Minocycline Provides Neuroprotection AgainstN-Methyl-d-aspartate Neurotoxicity by Inhibiting Microglia

Abstract

Glutamate excitotoxicity to a large extent is mediated through activation of the N-methyl-d-aspartate (NMDA)-gated ion channels in several neurodegenerative diseases and ischemic stroke. Minocycline, a tetracycline derivative with antiinflammatory effects, inhibits IL-1β-converting enzyme and inducible nitric oxide synthase up-regulation in animal models of ischemic stroke and Huntington’s disease and is therapeutic in these disease animal models. Here we report that nanomolar concentrations of minocycline protect neurons in mixed spinal cord cultures against NMDA excitotoxicity. NMDA treatment alone induced microglial proliferation, which preceded neuronal death, and administration of extra microglial cells on top of these cultures enhanced the NMDA neurotoxicity. Minocycline inhibited all these responses to NMDA. Minocycline also prevented the NMDA-induced proliferation of microglial cells and the increased release of IL-1β and nitric oxide in pure microglia cultures. Finally, minocycline inhibited the NMDA-induced activation of p38 mitogen-activated protein kinase (MAPK) in microglial cells, and a specific p38 MAPK inhibitor, but not a p44/42 MAPK inhibitor, reduced the NMDA toxicity. Together, these results suggest that microglial activation contributes to NMDA excitotoxicity and that minocycline, a tetracycline derivative, represents a potential therapeutic agent for brain diseases.

Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

“…Consistent with previous observations [44,45], minocycline afforded cytoprotection to neuronal cultures under conditions of NMDA receptor-mediated excitotoxicity, although at a concentration range higher than that needed to block inflammation and inflammation-induced neuronal death [21]. In cultures pre-treated with minocycline, the NMDA-induced [Ca 2+ ] cyt rise was dramatically inhibited.…”

“…Our results suggest that minocycline, although at concentrations higher than those shown to block inflammation and inflammation-induced neuronal death [21], prevents NMDA-induced excitotoxicity by diminishing NMDA-induced Ca 2+ entry and altering the m via mitochondrial Ca 2+ uptake.…”

Microglial Activation in Stroke: Therapeutic Targets

“…106,108 Stimulation with either glutamate or with ionotropic glutamate receptor agonists induces microglial proliferation, morphological changes characteristic of microglial activation, and release of IL-1␤, TNF␣, NO, and ATP. 100,101,104,109 Conversely, activation of most mGluR types inhibits microglial inflammatory responses, 107,110 -112 with the exception that mGluR2 activation promotes microglial neurotoxicity. 106,107 Microglia expression of glutamate receptor subtypes in vivo has not been extensively characterized, but protein expression of mGluR1, mGLuR2/3, and mGluR8 has been reported in microglia surrounding human multiple sclerosis lesions, 113 and expression of ionotropic glutamate receptors has been detected in reactive microglia in damaged areas of the hippocampus following ischemia.…”

Do glial cells control pain?

“…However, it fails to inhibit muscle pain, a pain condition that does not show any glial activation (Ledeboer et al, 2006). Minocycline, a tetracycline antibiotic, has been used as a microglia inhibitor and shows efficacy in several neurodegenerative conditions (Tikka & Koistinaho, 2001;Yong et al, 2004). Spinal injection of minocycline via intrathecal route was shown to attenuate neuropathic pain at early times but not at late times, suggesting a unique role of microglia in the development of nerve injury-induced neuropathic pain (Ledeboer et al, 2005b;Raghavendra et al, 2003).…”