Table 1.
Studies of immunomodulatory therapies for treatment of perinatal inflammation-induced brain injury
| Reference | Species, n | Insult | Treatment and dose | Treatment timing | Temp (T) | Sex | Pathological outcomes | Functional outcomes | Assessment time | Protective |
|---|---|---|---|---|---|---|---|---|---|---|
| Anti-fungal | ||||||||||
|
[61]
|
Fetal sheep 0.8 GA | C. albicans i.a | Fluconazole 30 mg, i.a | 2 d after insult | – | – |
↑ Iba-1 staining and ↓CNPase in white matter ↑ GFAP and Iba-1 staining in hippocampus in C.alb + flu (n = 5–6) vs. C.alb + veh (n = 6) |
– | 3 and 5 d | No |
| Corticosteroids | ||||||||||
|
[54]
|
Rat pups, P5 | LPS, 1 μg, i.c | Dexamethasone, 0.5 mg/kg, i.p., | 1 h before insult | – | – |
↓Microglial activation ↑Myelination in dex + LPS vs. veh + LPS (ns = not reported) |
↑Memory and sensory motor function in dex + LPS vs veh + LPS (ns = not reported) | 1, 3, and 9 d | Yes |
|
[54]
|
Rat pups, P5 | LPS, 1 μg, i.c | Betamethasone, 0.5 mg/kg, i.p., | 1 h before insult | – | – | ↓Microglial activation ↑Myelination in beta + LPS vs veh + LPS (ns = not reported) | ↑Memory and sensory motor function in beta + LPS vs veh + LPS (ns = not reported) | 1, 3, and 9 d | Yes |
|
[63]
|
Rat pups, P7 | HI, CAL, 8% O2, 2 h, | Dexamethasone, 0.5–0.1 mg/kg, i.p., daily | Days 3–1 before insult | Ambient T: 37 ℃ during HI | M | ↑Cell death DEX + HI vs. veh + HI (ns = not reported) | – | 1 d | No |
|
[62]
|
Rat pups, P7 | HI, CAL, 8% O2, 120–150 min |
Dexamethasone 1–30 µg, i.n |
2 h after insult | – | M + F | No improvement in infarct size HI + DEX (n = 8–14) vs. HI + veh (n = 8–17) | – | 2 d | No |
|
[62]
|
Rat pups, P7 | HI, CAL, 8% O2, 120–150 min | Hydrocortisone, 30 µg, ICV | 2 h after insult | – | M + F | ↓Infarct size HI + HCZ (n = 10) vs. HI + veh (n = 11) | – | 2 d | Yes |
|
[62]
|
Rat pups, P7 | HI, CAL, 8% O2, 120–150 min | Hydrocortisone, 50 µg, 100 µg, 300 µg, i.n., | 2 h after insult | – | M + F | ↓Infarct size with 300 µg in ♂ HI + HCZ (n = 10–17) vs. HI + veh (n = 17) | – | 2 d | Yes |
|
[62]
|
Rat pups, P7 | LPS i.p. + HI (CAL, 8% O2, 120–150 min) | Hydrocortisone, 300 µg, 1000 µg, i.n | 2 h after insult | – | M + F | ↓Infarct size with 300 µg HI + HCZ (n = 18) vs. HI + veh (n = 23) | – | 2 d | Yes |
|
[43]
|
Fetal sheep, 0.7 GA | Umbilical cord occlusion, 25 min | Maternal dexamethasone, 12 mg, i.m | 15 min after insult | – | M + F |
↓NeuN + cells in the hippocampus and striatum ↓Oligodendrocytes in PVWM HI + DEX (n = 10) vs. HI + veh (n = 10) |
↑ Proportion of slow wave seizure-like activity | 1 wk | No |
|
[44]
|
