Neuroprotective potential of adenosine A2A and cannabinoid CB1 receptor antagonists in an animal model of Parkinson disease

Silvia Cerri, Giovanna Levandis, Giulia Ambrosi, Elena Montepeloso, Gian Filippo Antoninetti, Rafael Franco, José Luis Lanciego, Younis Baqi, Christa E. Müller, Annalisa Pinna, Fabio Blandini, Marie Therese Armentero

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The development of nondopaminergic therapeutic strategies that may improve motor and nonmotor deficits, while possibly slowing down the neurodegenerative process and associated neuroinflammation, is a primary goal of Parkinson disease (PD) research. We investigated the neuroprotective and anti-inflammatory potential of combined and single treatment with adenosine A2A and cannabinoid CB1 receptor antagonists MSX-3 and rimonabant, respectively, in a rodent model of PD. Rats bearing a unilateral intrastriatal 6-hydroxydopamine lesion were treated chronically with MSX-3 (0.5or 1 mg/kg/d) and rimonabant (0.1 mg/kg/d) given as monotherapy or combined. The effects of the treatments to counteract dopaminergic cell death and neuroinflammation were assessed by immunohistochemistry for tyrosine hydroxylase and glial cell markers, respectively. Both rimonabant and MSX-3 (1 mg/kg/d) promoted dopaminergic neuron survival in the substantia nigra pars compacta (SNc) when given alone; this effect was weakened when the compounds were combined. Glial activation was not significantly affected by MSX-3 (1 mg/kg/d), whereas rimonabant seemed to increase astrocyte cell density in the SNc. Our findings demonstrate the neuroprotective potential of single treatments and suggest that glial cells might be involved in this protective effect. The results also indicate that the neuroprotective potential of combined therapy may not necessarily reflect or promote single-drug effects and point out that special care should be taken when considering multidrug therapies in PD.

Original languageEnglish
Pages (from-to)414-424
Number of pages11
JournalJournal of Neuropathology and Experimental Neurology
Volume73
Issue number5
DOIs
Publication statusPublished - 2014

Fingerprint

rimonabant
Cannabinoid Receptor Antagonists
Adenosine
Parkinson Disease
Animal Models
Neuroglia
Therapeutics
Oxidopamine
Dopaminergic Neurons
Tyrosine 3-Monooxygenase
Astrocytes
Rodentia
Cell Death
Anti-Inflammatory Agents
Cell Count
Immunohistochemistry
Research

Keywords

  • 6-Hydroxydopamine
  • Dopamine
  • Glial cells
  • Neurodegeneration
  • Neuroinflammation
  • Neuroprotection
  • Receptor heteromer

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Neuroprotective potential of adenosine A2A and cannabinoid CB1 receptor antagonists in an animal model of Parkinson disease. / Cerri, Silvia; Levandis, Giovanna; Ambrosi, Giulia; Montepeloso, Elena; Antoninetti, Gian Filippo; Franco, Rafael; Lanciego, José Luis; Baqi, Younis; Müller, Christa E.; Pinna, Annalisa; Blandini, Fabio; Armentero, Marie Therese.

In: Journal of Neuropathology and Experimental Neurology, Vol. 73, No. 5, 2014, p. 414-424.

Research output: Contribution to journalArticle

Cerri, S, Levandis, G, Ambrosi, G, Montepeloso, E, Antoninetti, GF, Franco, R, Lanciego, JL, Baqi, Y, Müller, CE, Pinna, A, Blandini, F & Armentero, MT 2014, 'Neuroprotective potential of adenosine A2A and cannabinoid CB1 receptor antagonists in an animal model of Parkinson disease', Journal of Neuropathology and Experimental Neurology, vol. 73, no. 5, pp. 414-424. https://doi.org/10.1097/NEN.0000000000000064
Cerri, Silvia ; Levandis, Giovanna ; Ambrosi, Giulia ; Montepeloso, Elena ; Antoninetti, Gian Filippo ; Franco, Rafael ; Lanciego, José Luis ; Baqi, Younis ; Müller, Christa E. ; Pinna, Annalisa ; Blandini, Fabio ; Armentero, Marie Therese. / Neuroprotective potential of adenosine A2A and cannabinoid CB1 receptor antagonists in an animal model of Parkinson disease. In: Journal of Neuropathology and Experimental Neurology. 2014 ; Vol. 73, No. 5. pp. 414-424.
@article{710d1eab5c204655965197846e19f9e4,
title = "Neuroprotective potential of adenosine A2A and cannabinoid CB1 receptor antagonists in an animal model of Parkinson disease",
abstract = "The development of nondopaminergic therapeutic strategies that may improve motor and nonmotor deficits, while possibly slowing down the neurodegenerative process and associated neuroinflammation, is a primary goal of Parkinson disease (PD) research. We investigated the neuroprotective and anti-inflammatory potential of combined and single treatment with adenosine A2A and cannabinoid CB1 receptor antagonists MSX-3 and rimonabant, respectively, in a rodent model of PD. Rats bearing a unilateral intrastriatal 6-hydroxydopamine lesion were treated chronically with MSX-3 (0.5or 1 mg/kg/d) and rimonabant (0.1 mg/kg/d) given as monotherapy or combined. The effects of the treatments to counteract dopaminergic cell death and neuroinflammation were assessed by immunohistochemistry for tyrosine hydroxylase and glial cell markers, respectively. Both rimonabant and MSX-3 (1 mg/kg/d) promoted dopaminergic neuron survival in the substantia nigra pars compacta (SNc) when given alone; this effect was weakened when the compounds were combined. Glial activation was not significantly affected by MSX-3 (1 mg/kg/d), whereas rimonabant seemed to increase astrocyte cell density in the SNc. Our findings demonstrate the neuroprotective potential of single treatments and suggest that glial cells might be involved in this protective effect. The results also indicate that the neuroprotective potential of combined therapy may not necessarily reflect or promote single-drug effects and point out that special care should be taken when considering multidrug therapies in PD.",
keywords = "6-Hydroxydopamine, Dopamine, Glial cells, Neurodegeneration, Neuroinflammation, Neuroprotection, Receptor heteromer",
author = "Silvia Cerri and Giovanna Levandis and Giulia Ambrosi and Elena Montepeloso and Antoninetti, {Gian Filippo} and Rafael Franco and Lanciego, {Jos{\'e} Luis} and Younis Baqi and M{\"u}ller, {Christa E.} and Annalisa Pinna and Fabio Blandini and Armentero, {Marie Therese}",
year = "2014",
doi = "10.1097/NEN.0000000000000064",
language = "English",
volume = "73",
pages = "414--424",
journal = "American Journal of Psychotherapy",
issn = "0002-9564",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - Neuroprotective potential of adenosine A2A and cannabinoid CB1 receptor antagonists in an animal model of Parkinson disease

