Additional Table 1.
Preclinical studies using minocycline
| Study | Rigor | Species, Sex, Weight, Age | Model, Controls | Dose, time to first dose, | Outcomes |
|---|---|---|---|---|---|
| Sanchez-Meija, 2001 | Randomization, yes; Blinded, NS | Mouse, Age NS, Sex NS | Moderate CCI, sham-CCI | 45 mg/kg, 12hpre-injury 90 mg/kg 30 min 12hand 24hpost-injury 90 mg/kg, 30 min 12hand 24hpost-injury |
1 d Rotarod ↑ 4 d Rotarod ↑ 4 h IL-1β ↑ 4 d LV ↑ 1dCaspase-1,3 ↑ |
| Sheng, 2006 | Randomization, yes; Blinded, yes | Rat, Male, 200-250g | Moderate CCI, sham-CHI-saline | Pretreatment 45/mg/kg twice daily 2dand 1d, once 30 minutes; posttreatment 1H, twice daily 1d, 2d | 1 d LV ↑ 4 d LV → 1-14 d NSS → 4–5 d Inclined plane ↑ 7 d LV ↑ 7 d CA1 neurons ↑ |
| Bye, 2007 | Randomization, NS; Blinded, NS | Mouse, Male, 12–14 weeks | Moderate CHI, Sham-CHI | 45 mg/kg 30 min PI, 45 mg/kg every 12huntil sacrifice | 1–4 d NSS → 1 d Beam test ↑ 1 d LV ↑ 4 d LV → 4 d Apoptosis → 4 d MP/MG ↑ 4 d Neutrophils → 4hCytokines (IL-1b, IL-6, G-CSF, MCP-1, CXCL4) ↑ |
| Homsi 2009 | Randomization, NS; Blinded, NS | Mouse, Male, 28–30 g | Moderate WD, sham-WD-saline, WD-saline | 45 mg/kg 5 min | 6 h IL-1b → 6 h MMP-9 → |
| Mouse, Male, 28–30 g | 90 mg/kg 5 min | 6 h IL-1b ↑ MMP-9 ↑ |
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| Mouse, Male, 28–30 g | 45 or 90mg/kg 5 min, 45 mg/kg 3h | 6 h GSH → | |||
| Mouse, Male, 28–30 g | 90 mg/kg 5 min, 45 mg/kg 3, 9 h | 1 d Edema → 1 d MMP-9 ↑ 1 d String test ↑ |
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| Abdel-Baki, 2009 | Randomization, NS; Blinded, NS | Rat, Male,250–300g | Moderate CCI, Sham-CCI | 45mg/kg 1h, 1d, 2d | 7 d APA entrances ↑, 12 d APA Time to first entrance → 14 d Myelin ↑ |
| Homsi,2010 | Randomization, yes; Blinded, yes | Mouse, Male, 28–30 g | Moderate WD, WD-saline | 90mg/kg 5 min, 45mg/kg 3 and 9h | 1 d MG ↑ 1 d LV ↑ 2–84 d Open field ↑ 2–84dBody weight ↑ |
| Sioppi,2011 | Randomization, yes; Blinding, NS | Mouse, Male, 28–30 g | Moderate WD, Naïve, WD-vehicle | 90mg/kg 5min, 45mg/kg 3h, 9h | 1 d sAAPa ↑ 84 d Corpus callosum volume ↑ 84 d Thalamus volume ↑ 84 d Lateral ventricle volume ↑ 84 d GFAP ↑ 84 d MP/MG ↑ |
| Sioppi,2012 | Randomization, NS; Blinding, Yes | Mouse, Male, 28–30 g | Moderate WD, Naïve, WD-vehicle | 90mg/kg 5min, 45mg/kg 3h, 9h | 7–84 d Odorant avoidance ↑ 84 d Olfactory bulb surface area ↑ 21–91 d NORT ↑ 21–91 d Elevated plus maze → 21–91 d Elevated zero maze → |
| Ng, 2012 | Randomization, Yes Blinding, Yes |
Mouse, Sex, NS, 28–34g | Moderate WD, Sham,WD-vehicle | 45mg/kg 30m, 45mg/kg every 12 h for 7d | 3–42 d NSS ↑ 7 d MP/MG ↑ 7 d Neurogenesis → |
| Kosvedi, 2012 | Randomization, NS; Blinding, NS | Rat, Male,245–265g | Mild Blast, Sham-Blast, saline, Sham-Blast-MINO, Blast-saline | 50 mg/kg 1h, 1–4d. | 9 d Elevated plus maze → 46 d Elevated plus maze → 10 d BM → 47 d BM → 51 d C-reactive peptide ↑ 51 d CCL2 ↑ 51 d Claudin 5 ↑ 51 d neuronal specific enolase ↑ 51 d Neurofilament heavy chain ↑ 51 d Tau ↑ 51 d S100B ↑ 51 d GFAP ↑ 51 d Corticosteroid ↑ 51dVascular endothelial growth factor receptor 2 ↑, |
| Haber,2013 | Randomization, NS; Blinding, NS | Rat,250–300g | Moderate CCI, sham-CHI-saline, CCI-saline, | 45mg/kg 1h, 1d, 2d | 7 d Conflict active place avoidance ↑ 7 d Spaced active place avoidance → 2 d MG activation ↑ |
| Lam, 2013 | Randomization, NS; Blinding, yes | Rat | Moderate CCI, CCI- vehicle | 25 mg/kg 1-7 d | 7–168dMP/MG ↑ 7 d GFAP ↑ 12 d GFAP → 168dGFAP ↑ 168dLV → 56 d Vermicelli handling → 56 d Thigmotaxis ↑ 56 d MWM ↑ |
| Vonder Haar, 2014 | Randomization, yes; Blinding, NS | Rat, Male, 350 g | Moderate CCI, Sham-CCI, CCI-vehicle | 50 mg/kg 1h, every 12h for 3d | 7–16 d Grid walk ↑ 7 d Rotarod → 15 d MWM → 25 d LV ↑ |
| Lopez-Rodriguez, 2015 | Randomization, yes; Blinding, yes | Mouse, Male, 28–30 g | Moderate WD, Naive | 90mg/kg 5min, 45mg/kg 3h, 9h | 1 d Edema ↑ 1 d NSS → 1 d MP/MG ↑ 1 d b-APP ↑ |
| Shochat, 2015 | Randomization, NS; Blinding, NS | Mouse, Male, 40 g | Mild WD | 45 mg/kg 20min | 1 h Oxyhemoglobin ↑ 1 h Total hemoglobin ↑ 1 h Arterial oxygen saturation ↑ 1 h Edema ↑ |
| Hanlon, 2017 | Randomization, yes; Blinding, yes | Rat, Male and Female, 11d | Moderate CCI, Sham-CCI, CCI plus vehicle | 45mg/kg 5min, every 12 h for 3d | 3 d MP/MG ↑ 7 d MP/MG → 3 d Cortical Fluorojade positive cells ↑ 7 d Cortical Fluorojade positive cells → 13 d MWM → |
| Chhor, 2017 | Randomization, yes; Blinding, yes | Mouse, MaleandFemale, 4–5g | Mild WD, Sham-WD saline, WD-saline | 45 mg/kg 5min, 1d, 2d | 1 d Inflammatory cytokines ↑ 1 d Ventricular volume ↑ 5 d Ventricular volume → 1 d Apoptosis cortex, hippocampus, striatum ↑ 1 d MP/MG ↑ 5 d LV → 5 d Myelin → |
| Haber,2018 | Randomization, yes; Blinding, no | Rat,Male,250–300g | Moderate CCI, Sham-CCI, CCI-saline | 45mg/kg 1h, 1d, 2d | 14 d Myelin 14 d ↑ 14 d Oligodendrocytes 14–4d ↑ 14 d Oligodendrocyte apoptosis ↑ 4 d MP/MG activation ↑ 7 d MP/MG activation ↑ |
| Sangobowale,2018a | Randomization, yes; Blinded, yes | Rat, Male,250–300g | Moderate CCI, Sham-CCI, CCI-saline | 22.5mg/kg 6h, 1 d and 2 d | 7 d BM ↑ 7 d APA, Entrances ↑ 7 d APA Time to first entrance → 14 d Hippocampal MAP2 → 14 d Myelin ↑ |
| 22.5mg/kg 12h, 1 d and 2 d | 7 d BM ↑ 7 d APA Entrances ↑ 7 d APA Time to first entrance → |
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| 22.5mg/kg 1d, 2 d and 3 d | 7 d BM ↑ 7 d APA, Entrances → 7 d APA Time to first entrance → 14 d Hippocampal MAP2 → 14 d Myelin → |
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| Mouse, Male, 28–30 g | Moderate CHI, Sham-CHI, CHI-saline | 22.5mg/kg 12 h, 1 d, 2 d | 7 d BM ↑ 7 d APA Entrances ↑ 7 d APA Time to first entrance → 14 d Hippocampal MAP2 → 14 d Myelin ↑ |
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| 22.5mg/kg 1 d, 2 d, 3 d | 7 d 12–24 h, BM ↑ 7 d 24 h APA, Entrances → 7 d 24 h APA, Time to first entrance → 14 d Hippocampal MAP2 14 d → 14 d Myelin → |
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| Sangobowale,2018b | Randomization, yes; Blinded, yes | Mouse, Male, 28–30 g | Moderate CHI, Sham-CHI, CHI-saline | 22.5 mg/kg 12h, 1d, 2d | 14 d Oligodendrocytes ↑ |
