| Reference | Injury model, subjects, and survival time | Treatment groups, sample size, drug administration | Antibiotics treatment effects |
---|---|---|---|---|
Ceftriaxone | Ceftriaxone treatment preserves cortical inhibitory interneuron function via transient salvage of GLT-1 in a rat traumatic brain injury model [72]. | LFP model of TBI, Sprague-Dawley male rats, 12 wk-old, survival 1 wk and 6 wk | 1. TBI-saline 2. TBI-ceftriaxone (250 mg/kg), i.p. 30 min after TBI, then every 24 h for 7 d, n = 5–7/group | 1. Transiently increased GLT-1 protein and glutamate transporter gene (SLC1A2) expression 2. Prevention of cortical interneuron dysfunction |
Neuroprotective effect of ceftriaxone in a rat model of traumatic brain injury [73]. | WD model of TBI Sprague-Dawley male rats, 10–12 wk-old, survival 1 d, 3 d, and 5 d | 1. sham-saline, n = 30 2. TBI-saline, n = 60 3. TBI-ceftriaxone (200 mg/kg), n = 60, i.p. immediately after TBI, then every 24 h for 5 d | 1. Attenuated brain edema 2. Improved spatial learning and cognitive function 3. Increased hippocampal GLT-1 protein expression 4. Reduced neuronal autophagy in the hippocampus | |
The beta-lactam antibiotic, ceftriaxone, provides neuroprotective potential via anti-excitotoxicity and anti-inflammation response in a rat model of traumatic brain injury [74]. | WD model of TBI, Sprague-Dawley male rats, 180–220 g in size, survival 1 d, 2 d, 3 d, and 7 d | 1. Sham-saline, n = 18 2. TBI-saline, n = 27 3. TBI-ceftriaxone (200 mg/kg), n = 27, i.v. after TBI (single dose) | 1. Reduced spatial learning and memory deficits at 7 d after TBI 2. Attenuated cerebral edema at 1–3 d after TBI 3. Reduced levels of IL-1β, IFN-ɣ, and TNF-α expression in brain tissue at 1–3 d after TBI 4. Transient up-regulation of GLT-1 in brain tissue at 48 h | |
Ceftriaxone treatment after traumatic brain injury restores expression of the glutamate transporter, GLT-1, reduces regional gliosis, and reduces post-traumatic seizures in the rat [75]. | LFP model of TBI, Long-Evans male rats, 8–9 wk-old, survival 7 d | 1. Sham-saline 2. TBI-saline 3. TBI-ceftriaxone (200 mg/kg), i.p., first dose at 30 min after TBI then every 24 h for 7 d, n = 7/group | 1. Preservation of GLT-1 protein expression at 7 d after TBI 2. Attenuated astrogliosis in brain tissue (anti-GFAP) 3. Reduction in length and frequency of post TBI seizures | |
Trovafloxacib | Trovafloxacin attenuates neuro-inflammation and improves outcome after traumatic brain injury in mice [76]. | Controlled cortical impact (CCI), C57BL/6 male mice, 10 wk-old, survival 1 d and 6 d | 1. Sham 2. TBI-saline 3. TBI-trovafloxacin (60 mg/kg), i.p. at 1 h, 24 h, and 48 h after CCI, n = 8/group | 1. Improved locomotor recovery 2. Reduced levels of MMP9 and SBDPs protein from brain tissue 3. Attenuated BBB leakage 4. Reduced hematoma size 5. Partially reduced mRNA levels of pro-inflammatory cytokines from brain tissue 6. Attenuated mRNA expression of neuroinflammatory markers MPO, GFAP, Iba1, CD68 |
Minocycline (MINO) | Minocycline Attenuates High Mobility Group Box 1 Translocation, Microglial Activation, and Thalamic Neurodegeneration after Traumatic Brain Injury in Post-Natal Day 17 Rats [77]. | CCI model, Sprague-Dawley male rats, postnatal day 17, survival 7 and 14 d | 1. Sham (naïve) 2. CCI-saline 3. CCI-MINO (90 mg/kg) i.p., first dose at 10 min and second dose at 20 h, n = 3–11/group | 1. Reduced expression of the damage biomarker HMGB1 in the brain after 24 h 2. Reduced number of microglia (anti-Iba1) 3. Reduced neuronal cell death (Fluoro-Jade) 4. Inconclusive effects on motor function 5. Slightly improved spatial memory determined (Morris Water Maze) |
