title: Assessment of the Effects of MPTP and Paraquat on Dopaminergic Neurons and Microglia in the Substantia Nigra Pars Compacta of C57BL/6 Mice.
abstract: The neurotoxicity of paraquat dichloride (PQ) was assessed in two inbred strains of 9- or 16-week old male C57BL/6 mice housed in two different laboratories and compared to the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PQ was administered by intraperitoneal injections; either once (20 mg/kg) or twice (10 mg/kg) weekly for 3 weeks, while MPTP-HCl was injected 4 times on a single day (20 mg/kg/dose). Brains were collected 8, 16, 24, 48, 96 or 168 hours after the last PQ treatment, and 48 or 168 hours after MPTP treatment. Dopamine neurons in the substantia nigra pars compacta (SNpc) were identified by antibodies to tyrosine hydroxylase (TH+) and microglia were identified using Iba-1 immunoreactivity. The total number of TH+ neurons and the number of resting and activated microglia in the SNpc at 168 hours after the last dose were estimated using model- or design-based stereology, with investigators blinded to treatment. In a further analysis, a pathologist, also blinded to treatment, evaluated the SNpc and/or striatum for loss of TH+ neurons (SNpc) or terminals (striatum), cell death (as indicated by amino cupric silver uptake, TUNEL and/or caspase 3 staining) and neuroinflammation (as indicated by Iba-1 and/or GFAP staining). PQ, administered either once or twice weekly to 9- or 16-week old mice from two suppliers, had no effect on the number of TH+ neurons or microglia in the SNpc, as assessed by two groups, each blinded to treatment, using different stereological methods. PQ did not induce neuronal cell loss or degeneration in the SNpc or striatum. Additionally, there was no evidence of apoptosis, microgliosis or astrogliosis. In MPTP-treated mice, the number of TH+ neurons in the SNpc was significantly decreased and the number of activated microglia increased. Histopathological assessment found degenerating neurons/terminals in the SNpc and striatum but no evidence of apoptotic cell death. MPTP activated microglia in the SNpc and increased the number of astrocytes in the SNpc and striatum.
authors: St. Jude Children's Research Hospital, Dept. of Developmental Neurobiology, 262 Danny Thomas Place, Memphis, TN 38105, United States of America.
authors: Richard Jay
authors: RJ
authors: Smeyne
authors: Syngenta Crop Protection, LLC, P.O. Box 18300, Greensboro, NC 27419-8300, United States of America.
authors: Charles B
authors: CB
authors: Breckenridge
authors: WIL Research Laboratories, LLC., Ashland, OH 44805, United States of America.
authors: Melissa
authors: M
authors: Beck
authors: St. Jude Children's Research Hospital, Dept. of Developmental Neurobiology, 262 Danny Thomas Place, Memphis, TN 38105, United States of America.
authors: Yun
authors: Y
authors: Jiao
authors: Tox Path Specialists, LLC, 8747 Chestnut Grove Road, Frederick, MD 21701-2607, United States of America.
authors: Mark T
authors: MT
authors: Butt
authors: Experimental Pathology Laboratories, Inc., 45600 Terminal Drive, Sterling, VA 20166, United States of America.
authors: Jeffrey C
authors: JC
authors: Wolf
authors: Experimental Pathology Laboratories, Inc., 45600 Terminal Drive, Sterling, VA 20166, United States of America.
authors: Dan
authors: D
authors: Zadory
authors: Syngenta Crop Protection, LLC, P.O. Box 18300, Greensboro, NC 27419-8300, United States of America.
authors: Daniel J
authors: DJ
authors: Minnema
authors: Syngenta Limited, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom.
authors: Nicholas C
authors: NC
authors: Sturgess
authors: Syngenta Limited, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom.
authors: Kim Z
authors: KZ
authors: Travis
authors: Syngenta Limited, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom.
authors: Andrew R
authors: AR
authors: Cook
authors: University of Leicester, University Road, Leicester LE1 7RH, United Kingdom.
authors: Lewis L
authors: LL
authors: Smith
authors: Syngenta Limited, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom.
authors: Philip A
authors: PA
authors: Botham
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004435:Eating / Q000187:drug effects; D020267:MPTP Poisoning / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D010269:Paraquat / Q000633:toxicity*; D065842:Pars Compacta / Q000166:cytology* / Q000473:pathology; D016019:Survival Analysis; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D014446:Tyrosine 3-Monooxygenase; D010269:Paraquat