title: Endotoxin induces a delayed loss of TH-IR neurons in substantia nigra and motor behavioral deficits.
abstract: We have previously reported that a single injection of endotoxin, lipopolysaccharide (LPS, 5mg/kg, i.p.), causes a delayed and progressive loss of TH-IR neurons in the substantia nigra (SN) in C57BL/six male mice. In this study, we determined sex differences and behavioral deficits accompanying the loss of TH-IR neurons in response to peripheral LPS injection. A single injection of LPS (5mg/kg, i.p.) failed to produce any loss of TH-IR neurons in the SN of female mice over a 12-month period. To determine if multiple-injections were required, female mice received five injections of LPS (5mg/kg, i.p.) at either weekly or monthly intervals. Behavioral motor ability and TH-IR neuronal loss were determined after the first injection of LPS. We found significant differences in both behavioral activities and neuronal loss between these two injection paradigms. Between 7 and 20 months after the first injection of LPS, progressive behavioral changes, measured by rotor-rod and open-field activities, and neuronal loss in SN were observed in monthly injected, but not in weekly injected mice. In addition, reduced rotor-rod ability in monthly injected mice were restored following treatment of l-dopa/carbidopa (30 mg/3mg/kg), i.p.). Approximately 40 and 50% loss of TH-IR neurons at 9 and 20 months, respectively, was observed after exposure to LPS, suggesting that the behavioral deficit is related to loss of dopamine function in the nigra-striatal pathway. More intense immuno-staining of alpha-synuclein and inflammatory markers were detected in brain sections exposed to LPS. In conclusion, these results show that multi-LPS monthly injections can induce a delayed and progressive loss of TH-IR neurons and motor deficits which resemble the progressive nature of Parkinson's disease. Further, the present study reveals a clear sex difference: female mice are more resistant to LPS than male mice. Repeated monthly LPS injections are required to cause both motor behavioral deficits and DA neuronal loss in female mice.
authors.affiliation: Neuropharmacology Section, National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Liu
authors.forename: Liya
authors.initials: L
authors.lastname: Qin
authors.forename: Belinda
authors.initials: B
authors.lastname: Wilson
authors.forename: Xuefei
authors.initials: X
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Granholm
authors.forename: Fulton T
authors.initials: FT
authors.lastname: Crews
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015259:Dopamine Agents / Q000494:pharmacology; D004731:Endotoxins / Q000633:toxicity*; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D007980:Levodopa / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D045442:Rotarod Performance Test; D012737:Sex Factors; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D015259:Dopamine Agents; D004731:Endotoxins; D008070:Lipopolysaccharides; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase