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.
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.
Price
David A
DA
Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, USA.
Martinez
Alex A
AA
Seillier
Alexandre
A
Koek
Wouter
W
Acosta
Yolanda
Y
Fernandez
Elizabeth
E
Strong
Randy
R
Lutz
Beat
B
Marsicano
Giovanni
G
Roberts
James L
JL
Giuffrida
Andrea
A
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids / Q000494:pharmacology / Q000627:therapeutic use; D002452:Cell Count; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D020267:MPTP Poisoning / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000517:prevention & control*; D043882:Receptors, Cannabinoid / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology
D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D018696:Neuroprotective Agents; D043882:Receptors, Cannabinoid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine