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Review
. 2017 May;12(5):702-713.
doi: 10.4103/1673-5374.206633.

Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury

Robert B Shultz  1 , Yinghui Zhong  1
Affiliations
Review

Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury

Robert B Shultz et al. Neural Regen Res. 2017 May.

Abstract

Minocycline hydrochloride (MH), a semi-synthetic tetracycline derivative, is a clinically available antibiotic and anti-inflammatory drug that also exhibits potent neuroprotective activities. It has been shown to target multiple secondary injury mechanisms in spinal cord injury, via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. The secondary injury mechanisms that MH can potentially target include inflammation, free radicals and oxidative stress, glutamate excitotoxicity, calcium influx, mitochondrial dysfunction, ischemia, hemorrhage, and edema. This review discusses the potential mechanisms of the multifaceted actions of MH. Its anti-inflammatory and neuroprotective effects are partially achieved through conserved mechanisms such as modulation of p38 mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways as well as inhibition of matrix metalloproteinases (MMPs). Additionally, MH can directly inhibit calcium influx through the N-methyl-D-aspartate (NMDA) receptors, mitochondrial calcium uptake, poly(ADP-ribose) polymerase-1 (PARP-1) enzymatic activity, and iron toxicity. It can also directly scavenge free radicals. Because it can target many secondary injury mechanisms, MH treatment holds great promise for reducing tissue damage and promoting functional recovery following spinal cord injury.

Keywords: P38 MAPK; PI3K/Akt; anti-oxidant; calcium influx; cytochrome c; glutamate exitotoxicity; inflammation; minocycline; neuroprotection; oxidative stress.

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Conflict of interest statement

Conflicts of interest: The authors declare no financial conflicts of interest.

Figures

Figure 1
Figure 1
Inflammatory pathways involved in the anti-inflammatory action of MH. Red x indicates direct inhibitory effect of MH. Purple x indicates that it is uncertain whether the inhibitory effect of MH is direct or indirect or both. 5-LOX: 5-Lipoxygenase; AP-1: activator protein 1; ATF2: activating transcription factor 2; COX2: cyclooxygenase-2; cPLA2: cytosolic phospholipases A2; IL-1β: interleukin-1β; iNOS: inducible nitric oxide synthase; LITAF: lipopolysaccharide-induced tumor necrosis factor-alpha factor; MCP-1: monocyte-chemoattractant protein-1; MH: minocycline hydrochloride; NADPH: nicotinamide adenine dinucleotide phosphate; NF-κB: nuclear factor kappaB; Nur77: nerve growth factor IB; p38 MAPK: p38 mitogen-activated protein kinases; PI3K: phosphoinositide 3-kinase; proNGF: proNerve Growth Factor; ROS: reactive oxygen species; TNFα: tumor necrosis factor α; sPLA2: secretory phospholipases A2.
Figure 2
Figure 2
Chemical structure of minocycline hydrochloride (MH). The blue box indicates metal ion chelating sites, the red box indicates the site with direct anti-oxidative activity, and the green box indicates the site with poly(ADP-ribose) polymerase-1 (PARP-1) inhibitory activity.
Figure 3
Figure 3
MH inhibits glutamate excitotoxicity in neurons. Red x indicates direct inhibitory effect of MH. Purple x indicates that it is uncertain whether the inhibitory effect of MH is direct or indirect or both. AIF: Apoptosis inducing factor; cPLA2: cytosolic phospholipases A2; CytC: cytochrome c; MH: minocycline hydrochloride; mPTP: mitochondrial permeability transition pore; NMDA: N-methyl-D-aspartate; p38 MAPK: p38 mitogen-activated protein kinases; PARP-1: poly(ADP-ribose) polymerase-1; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species.
See this image and copyright information in PMC

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