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Neuroinflammation in l-DOPA-induced dyskinesia: beyond the immune function

  • Neurology and Preclinical Neurological Studies - Review Article
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Abstract

Neuroinflammation is a main component of Parkinson’s disease (PD) neuropathology, where unremitting reactive microglia and microglia-secreted soluble molecules such as cytokines, contribute to the neurodegenerative process as part of an aberrant immune reaction. Besides, pro-inflammatory cytokines, predominantly TNF-α, play an important neuromodulatory role in the healthy and diseased brain, being involved in neurotransmitter metabolism, synaptic scaling and brain plasticity. Recent preclinical studies have evidenced an exacerbated neuroinflammatory reaction in the striatum of parkinsonian rats that developed dyskinetic responses following l-DOPA administration. These findings prompted investigation of non-neuronal mechanisms of l-DOPA-induced dyskinesia (LID) involving glial cells and glial-secreted soluble molecules. Hence, besides the classical mechanisms of LID that include abnormal corticostriatal neurotransmission and maladaptive changes in striatal medium spiny neurons (MSNs), here we review studies supporting a role of striatal neuroinflammation in the development of LID, with a focus on microglia and the pro-inflammatory cytokine TNF-α. Moreover, we discuss several mechanisms that have been involved in the development of LID, which are directly or indirectly under the control of TNF-α, and might be abnormally affected by its chronic overproduction and release by microglia in PD. It is proposed that TNF-α may contribute to the altered neuronal responses occurring in LID by targeting receptor trafficking and function in MSNs, but also dopamine synthesis in preserved dopaminergic terminals and serotonin metabolism in serotonergic neurons. Therapeutic approaches specifically targeting glial-secreted cytokines may represent a novel target for preventing or treating LID.

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Authors and Affiliations

  1. Institute of Neuroscience, National Research Council, SS 554 km 4.500, Monserrato, 09042, Cagliari, Italy

    Augusta Pisanu

  2. Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. N. 8, Monserrato, 09042, Cagliari, Italy

    Laura Boi, Sandro Fenu & Anna R. Carta

  3. Department of Life and Environmental Sciences, University of Cagliari, Via Fiorelli 1, Cagliari, Italy

    Giovanna Mulas & Saturnino Spiga

Authors
  1. Augusta Pisanu
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  2. Laura Boi
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  3. Giovanna Mulas
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  4. Saturnino Spiga
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  5. Sandro Fenu
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  6. Anna R. Carta
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Corresponding author

Correspondence to Anna R. Carta.

Additional information

This paper is dedicated to the memory of our wonderful and unforgettable colleague, Dr. Sandro Fenu, who recently passed away.

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Pisanu, A., Boi, L., Mulas, G. et al. Neuroinflammation in l-DOPA-induced dyskinesia: beyond the immune function. J Neural Transm 125, 1287–1297 (2018). https://doi.org/10.1007/s00702-018-1874-4

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  • DOI: https://doi.org/10.1007/s00702-018-1874-4

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