Fetal sheep, 0.7 GA | Umbilical cord occlusion, 25 min | Maternal dexamethasone, 12 mg, i.m | 4 h before insult | – | M + F | ↑White and grey matter tissue loss dex + HI (n = 7) vs veh + HI (n = 9) | ↑Seizures | 1 wk | No |
|
[64]
|
Newborn lambs 0.8 GA, | High tidal volume mechanical ventilation | Maternal betamethasone × 2 11.2 mg, i.m. 24 h apart | 2 and 1 d before insult | Core T: 38–39 ℃ | M + F |
↑ Iba-1 and GFAP in white matter ↑ vascular extravasation ↑ CSF oxidative stress BM + vent (n = 7) vs. saline + vent (n = 5) |
– | 1 h 25 min | No |
| Inter-Alpha Inhibitor Proteins | ||||||||||
|
[65]
|
Rat pups, P7 | HI, CAL, 8% O2, 90 min, | Inter-alpha inhibitor protein, 30 mg/kg, i.p | Immediately, then 1 and 2 d after insult | Ambient T: 36 ℃ during HI | M + F | ↓Infarct volume, ↓cell death in the cortex and ↑myelin density in corpus callosum and internal capsule in males; HI + IAPS (n = 43) vs HI + veh (n = 39) | – | 3 d | Yes |
|
[65]
|
Rat pups, P7 | HI, CAL, 8% O2, 90 min, | Inter-alpha inhibitor protein, 30 mg/kg, i.p | 6 h, then 1, and 2 d after insult | Ambient T: 36 ℃ during HI | M + F | No improvement in pathological score HI + IAPS (n = 35) vs HI + veh (n = 33) groups | – | 3 d | No |
|
[66]
|
Rat pups, P7 | HI, CAO, 8% O2, 120 min | Inter-alpha inhibitor protein, 30 mg/kg, i.p | 1 and 25 h after insult | Core T: 36 ℃ during HI | M | – | ↑Working memory in juveniles HI + IAPS (n = 13) vs HI + veh (n = 10) | 81 d | Yes |
|
[66]
|
Rat pups, P7 | HI, CAO, 8% O2, 120 min | Inter-alpha inhibitor protein, 30 mg/kg, i.p | 1 and 25 h after insult | Core T: 36 ℃ during HI | M | – | No improvement in working memory in adolescents HI + IAPS (n = 10) vs HI + veh (n = 12) | 102 d | No |
| Complement inhibitors | ||||||||||
|
[67]
|
Rat pups, P10 | HI, CAL, 8% O2, 45 min | RLS-0071, 2 doses of 10 mg/kg, 4 h apart, i.p | 1 h after insult | Ambient T: 37 ℃ |
M + F, Ns not reported |
No improvement in cortical infarct area No improvement in lesion volume or tissue oedema HI + RLS-0071 (n = 9) vs HI + veh (n = 9) |
No improvement in cognition OR motor function HI + RLS-0071 (n = n = 4–7) vs HI + veh (n = 3–18) |
Pathology: 2 d MRI: 1 and 3 d Cognition: 6 wks |
No |
|
[67]
|
Rat pups, P10 | HI, CAL, 8% O2, 45 min, n = 9 | RLS-0071, 2 doses of 10 mg/kg, 4 h apart, i.p. AND hypothermia, n = 9 | 1 h after insult | Core T: 28–30 °C |
M + F, Ns not reported |
↓Cortical infarct area ↓Lesion volume HI + RLS-0071 + HT (n = 10) vs. HI + veh + HT (n = 9) |
↑Cognition HI + RLS-0071 + HT (n = 12) vs. HI + veh + HT (n = 20) No improvement in motor function |
Pathology: 2 d MRI: 1 d Cognition: 6 wks |
Yes |
| TLR7 agonist | ||||||||||
|
[41]
|
