title: Neonatal exposure to lipopolysaccharide enhances vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life.
abstract: Brain inflammation in early life has been proposed to play important roles in the development of neurodegenerative disorders in adult life. To test this hypothesis, we used a neonatal rat model of lipopolysaccharide (LPS) exposure (1000 EU/g body weight, intracerebral injection on P5) to produce brain inflammation. By P70, when LPS-induced behavioral deficits were spontaneously recovered, animals were challenged with rotenone, a commonly used pesticide, through subcutaneous mini-pump infusion at a dose of 1.25 mg/kg per day for 14 days. This rotenone treatment regimen ordinarily does not produce toxic effects on behaviors in normal adult rats. Our results show that neonatal LPS exposure enhanced the vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Rotenone treatment resulted in motor neurobehavioral impairments in rats with the neonatal LPS exposure, but not in those without the neonatal LPS exposure. Rotenone induced losses of tyrosine hydroxylase immunoreactive neurons in the substantia nigra and decreased mitochondrial complex I activity in the striatum of rats with neonatal LPS exposure, but not in those without this exposure. Neonatal LPS exposure with later exposure to rotenone decreased retrogradely labeled nigrostriatal dopaminergic projecting neurons. The current study suggests that perinatal brain inflammation may enhance adult susceptibility to the development of neurodegenerative disorders triggered later on by environmental toxins at an ordinarily non-toxic or sub-toxic dose. Our model may be useful for studying mechanisms involved in the pathogenesis of nonfamilial Parkinson's disease and the development of potential therapeutic treatments.
authors.affiliation: Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Lir-Wan
authors.initials: LW
authors.lastname: Fan
authors.forename: Lu-Tai
authors.initials: LT
authors.lastname: Tien
authors.forename: Rick C S
authors.initials: RC
authors.lastname: Lin
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Simpson
authors.forename: Philip G
authors.initials: PG
authors.lastname: Rhodes
authors.forename: Zhengwei
authors.initials: Z
authors.lastname: Cai
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D039481:CD11b Antigen / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000648:ultrastructure; D004357:Drug Synergism; D042967:Electron Transport Complex I / Q000378:metabolism; D005260:Female; D055104:Infusions, Subcutaneous / Q000379:methods; D007306:Insecticides / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D009043:Motor Activity / Q000187:drug effects; D009068:Movement / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011247:Pregnancy; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000633:toxicity*; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000166:cytology*; D014738:Vibrissae / Q000294:innervation
chemical_list: C100745:Aif1 protein, rat; D039481:CD11b Antigen; D002135:Calcium-Binding Proteins; D007306:Insecticides; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D012402:Rotenone; D042967:Electron Transport Complex I