Table 2 Selected studies providing evidence for neuroprotective effects of antibiotics in rodent models of TBI

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