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The Journal of Neuroscience, April 15, 2001, 21(8):2580-2588

Minocycline, a Tetracycline Derivative, Is Neuroprotective against Excitotoxicity by Inhibiting Activation and Proliferation of Microglia

Tiina Tikka¹, Bernd L. Fiebich³, Gundars Goldsteins¹, Riitta Keinänen¹, and Jari Koistinaho^{1, 2}

¹ A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FIN-70211 Kuopio, Finland, ² Department of Clinical Pathology, Kuopio University Hospital, FIN-70211 Kuopio, Finland, and ³ Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, D-79104 Freiburg, Germany

Minocycline, a semisynthetic tetracycline derivative, protects brain against global and focal ischemia in rodents. We examined whether minocycline reduces excitotoxicity in primary neuronal cultures. Minocycline (0.02 µM) significantly increased neuronal survival in mixed spinal cord (SC) cultures treated with 500 µM glutamate or 100 µM kainate for 24 hr. Treatment with these excitotoxins induced a dose-dependent proliferation of microglia that was associated with increased release of interleukin-1 (IL-1) and was followed by increased lactate dehydrogenase (LDH) release. The excitotoxicity was enhanced when microglial cells were cultured on top of SC cultures. Minocycline prevented excitotoxin-induced microglial proliferation and the increased release of nitric oxide (NO) metabolites and IL-1. Excitotoxins induced microglial proliferation and increased the release of NO metabolites and IL-1 also in pure microglia cultures, and these responses were inhibited by minocycline. In both SC and pure microglia cultures, excitotoxins activated p38 mitogen-activated protein kinase (p38 MAPK) exclusively in microglia. Minocycline inhibited p38 MAPK activation in SC cultures, and treatment with SB203580, a p38 MAPK inhibitor, but not with PD98059, a p44/42 MAPK inhibitor, increased neuronal survival. In pure microglia cultures, glutamate induced transient activation of p38 MAPK, and this was inhibited by minocycline. These findings indicate that the proliferation and activation of microglia contributes to excitotoxicity, which is inhibited by minocycline, an antibiotic used in severe human infections.

Key words: ischemia; Alzheimer's disease; inflammation; glutamate; mitogen-activated protein kinase; MAPK; cell culture

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2182580-09$05.00/0

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