title: The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation.
abstract: Sustained reactive microgliosis may contribute to the progressive degeneration of nigral dopaminergic neurons in Parkinson's disease (PD), in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposed human and in non-human primates. However, the temporal relationship between glial cell activation and nigral cell death is relatively unexplored. Consequently, the effects of acute (24 h) and chronic (30 days) glial cell activation induced by unilateral supranigral lipopolysaccharide (LPS) administration were studied in rats. At 24 h, LPS administration caused a marked reduction in the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra (SN) but striatal TH-ir was unaffected. By 30 days, the loss of TH-positive neurons in the LPS-treated nigra was no greater than at 24 h although a heterogeneous loss of striatal TH-ir was present. The loss of nigrostriatal neurons was of functional significance, as at 30 days, LPS-treated rats exhibited ipsiversive circling in response to (+)-amphetamine administration. At 24 h, there was a moderate increase in glial fibrillary acidic protein (GFAP)-ir astrocytes in the SN but a marked elevation of p47phox positive OX-42-ir microglia, and intense inducible nitric oxide synthase (iNOS)-ir and 3-nitrotyrosine (3-NT)-ir was present. However, by 30 days the morphology of OX-42-ir microglia returned to a resting state, the numbers were greatly reduced and no 3-NT-ir was present. At 30 days, GFAP-ir astrocytes were markedly increased in number and iNOS-ir was present in fibrillar astrocyte-like cells. This study shows that acute glial activation leading to dopaminergic neuron degeneration is an acute short-lasting response that does not itself perpetuate cell death or lead to prolonged microglial activation.
authors.affiliation: Neurodegenerative Disease Research Centre, GKT School of Biomedical Sciences, King's College, London, SE1 1UL, UK.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Iravani
authors.forename: Clement C M
authors.initials: CC
authors.lastname: Leung
authors.forename: Mona
authors.initials: M
authors.lastname: Sadeghian
authors.forename: Claire O
authors.initials: CO
authors.lastname: Haddon
authors.forename: Sarah
authors.initials: S
authors.lastname: Rose
authors.forename: Peter
authors.initials: P
authors.lastname: Jenner
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D039481:CD11b Antigen / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D003952:Diagnostic Imaging / Q000379:methods; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010080:Oxazoles / Q000378:metabolism; D051381:Rats; D009418:S100 Proteins / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects*; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C119678:4-ethoxymethylene-2-phenyl-2-oxazoline-5-one; D039481:CD11b Antigen; D018765:Dopamine Uptake Inhibitors; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D010080:Oxazoles; D009418:S100 Proteins; C002744:3-nitrotyrosine; D014443:Tyrosine; D000661:Amphetamine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine