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Pharmacological sti...
Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism
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- Francardo, Veronica (author)
- Lund University,Lunds universitet,Basala gangliernas patofysiologi,Forskargrupper vid Lunds universitet,Basal Ganglia Pathophysiology,Lund University Research Groups
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- Bez, Francesco (author)
- Lund University,Lunds universitet,Basala gangliernas patofysiologi,Forskargrupper vid Lunds universitet,Basal Ganglia Pathophysiology,Lund University Research Groups
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- Wieloch, Tadeusz (author)
- Lund University,Lunds universitet,Neurokirurgi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Neurosurgery,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Nissbrandt, Hans, 1952 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology
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- Ruscher, Karsten (author)
- Lund University,Lunds universitet,Neurokirurgi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Neurosurgery,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine
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Cenci, M. A. (author)
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- Cenci Nilsson, Angela (author)
- Lund University,Lunds universitet,Basala gangliernas patofysiologi,Forskargrupper vid Lunds universitet,Basal Ganglia Pathophysiology,Lund University Research Groups
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(creator_code:org_t)
- 2014-04-22
- 2014
- English.
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 137, s. 1998-2014
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Abstract
Subject headings
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- Sigma-1 receptor ligands may have neuroprotective and neurorestorative properties. In a mouse model of parkinsonism, Francardo et al. show that chronic treatment with the sigma-1 receptor agonist PRE-084 increases the density of striatal dopaminergic fibres and improves forelimb use. Boosting sigma-1 receptor activity may have disease-modifying effects in ParkinsonA ' s disease.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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- mouse
- neuroprotection
- 6-hydroxydopamine
- Parkinson's disease
- MAPK signalling
- CENTRAL-NERVOUS-SYSTEM
- NITRIC-OXIDE SYNTHASE
- BINDING-SITES
- RAT MODEL
- NEUROTROPHIC FACTOR
- SIGNALING PATHWAYS
- SUBSTANTIA-NIGRA
- DOPAMINERGIC
- NEURODEGENERATION
- NEURONAL PLASTICITY
- EXPERIMENTAL STROKE
- Clinical Neurology
- Neurosciences
Publication and Content Type
- ref (subject category)
- art (subject category)
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