Sex Differences in Thermal, Stress, and Inflammatory Responses to Minocycline Administration in Rats with Traumatic Brain Injury [78] | CCI model, male and female rats, 8–10 wk-old, survival 35 d | 1. Sham-saline 2. Sham-MINO (50 mg/kg) 3. TBI-saline 4. TBI-MINO (50 mg/kg), i.p., first dose 1 h after CCI, then once daily for 3 d, n = 14–16/group | 1. Suppressed restraint stress-induced increase of plasma corticosterone 2. Inhibited CCI-induced hyperthermia 3. Increased IL-6 and IL-1β levels in the hippocampus of female rats but not in male rats | |
Acute minocycline administration reduces brain injury and improves long-term functional outcomes after delayed hypoxemia following traumatic brain injury [79] | CCI model with delayed hypoxemia, male and female C57BL/6J mice, 8 wk-old, survival 7 d and 6 mths | 1. sham 2. TBI-saline 3. TBI-MINO, i.p, 45 mg/kg, 90 mg/kg, 180 mg/kg in saline (dose finding study), first dose 22–25 h after CCI, repeated twice at 2 d and 3 d after CCI (pre-clinical study), n = 13–15/group | 1. 180 mg/kg MINO resulted in 80% mortality at 3 d after CCI, 45 mg/kg was ineffective 2. 90 mg/kg followed by 5 × 45 mg/kg MINO reduced hippocampal microglia activation and neurodegeneration 7 d after CCI 3. 90 mg/kg followed by 5 × 45 mg/kg MINO improved long-term fear memory responses and synapse density 6 mths after CCI No sex-specific differences were reported | |
Minocycline + N-acetylcyteine (MINO + NAC) | Minocycline plus N-acetylcysteine protect oligodendrocytes when first dosed 12 h after closed head injury in mice [80]. | Closed head injury (CHI), C57BL/6 male mice, 15–17 wk-old, survival 2 d, 4 d, 7 d, and 14 d | 1. Sham-saline 2. TBI-saline 3. TBI-NAC (75 mM) 4. TBI-MINO (22.5 mM) 5. TBI-MINO + NAC (22.5 mM + 75 mM), i.p. at 12 h, 24 h, and 48 h after CCI, no sample size provided | CHI-MINO + NAC resulted in; 1. Preservation of oligodendrocytes in the corpus callosum 2. Attenuated loss of CNPase and PLP in the corpus callosum |
Minocycline plus N-Acetylcysteine Reduce Behavioral Deficits and Improve Histology with a Clinically Useful Time Window [81]. | CHI, C57BL/6 male mice, 15–17 wk-old, CCI model, male rats (strain and age not specified), survival 14 d | 1. Sham-saline 2. TBI-saline 3. TBI-NAC (75 mM) 4. TBI-MINO (22.5 mM) 5. TBI MINO + NAC (22.5 mM + NAC 75 mM), i.p., first dose at 6 h, 12 h, or 24 h after CCI and the second and third dose at 2 d and 3 d after CHI, respectively, n = 4–11/group | 1. Improvement in spatial navigation, learning and memory (Barnes Maze, place avoidance test) 2. Improved preservation of neurons 3. improved preservation of myelin in the corpus callosum | |
Doxycycline (DOX) | Doxycycline alleviates acute traumatic brain injury by suppressing neuroinflammation and apoptosis in a mouse model [82]. | Weight-drop model of TBI, Swiss Albino male mice, 25–35 g, survival 72 h | 1. Sham-Saline 2. TBI-Saline 3. TBI-low dose DOX (10 mg/kg) 4. TBI-high dose DOX (100 mg/kg), i.p., first dose 30 min after TBI then every 8 h for 6 more doses, n = 5/group | 1. Dose-dependent reduction in brain edema and hemorrhage 2. Reduced expression of the T cell marker CD3 in brain tissue 3. Reduced number of microglia (anti-Iba-1) 4. Attenuated expression of the proinflammatory cytokine IL-6 in brain tissue 5. Attenuated neuronal and glial cell death (TUNEL assay) |
Doxycycline improves traumatic brain injury outcomes in a murine survival model [83] | CCI model, C57BL/6J mice, survival 6 d | 1. sham 2. TBI 3. TBI + DOX (20 mg/kg), i.v., first dose 2 h after CCI and then every 12 h until 6 d after CCI, n = 10–15/group | DOX improved neurological outcome, wire grip and ataxia scores | |
Doxycycline prevents blood-brain barrier dysfunction and microvascular hyperpermeability after traumatic brain injury [84] | CCI model, C57BL/6 mice (18–25 g), intravital microscopy at 10–70 min after TBI, n = 5–7/group | 1. Sham 2. TBI 3. TBI + DOX (20 mg/kg), i.v. 10 min after TBI | 1. DOX decreased BBB hyperpermeability 2. DOX inhibited MMP-9 enzyme activity |