Fetal sheep, 0.7 GA | Umbilical cord occlusion, 25 min | GDQ, 1.8 mg/kg, ICV | 1 h after insult | Not reported | M + F |
↑Olig2, ↓Caspase-3 ↓GFAP ↑Neurons in caudate nucleus, dentate gyrus and thalamus UCO + GDQ (n = 7) vs. UCO + veh (n = 9) |
– | 3 d | Yes |
|
[42]
|
Fetal sheep, 0.7 GA | Umbilical cord occlusion, 25 min, | GDQ, 1 mg/kg, ICV | 1 h after insult | Not reported | M + F | ↓Neurons in striatum and hippocampus UCO + GDQ (n = 7) vs. UCO + veh (n = 7) | ↑Epileptiform discharges UCO + GDQ (n = 7) vs. UCO + veh (n = 7) | 1 wk | No |
| Antibiotics | ||||||||||
|
[58]
|
Mouse pups, P4 | S. epidermidis, i.p. + HI, | Vancomycin, 15 mg/kg, i.p | 2 min after insult | Core T monitored throughout | M + F | ↓ % tissue loss in cortical and deep grey matter and white matter S.epi + HI + Van (n = 11) vs. S.epi + HI + veh (n = 9) | – | 9 d | Yes |
|
[58]
|
Mouse pups, P4 | S. epidermidis, i.p. + HI | Vancomycin, 15 mg/kg, i.p, + pentoxifylline 40 mg/kg, i.p | 2 min after insult | Core T monitored throughout | M + F | No improvement in % tissue loss in cortical and deep grey matter or white matter S.epi + HI + Van + PTX (n = 9) vs. S.epi + HI + Van + veh (n = 9) | – | 9 d | No |
|
[68]
|
Rat pups, P7 | HI, CAL, 8% O2 60 min | Doxycycline, 10 mg/kg, i.p., | 1 h after insult | Ambient 36 ± 0.5 °C during hypoxia | M + F | ↓Lesion size and ↓neuronal loss in HI + doxy (n = 8) vs HI + veh (n = 8) | – | 42 d | Yes |
[57]
|
Rat pups, P11 | S. pneumonia, i.c., | Ceftriaxone, 100 mg/kg, i.p. + daptomycin, 10 mg/kg/, s.c, | 18 h after insult | Ambient T: 22 ± 2 °C | M + F |
↓ Cortical necrosis, no difference in hippocampal apoptosis S.pne + CRO + DAP (n = 18) vs. S.pne + CRO (n = 12) |
– | 42 h | Yes |
|
[57]
|
Rat pups, P11 | S. pneumonia, i.c | Ceftriaxone, 100 mg/kg, i.p. + Trocade (MMP inhibitor), 2 × 75 mg/kg/d, i.p | 18 h after insult | Ambient T: 22 ± 2 °C | M + F | ↓Hippocampal apoptosis, no difference in cortical necrosis S.pne + CRO + TRO (n = 19) vs. S.pne + CRO (n = 12) | – | 42 h | Yes |
|
[57]
|
Rat pups, P11 | S. pneumonia, i.c | Ceftriaxone, 100 mg/kg, i.p. + daptomycin, 10 mg/kg, s.c. + Trocade (MMP inhibitor), 2 × 75 mg/kg/d, i.p | 18 h after insult | Ambient T: 22 ± 2 °C | M + F |
↓Hippocampal apoptosis ↓Cortical necrosis ↓CSF IL-1β, TNF, IL-6, and IL-10 in the CSF S.pne + CRO + DAP + TRO (n = 35) vs. S.pne + CRO (n = 12) |
– | 42 h | Yes |
|
[57]
|
Rat pups, P11 | S. pneumoniae, i.c | Ceftriaxone, 100 mg/kg, i.p | 18 h after insult | Ambient T: 22 ± 2 °C | M + F | – | ↓Learning and memory S.pne + CRO (n = 14) vs. S.pne + veh (n = 20) | 3 wks | No |
|
[57]
|
