Tikka, et al. (2001). Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia

[Wise Young]

Tikka T, Fiebich BL, Goldsteins G, Keinanen R and Koistinaho J (2001). Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci. 21 (8): 2580-8. Summary: 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 microm) significantly increased neuronal survival in mixed spinal cord (SC) cultures treated with 500 microm glutamate or 100 microm kainate for 24 hr. Treatment with these excitotoxins induced a dose-dependent proliferation of microglia that was associated with increased release of interleukin-1beta (IL-1beta) 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-1beta. Excitotoxins induced microglial proliferation and increased the release of NO metabolites and IL-1beta 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. <http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=11306611
http://www.jneurosci.org/cgi/content/full/21/8/2580
http://www.jneurosci.org/cgi/content/abstract/21/8/2580> A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FIN-70211 Kuopio, Finland.

[Carl R]

will this be for acutes only? Am I right in concluding that this drug will minimize the damage or does it go further than that?

[Wise Young]

Carl R,

Yes, the recent reports concerning spinal cord injury involve early administration of the drug within 24 hours and they may well act by protecting cells against progressive tissue damage. However, some data suggest that it may do more than protect cells. It may also enhance regeneration.

Minocycline has been reported to inhibit metalloproteases which may prevent the formation of extracellular matric proteins that stop axonal growth. It has also been reported to prevent apoptosis in brain by blocking caspase 1 and 3, two critical molecules associated with programmed cell death in the spina cord. Minocyline was approved in 1996 for use in arthritis. It has anti-inflammatory effect and also seems to stimulate tissue repair.

Wise.