| Simon, 2018 | Randomization, yes; Blinded, NS | Rat, 35–40 g | Moderate CCI, Sham-CCI, CCI-saline | 90 mg/kg 10 min and 20 h | 1 d High mobility group B1 ↑ 7 d MP/MG ↑ 7 dFluorJade positive cells → 14 d Thalamic neurons ↑ 14 d LV → 5 d Balance Beam, Inclined Plane ↑ 14 d MWM ↑ |
| Taylor, 2018 | Randomization, yes; Blinded, NS | Rat, MaleandFemale, 60–70d | Moderate CCI, Sham-CCI saline, Sham-CCI MINO, CCI-saline | 50 mg/kg 1h1d, 2d, 3d | IL-1β35 d male →, female → IL-6 35 d male →, female → TNFα35dmale →, female → |
| Zhang, 2020 | Randomization, NS; Blinded, NS | Rat , Male, 150–180g | Moderate CCI Sham-CCI saline, CCI-saline | 10 mg/kg 12hand daily 2–7d | 5–14dBody weight → 7–14dFoot fault → 7–14dCylinder test → 7–14dWire hang → 21 d MWM → |
| 20 mg/kg 12hand daily 2–7d | 5–14 d Body weight 20 mg/kg → 7–14 d Foot fault ↑ 7–14dCylinder test ↑ 7–14 d Wire hang → 21 d MWM ↑ 7 d Hippocampal neurons ↑ 7 d Cortical Nissl postive cells ↑ 7dSerum iron ↑ 7dCSF iron ↑ 7 d Brain tissue iron ↑ 7 d Ferritin ↑ 7 d Transferrin receptor 1 ↑ 7 d Divalent metal transporter 1 ↑ 7 d Ferroportin 1 ↑ 7 d Hepcidin ↑ |
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| 40 mg/kg 12hand daily 2–7d | 5–14dBody weight 40mg/kg ↑ 7–14dFoot fault ↑ 7–14dCylinder test ↑ 7–14 d Wire hang → 21 d MWM ↑ |
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| Pernici, 2020 | Randomization, yes; Blinded, yes Randomization, NS; Blinded, NS |
Mouse,MaleandFemale, 20–30g | Mild FPI. Sham-FPI, FPI-saline | 45 mg/kg 45min 2d, 3d | 2–7 d NSS ↑ 2–7 d Rotarod → 60 d NORT → 60 d Open field → 60 d Tail suspension → |
| 30 d Axon loss ↑ | |||||
| 45 mg/kg 3 d, 4 d or 5 d | 2–7 d NSS → 2–7 d Rotarod → 60 d NORT → 60 d Open field → 60 d Tail suspension → 30 d Axon loss → |
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| He, 2021 | Randomization, yes; Blinded, NS | Rat, Male,250–300g | Moderate CCI, Sham-CCI, CCI-saline | 40mg/kg 5 minprior to injury | 3 d Cortical apoptosis ↑ 3 d Bax ↑ 3 d Cleaved caspase 3 ↑ 3 d Bcl-2 ↑ |
| Wang, 2021 | Mouse, Male, 20–35 g | Moderate CCI, Sham-CCI | 20mg/kg 30 min, 1d, 2d, 3d | 3dGarcia neurobehavioral score ↑ 1 d Edema ↑ 1 d Occuldin 1 ↑ 1 d C/EBP homologous protein ↑ 1 d Growth related protein73 ↑ 1 d b-catenin ↑ 3 d IL-6 ↑ 3 d TNFa ↑ 3 d Apoptosis ↑ |
Rigor for each study is provided followed by species, injury model plus severity and control groups and details of dosing of MINO. Time after injury is followed by whether MINO improved (↑) or had no difference (→) in the experimental outcome. APA: Active place avoidance; BM: Barnes maze; CCI: controlled cortical injury; CHI: closed head injury; FPI: fluid percussion injury; GFAP: glial fibrillary acid protein; GSH: glutathione; LV: lesion volume; MMP-9: matrix metaloprotease 9; MP/MG: macrophage/microglia; MWM: Morris water maze; NORT: novel object recognition; NS: not specified; NSS: neurological severity score; NSS: neurological severity score; WD: weight drop.