Endotoxin induces a delayed loss of TH-IR neurons in substantia nigra and motor behavioral deficits.
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.
Liu
Yuxin
Y
Neuropharmacology Section, National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
Qin
Liya
L
Wilson
Belinda
B
Wu
Xuefei
X
Qian
Li
L
Granholm
Ann-Charlotte
AC
Crews
Fulton T
FT
Hong
Jau-Shyong
JS
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
D015259:Dopamine Agents; D004731:Endotoxins; D008070:Lipopolysaccharides; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase