Neuroscience Letters 510 (2012) 138–142 Contents lists available at SciVerse ScienceDirect Neuroscience Letters j our nal ho me p ag e: www.elsevier.com/locate/neulet Lipopolysaccharide-induced nigral inflammation leads to increased IL-1 tissue content and expression of astrocytic glial cell line-derived neurotrophic factor Mahmoud M. Iravani ∗ , Mona Sadeghian, Clement C.M. Leung, Peter Jenner, Sarah Rose Neurodegenerative Disease Research Centre, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King’s College London, SE1 1UL London, UK a r t i c l e i n f o Article history: Received 8 October 2011 Received in revised form 27 November 2011 Accepted 8 January 2012 Keywords: Astrocytes Glial cell line-derived neurotrophic factor (GDNF) Interleukin-1 (IL-1) Lipopolysaccharide (LPS) Substantia nigra Tumour necrosis factor- (TNF-) a b s t r a c t Reactive gliosis and inflammatory change is a key component of nigral dopaminergic cell death in Parkin- son’s disease (PD). Astrocyte derived glial cell line-derived neurotrophic factor (GDNF) promotes the survival and growth of dopaminergic neurones and it protects against or reverses nigral degeneration induced by 6-OHDA and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rodents and primates. But the effect of increased levels of pro-inflammatory cytokines on the release of GDNF is unknown. This study examined the relationship between release of tumour necrosis factor- (TNF-) and interleukin- 1 (IL-1) and the expression of GDNF in rats following nigral lipopolysaccharide (LPS) administration. Acute nigral administration of LPS led to marked elevation of IL-1 but insignificant TNF- tissue content and to a prominent expression of GDNF immunoreactivity in astrocytes but not microglia. The results suggest that inflammation is not only involved in neuronal loss but could promote neuronal survival through increased release of GDNF following up-regulation of IL-1. © 2012 Elsevier Ireland Ltd. All rights reserved. Nigral dopaminergic cell degeneration in PD is linked to activa- tion of both microglia and astrocytes and to inflammatory change that is proposed to contribute to disease progression [22,27]. As a consequence, the control of inflammation is thought of as a means of limiting neuronal loss and for preventing a worsening of motor deficits [9,18,25]. Indeed, increased levels of cytokines including IL-1 and TNF-, up-regulation of inducible nitric oxide synthase (iNOS) and the presence of 3-nitrotyrosine adducts accompany glial cell activation in PD [12]. Dopaminergic toxins, such as 6-OHDA and MPTP, also induce glial cell activation in both ventral mesen- cephalic (VM) cultures and in the rat substantia nigra that leads to cytokine release and increased oxidative and nitrative stress [3]. These changes are generally thought of as harmful to remaining dopaminergic neurons [3,31,35,42]. However, glial cell activation and inflammation is a double- edged sword and an alternate view is that it may serve a protective or restorative role for neurones [43]. Specifically neurotoxic dam- age to the nigrostriatal tract in MPTP treated mice leads to astrocyte Abbreviations: DA, dopamine; ELISA, enzyme linked immunosorbent assay; GDNF, glial cell lined-derived neurotrophic factor; GFAP, glial fibrillary acidic pro- tein; 6-OHDA, 6-hydroxydopamine; IL-1b, interleukin 1 beta; IL-1ra, interleukin 1 receptor antagonist; iNOS, inducible nitric oxide synthase; LPS, lipopolysac- charide; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson’s disease; TNF-a, tumour necrosis factor. ∗ Corresponding author. Tel.: +44 020 7848 6881. E-mail address: m.iravani@kcl.ac.uk (M.M. Iravani). up-regulation of glial cell line-derived neurotrophic factor (GDNF) that may serve a neuroprotective function [6,7]. GDNF has a potent ability to protect and regenerate nigrostriatal dopaminergic neu- rons in mouse, rat and primate models of Parkinson’s disease [8,14,24,40]. In astrocyte cultures, both LPS and MPP+ elevate GDNF protein levels [28] and both exogenous and endogenous TNF- induce GDNF expression via TNF receptors showing that cytokine production from activated astrocytes triggers the production of neurotrophic factors [20]. However, in normal animals, the levels of GDNF and its mRNA in the ventral mesencephalon and in the striatum are extremely low and it is only possible to detect GDNF mRNA in astrocytes using PCR techniques [38]. Nothing appears known about the levels of GDNF in substantia nigra following glial activation but following striatal lesions induced by 6-OHDA, MPTP or quinolic acid [4,26], the normally low to undetectable levels of striatal GDNF protein are selectively increased in astrocytes [6,44]. The inflammogen, lipopolysaccharide is widely used to destroy nigral dopaminergic neurones through glial cell activation fol- lowing direct intranigral application. However, in rat primary cortical cultures, LPS treatment not only releases proinflammatory cytokines such as TNF- and IL-1 but also elevates GDNF mRNA and protein [2,34]. This may be important as there is a marked difference in the nature of the inflammatory response at shorter compared to longer time intervals following LPS administration in to rat substantia nigra. Acute treatment leads to marked astrocy- tosis, microgliosis and the degeneration of dopaminergic neurones [15–17]. However, one month following LPS treatment, microglial 0304-3940/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2012.01.022