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

Abstract

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 M) significantly increased neuronal survival in mixed spinal cord (SC) cultures treated with 500 M glutamate or 100 M 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.

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.…”

Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats

“…Thus, the acute fever in the neonate is not responsible for the increased seizure susceptibility in adulthood. The anti-inflammatory properties of minocycline appears to stem from its ability to decrease cytokine release from microglial cells (Tikka et al, 2001), therefore it does not have a classic anti-pyretic role and did not influence the POLY I:C-induced fever. The magnitude of the fever evoked by the viral mimetic is similar to what has been reported by other immune stimulants like LPS, which is considered a mild immunological challenge relative to other pyretic agents.…”

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.…”