Brain, Vol. 125, No. 4, 722-731,
April 2002
© 2002 Guarantors of Brain
Minocycline prevents neurotoxicity induced by cerebrospinal fluid from patients with motor neurone disease
1 A.I. Virtanen Institute for Molecular Sciences, 2 Department of Clinical Pathology, Kuopio University Hospital, University of Kuopio, Finland, 3 Brain Research Center, University of Tampere Medical School and Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland, 4 Department of Pharmacology and Clinical Neurosciences, Umeå University Hospital and 5 Department of Medical Biosciences, Clinical Chemistry, Umeå University Hospital, Umeå, Sweden
Correspondence to: J. Koistinaho, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland E-mail: jari.koistinaho{at}uku.fi
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 
-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.
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