title: Minocycline prevents neurotoxicity induced by cerebrospinal fluid from patients with motor neurone disease.
abstract: CSF from patients with motor neurone disease (MND) has been reported to be toxic to cultured primary neurones. We found that CSF from MND patients homozygous for the D90A CuZn-superoxide dismutase (CuZn-SOD) mutation, patients with sporadic MND and patients with familial MND without CuZn-SOD mutations significantly increased apoptosis and reduced phosphorylation of neurofilaments in cultured spinal cord neurones when compared with the effects of CSF from patients with other neurological diseases. Exposure of spinal cord cultures to MND CSF also triggered microglial activation. The toxicity of MND CSF was independent of the presence of the CuZn-SOD mutation, and it did not correlate with gelatinase activity or the presence of immunoglobulin G autoantibodies in the CSF. The concentrations of glutamate, aspartate and glycine in MND CSF were not elevated. Antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate receptors prevented the toxic CSF-induced neuronal death but not microglial activation, whereas minocycline, a tetracycline derivative with anti-inflammatory potential independent of antimicrobial activity, reduced both the apoptotic neuronal death and microglial activation. We conclude that the cytotoxic action of CSF is prevalent in all MND cases and that microglia may mediate the toxicity of CSF by releasing excitotoxicity-enhancing factors.
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland.
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Tikka
authors.forename: Nina E
authors.initials: NE
authors.lastname: Vartiainen
authors.forename: Gundars
authors.initials: G
authors.lastname: Goldsteins
authors.forename: Simo S
authors.initials: SS
authors.lastname: Oja
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Stefan L
authors.initials: SL
authors.lastname: Marklund
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002556:Cerebrospinal Fluid Proteins / Q000378:metabolism / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D016472:Motor Neuron Disease / Q000134:cerebrospinal fluid* / Q000188:drug therapy* / Q000235:genetics; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D002556:Cerebrospinal Fluid Proteins; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018698:Glutamic Acid; D013482:Superoxide Dismutase; D008911:Minocycline