title: Lymphocyte-mediated neuroprotection in in vitro models of excitotoxicity involves astrocytic activation and the inhibition of MAP kinase signalling pathways.
abstract: It is well established that immunosurveillance is active in the CNS and plays a key role in several CNS disorders but the exact role of immune cells remains elusive. Thus, in the present study we investigated whether lymphocytes are protective/detrimental in in vitro models of excitotoxicty. Kainate (KA)-induced neuronal death was significantly reduced following exposure to mixed lymphocytes or purified T lymphocytes containing either activated or non-activated T-lymphocytes. Conditioned media from lymphocyte preparations, but not boiled conditioned media, was protective against KA-induced toxicity indicating soluble mediators underlie the observed neuroprotection with cytokine arrays indicating IL-16 as the likely candidate. A role for astrocytes was established as the neuroprotection was abolished in the presence of the glial toxin, fluoroacetate. Furthermore, lymphocytes inhibited p38 MAPK and ERK signalling pathways with pharmacological inhibition of these pathways mimicking the protective effect of lymphocytes. Similarly, lymphocytes were neuroprotective against oxygen-glucose deprivation (OGD)-induced cell death with the inhibition of p38 MAPK and ERK signalling pathways involved. These data indicate that lymphocytes are neuroprotective under our experimental conditions and we suggest that astrocytic activation and inhibition of MAPK signalling cascades are involved but further studies are required to investigate whether similar mechanisms underlie the actions of lymphocytes in in vivo experimental models of disease. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Shrestha
authors.forename: Owain
authors.initials: O
authors.lastname: Millington
authors.forename: James
authors.initials: J
authors.lastname: Brewer
authors.forename: Kumlesh K
authors.initials: KK
authors.lastname: Dev
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Bushell
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology; D005463:Fluoroacetates / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity*; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000276:immunology*; D018696:Neuroprotective Agents / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D005463:Fluoroacetates; D018696:Neuroprotective Agents; C014815:fluoroacetic acid; D007608:Kainic Acid
keywords: APCs; Astrocytes; BBB; CM; CNS; Central nervous system; ERK; FAc; GFP; KA; LCM; Lymphocytes; MAP kinases; MAPK; MHC; Neuroinflammation; Neuroprotection; OGD; OSCs; T cells; antigen presenting cells; blood–brain barrier; conditioned media; extracellular signal-regulated kinases; fluoroacetate; green fluorescent protein; kainate; lymphocyte conditioned media; major histocompatibility complex; mitogen activated protein kinases; organotypic hippocampal slice cultures; oxygen-glucose deprivation