WIN55,212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease.
European Journal of Neuroscience. 2009-06-01; 29(11): 2177-2186
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1. Eur J Neurosci. 2009 Jun;29(11):2177-86. doi: 10.1111/j.1460-9568.2009.06764.x.
Epub 2009 May 21.
WIN55,212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell
loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of
Price DA(1), Martinez AA, Seillier A, Koek W, Acosta Y, Fernandez E, Strong R,
Lutz B, Marsicano G, Roberts JL, Giuffrida A.
(1)Department of Pharmacology, University of Texas Health Science Center, San
Antonio, TX, USA.
Parkinson’s disease (PD) is characterized by the progressive loss of
nigrostriatal dopamine neurons leading to motor disturbances and cognitive
impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to
prevent or slow down the disease progression. In this study, we investigated the
molecular mechanisms by which the non-selective cannabinoid receptor agonist
WIN55,212-2 (WIN) protects mouse nigrostriatal neurons from
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity and
neuroinflammation. Stereological analyses showed that chronic treatment with WIN
(4 mg/kg, intraperitoneal), initiated 24 h after MPTP administration, protected
against MPTP-induced loss of tyrosine hydroxylase-positive neurons in the
substantia nigra pars compacta independently of CB1 cannabinoid receptor
activation. The neuroprotective effect of WIN was accompanied by increased
dopamine and 3,4-dihydroxyphenylacetic acid levels in the substantia nigra pars
compacta and dorsal striatum of MPTP-treated mice. At 3 days post-MPTP, we found
significant microglial activation and up-regulation of CB2 cannabinoid receptors
in the ventral midbrain. Treatment with WIN or the CB2 receptor agonist JWH015 (4
mg/kg, intraperitoneal) reduced MPTP-induced microglial activation, whereas
genetic ablation of CB2 receptors exacerbated MPTP systemic toxicity.
Furthermore, chronic WIN reversed MPTP-associated motor deficits, as revealed by
the analysis of forepaw step width and percentage of faults using the inverted
grid test. In conclusion, our data indicate that agonism at CB2 cannabinoid
receptors protects against MPTP-induced nigrostriatal degeneration by inhibiting
microglial activation/infiltration and suggest that CB2 receptors represent a new
therapeutic target to slow the degenerative process occurring in PD.
PMID: 19490092 [Indexed for MEDLINE]