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Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism

Veronica Francardo, Francesco Bez, Tadeusz Wieloch, Hans Nissbrandt, Karsten Ruscher, M. Angela Cenci
DOI: http://dx.doi.org/10.1093/brain/awu107 1998-2014 First published online: 22 April 2014

Summary

The sigma-1 receptor, an endoplasmic reticulum-associated molecular chaperone, is attracting great interest as a potential target for neuroprotective treatments. We provide the first evidence that pharmacological modulation of this protein produces functional neurorestoration in experimental parkinsonism. Mice with intrastriatal 6-hydroxydopamine lesions were treated daily with the selective sigma-1 receptor agonist, PRE-084, for 5 weeks. At the dose of 0.3 mg/kg/day, PRE-084 produced a gradual and significant improvement of spontaneous forelimb use. The behavioural recovery was paralleled by an increased density of dopaminergic fibres in the most denervated striatal regions, by a modest recovery of dopamine levels, and by an upregulation of neurotrophic factors (BDNF and GDNF) and their downstream effector pathways (extracellular signal regulated kinases 1/2 and Akt). No treatment-induced behavioural-histological restoration occurred in sigma-1 receptor knockout mice subjected to 6-hydroxydopamine lesions and treated with PRE-084. Immunoreactivity for the sigma-1 receptor protein was evident in both astrocytes and neurons in the substantia nigra and the striatum, and its intracellular distribution was modulated by PRE-084 (the treatment resulted in a wider intracellular distribution of the protein). Our results suggest that sigma-1 receptor regulates endogenous defence and plasticity mechanisms in experimental parkinsonism. Boosting the activity of this protein may have disease-modifying effects in Parkinson’s disease.

  • mouse
  • neuroprotection
  • 6-hydroxydopamine
  • Parkinson’s disease
  • MAPK signalling
  • Abbreviations
    ERK1/2
    extracellular signal-regulated kinases
    PRE-084
    2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate
    Sig-1R
    sigma-1 receptor
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