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

By Tiina M. Tikka, B. Fiebich, G. Goldsteins, R. Keinänen, J. Koistinaho. Journal of Neuroscience, 2001

977 citations recorded by the source corpus.

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-1β (IL-1β) 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-1β. Excitotoxins induced microglial proliferation and increased the release of NO metabolites and IL-1β 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.

Subfields: Computational Theory and Mathematics, Neurology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/411944922cc5dabe94d2b781db621e80071d298f

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Citations in the corpus

Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior (2012, background): “…production of IL-1 and NO, has been shown to inhibit p38 MAPK as well as poly(ADP-ribose) polymerase-1, which along with inhibition of NF-kB (see below), may serve as the basis for its anti-inflammatory efficacy (Tikka et al, 2001; Tikka and Koistinaho, 2001; Si et al, 2004; Alano et al, 2006).”
Microglia regulate the number of neural precursor cells in the developing cerebral cortex (2013, result): “We also tested the capacity of minocycline to deactivate microglia in the prenatal cerebral cortex, since previous work has shown that minocycline reduces the activation state of microglia (Yrjänheikki et al., 1998; Tikka et al., 2001; Ekdahl et al., 2003; Fan et al., 2007).”
Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. (2012, positive): “Minocycline is a potent anti-inflammatory drug that suppresses the production of several pro-inflammatory cytokines (Choi et al., 2005; Seabrook et al., 2006), and inhibits microglial-mediated neurotoxicity (Tikka et al., 2001).”
Inhibition of Microglial Activation Attenuates the Development but Not Existing Hypersensitivity in a Rat Model of Neuropathy (2003, background): “Minocycline has emerged as a potent inhibitor of microglial activation and has no direct action on astroglia or neurons (Amin et al., 1996; Tikka and Koistinaho, 2001; Tikka et al., 2001a,b).”
NMDA receptors with incomplete Mg2+ block enable low-frequency transmission through the cerebellar cortex (2012, methodology): “Parasagittal slices (300 M) were cut on a HM650V vibratome (Microm) in the following solution (in mM): 130 K-gluconate, 15 KCl, 2 EGTA, 20 HEPES, 25 glucose, 0.05 APV, and 0.00005 Minocycline to inhibit microglia and protect against focal ischemia (Tikka et al., 2001); pH adjusted to 7.4 by NaOH.”
Immune modulation of learning, memory, neural plasticity and neurogenesis. (2011, neutral): “This chain of inflammatory events results in a positive feedback loop that can lead to excitotoxicity (Tikka et al., 2001) and eventually even to apoptosis and neurodegeneration (Block and Hong, 2005).”
ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model (2005, background): “, 2003), possibly by suppressing p38 activation (Tikka et al., 2001).”
Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation (2005, background): “, 2002), and glutamate-induced neurotoxicity (Tikka and Koistinaho, 2001; Tikka et al., 2001).”
Selective Ablation of Proliferating Microglial Cells Exacerbates Ischemic Injury in the Brain (2007, background): “In addition, attenuation of brain inflammatory response and microglial activation has conferred neuroprotection in various models of neurodegeneration (Yrjanheikki et al., 1999; Tikka et al., 2001; Kriz et al., 2002, 2003).”
Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. (2008, positive): “Minocycline, a semisynthetic second-generation tetracycline with adequate penetration into the brain and cerebrospinal fluid [4, 14, 131], has emerged as a potent inhibitor of microglial activation and proliferation, without any known direct action on astrocytes or neurons [1, 116].”
The biphasic function of microglia in ischemic stroke (2017, positive): “Inhibition of microglia activation by minocycline treatment after MCAO reduced infarct volume, hemorrhagic transformation, and BBB permeability, partly via preventing the degradation of collagen IV and laminin (Machado et al., 2009; Tikka et al., 2001; Yenari et al., 2006).”
Blockade of Microglial Activation Is Neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson Disease (2002, methodology): “However, in light of what we know about how minocycline presumably mitigates cellular damage in a variety of experimental models (Tikka and Koistinaho, 2001; Tikka et al., 2001a), the aforementioned possibility appears unlikely.”
GLIA: A novel drug discovery target for clinical pain (2003, background): “Little information is available as to what neurotransmitters excite dorsal spinal cord glia to produce and release neuroactive substance”
Pathophysiology and pharmacologic treatment of acute spinal cord injury. (2004, background): “Minocycline, a tetracycline antibiotic, has been shown to inhibit excitotoxicity [123] and provide neuroprotection in models of Parkinson disease [124], autoimmune encephalomyelitis [125], amyotrophic lateral sclerosis [126] and adult and neonatal brain ischemia [125,127,128], most likely through it”