causative linkage among the increased levels of proinflammatory cytokines and the decreased levels of neurotrophins, candidate parkinsonism-producing neurotoxins such as isoquinoline neurotoxins (Review; Nagatsu, 1997), and the genetic susceptibility to toxic factors, remains for further investigation in the molecular mechanism of PD. The increased cytokine levels, decreased


Nerve Growth Factor Substantia Nigra Neopterin Level Atypical Parkinsonism Parkinsonian Brain 
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Copyright information

© Springer-Verlag Wien 2000

Authors and Affiliations

  • T. Nagatsu
    • 1
  • M. Mogi
    • 2
  • H. Ichinose
    • 1
  • A. Togari
    • 2
  1. 1.Institute for Comprehensive Medical ScienceGraduate School of Medicine, Fujita Health UniversityToyoake, AichiJapan
  2. 2.Department of PharmacologySchool of Dentistry, Aichi-Gakuin UniversityNagoya, AichiJapan

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