title: Neuroprotective effects of the novel D3/D2 receptor agonist and antiparkinson agent, S32504, in vitro against 1-methyl-4-phenylpyridinium (MPP+) and in vivo against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a comparison to ropinirole.
abstract: The novel naphtoxazine derivative and preferential D(3) vs D(2) receptor agonist, S32504, restores perturbed motor function in rodent and primate models of antiparkinsonian activity with a potency superior to those of two further, preferential D(3) receptor agonists, pramipexole and ropinirole. However, potential neuroprotective properties of S32054 have not, to date, been evaluated. Herein, employing several measures of cellular integrity, we demonstrate that S32504 robustly, concentration-dependently and completely protects terminally differentiated SH-SY5Y cells against 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in vitro. Further, S32504 was substantially more potent than pramipexole and ropinirole, the latter of which was neurotoxic at high concentrations. In vivo, subchronic treatment with low (0.25 mg/kg) and high (2.5 mg/kg) doses of S32504 prior to and during treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP, provided complete protection against MPTP-induced tyrosine hydroxylase immunoreactive (TH-IR) neuronal death in the substantia nigra pars compacta and ventral tegmental area. A high dose of ropinirole (2.5 mg/kg) provided some protection but statistical significance was not attained, and a low dose (0.25 mg/kg) was ineffective. Neither drug afforded protection against the MPTP-induced loss of DA fibers in the striatum, as measured by TH-IR and dopamine transporter immunoreactive fiber counts. In conclusion, the novel naphotoxazine and dopaminergic agonist, S32504, robustly protects dopaminergic neurones against the neurotoxic effects of MPP(+) and MPTP in in vitro and in vivo models, respectively. The underlying mechanisms and therapeutic pertinence of these actions will be of interest to further evaluate in view of its potent actions in behavioral models of antiparkinson activity.
authors.affiliation: Thomas H. Christopher Center for Parkinson's Disease Research, Sun Health Research Institute, 852622, Sun City, AZ, USA. Jeff.Joyce@sunwealth.org
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Joyce
authors.forename: Steve
authors.initials: S
authors.lastname: Presgraves
authors.forename: Lynn
authors.initials: L
authors.lastname: Renish
authors.forename: Sabinne
authors.initials: S
authors.lastname: Borwege
authors.forename: Tracy
authors.initials: T
authors.lastname: Osredkar
authors.forename: Diane
authors.initials: D
authors.lastname: Hagner
authors.forename: Maria
authors.initials: M
authors.lastname: Replogle
authors.forename: Mateo
authors.initials: M
authors.lastname: PazSoldan
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors*; D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D052160:Benzothiazoles; D002452:Cell Count; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D015259:Dopamine Agents / Q000633:toxicity*; D018491:Dopamine Agonists / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents; D010078:Oxazines / Q000494:pharmacology*; D000077487:Pramipexole; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3; D013778:Tetrazolium Salts; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000978:Antiparkinson Agents; D052160:Benzothiazoles; C493593:DRD3 protein, human; D015259:Dopamine Agents; D018491:Dopamine Agonists; C493594:Drd3 protein, mouse; D007211:Indoles; D018696:Neuroprotective Agents; D010078:Oxazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C478818:S 32504; D013778:Tetrazolium Salts; D013844:Thiazoles; C046649:ropinirole; D000077487:Pramipexole; D004247:DNA; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C022616:thiazolyl blue; D015655:1-Methyl-4-phenylpyridinium