AU - Cerri, Silvia

AU - Levandis, Giovanna

AU - Ambrosi, Giulia

AU - Montepeloso, Elena

AU - Antoninetti, Gian Filippo

AU - Franco, Rafael

AU - Lanciego, José Luis

AU - Baqi, Younis

AU - Müller, Christa E.

AU - Pinna, Annalisa

AU - Blandini, Fabio

AU - Armentero, Marie Therese

PY - 2014

Y1 - 2014

N2 - The development of nondopaminergic therapeutic strategies that may improve motor and nonmotor deficits, while possibly slowing down the neurodegenerative process and associated neuroinflammation, is a primary goal of Parkinson disease (PD) research. We investigated the neuroprotective and anti-inflammatory potential of combined and single treatment with adenosine A2A and cannabinoid CB1 receptor antagonists MSX-3 and rimonabant, respectively, in a rodent model of PD. Rats bearing a unilateral intrastriatal 6-hydroxydopamine lesion were treated chronically with MSX-3 (0.5or 1 mg/kg/d) and rimonabant (0.1 mg/kg/d) given as monotherapy or combined. The effects of the treatments to counteract dopaminergic cell death and neuroinflammation were assessed by immunohistochemistry for tyrosine hydroxylase and glial cell markers, respectively. Both rimonabant and MSX-3 (1 mg/kg/d) promoted dopaminergic neuron survival in the substantia nigra pars compacta (SNc) when given alone; this effect was weakened when the compounds were combined. Glial activation was not significantly affected by MSX-3 (1 mg/kg/d), whereas rimonabant seemed to increase astrocyte cell density in the SNc. Our findings demonstrate the neuroprotective potential of single treatments and suggest that glial cells might be involved in this protective effect. The results also indicate that the neuroprotective potential of combined therapy may not necessarily reflect or promote single-drug effects and point out that special care should be taken when considering multidrug therapies in PD.

AB - The development of nondopaminergic therapeutic strategies that may improve motor and nonmotor deficits, while possibly slowing down the neurodegenerative process and associated neuroinflammation, is a primary goal of Parkinson disease (PD) research. We investigated the neuroprotective and anti-inflammatory potential of combined and single treatment with adenosine A2A and cannabinoid CB1 receptor antagonists MSX-3 and rimonabant, respectively, in a rodent model of PD. Rats bearing a unilateral intrastriatal 6-hydroxydopamine lesion were treated chronically with MSX-3 (0.5or 1 mg/kg/d) and rimonabant (0.1 mg/kg/d) given as monotherapy or combined. The effects of the treatments to counteract dopaminergic cell death and neuroinflammation were assessed by immunohistochemistry for tyrosine hydroxylase and glial cell markers, respectively. Both rimonabant and MSX-3 (1 mg/kg/d) promoted dopaminergic neuron survival in the substantia nigra pars compacta (SNc) when given alone; this effect was weakened when the compounds were combined. Glial activation was not significantly affected by MSX-3 (1 mg/kg/d), whereas rimonabant seemed to increase astrocyte cell density in the SNc. Our findings demonstrate the neuroprotective potential of single treatments and suggest that glial cells might be involved in this protective effect. The results also indicate that the neuroprotective potential of combined therapy may not necessarily reflect or promote single-drug effects and point out that special care should be taken when considering multidrug therapies in PD.

KW - 6-Hydroxydopamine

KW - Dopamine

KW - Glial cells

KW - Neurodegeneration

KW - Neuroinflammation

KW - Neuroprotection

KW - Receptor heteromer

UR - http://www.scopus.com/inward/record.url?scp=84899586462&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899586462&partnerID=8YFLogxK

U2 - 10.1097/NEN.0000000000000064

DO - 10.1097/NEN.0000000000000064

M3 - Article

VL - 73

SP - 414

EP - 424

JO - American Journal of Psychotherapy

JF - American Journal of Psychotherapy

SN - 0002-9564

IS - 5

ER -