Rat pups, P11 | S. pneumonia, i.c | Ceftriaxone, 100 mg/kg, i.p. + daptomycin, 10 mg/kg, s.c. + Trocade (MMP9 inhibitor) 2 × 75 mg/kg/d, i.p | 18 h after insult | Ambient T: 22 ± 2 °C | M + F | – | ↑Learning and memory S.pne + CRO + DAP + TRO (n = 15) vs. S.pne + CRO (n = 14) | 3 wks | Yes |
| NF-κB inhibitors | ||||||||||
|
[59]
|
Rat pups, P7 | LPS, 0.3 mg/kg i.p. + HI 4 h later (CAL, 10%, 90 min) | Tat-NBD peptide, 1.4 mg/kg, i.n., | 10 min after insult | Ambient T: 37–38 °C during hypoxia |
M + F, Ns not reported |
↓% tissue loss in the cortex, hippocampus, and striatum LPS + HI + Tat-NBD (n = 10) vs LPS + HI + veh (n = 10) | – | 1 wk | Yes |
|
[59]
|
Rat pups, P7 | LPS, 0.3 mg/kg i.p. + HI 72 h later (CAL, 10% O2, 90 min) | Tat-NBD peptide, 1.4 mg/kg, i.n | 10 min after insult | Ambient T: 37–38 °C during hypoxia |
M + F, Ns not reported |
↓% tissue loss in the cortex, hippocampus, and striatum LPS + HI + Tat-NBD (n = 10) vs LPS + HI + veh (n = 10) | – | 1 wk | Yes |
|
[59]
|
Rat pups, P7 | HI, CAL, 10% O2, 90 min | Tat-NBD peptide, 1.4 mg/kg, i.n | 10 min after insult | Ambient T: 37–38 °C during hypoxia |
M + F, Ns not reported |
No improvement in % tissue loss or MMP9 activity between HI + Tat-NBD (n = 4–10) vs. HI + veh (n = 4–10) | – | 1 wk | No |
| Fingolimod | ||||||||||
|
[47]
|
Fetal rats E17 | Maternal LPS, 1 mg/kg, i.p | Maternal FTY720, 4 mg/kg, i.p | 30 min after insult | – | – |
↓IL-6, ↓Caspase-3 and ↓S100B + cells in white matter LPS + FTY720 (n = 29) vs. LPS + veh (n = 20) |
– | 6 h | Yes |
|
[48]
|
Fetal rats, E17 | Maternal LPS, 1 mg/kg, i.p., | Maternal FTY720, 1 mg/kg, i.p | Immediately after insult | Ambient T: of 21–22 °C | – | ↓S100β, ↓IL-6 and ↓IL-10 in the cortex LPS + FTY720 (n = 4) vs. LPS + veh (n = 4) | – | 4 h | Yes |
|
[70]
|
Mouse pups, P9 | HI, CAL, 10% O2, 1 h | FTY720, 1 mg/kg, i.p | 20 min after insult | Core T maintained during hypoxia | M + F |
↑Tissue loss in cortex ↑Brain injury score in cortex and hippocampus ↓ MAP2 and MBP protein expression HI + FTY720 (n = 14) vs. HI + veh (n = 14) |
– | 1 wk | No |
|
[37]
|
Rat pups, P10 | Hypoxia, 5% O2, 15 min | FTY720, 0.3 mg/kg, i.p | 45 min after HI, then daily for 11 d | – | M + F | ↓TNF in the hippocampus HI + FTY720 (n = 13) vs. HI + veh (n = 16) |
↓Seizures ↓Anxiety-like behaviour and ↑Memory HI + FTY720 (n = 12) vs. HI + veh (n = 16–26) |
7 wks | Yes |
| GSK3β inhibitor | ||||||||||
|
[71]
|
Mouse pups, P9 | HI, CAL, 10% O2, 20 min |
SB216763, 10 mg/kg, i.p |
14 h and immediately before, then immediately and 3 h after insult | Ambient T: 36 °C during hypoxia | – |
↓Caspase-3 in the cortex and hippocampus at 6 h ↓TNFα, IL-6 mRNA and STAT3 in cortex and hippocampus at 6 h ↓% tissue loss at 7 d in SB216763 + HI (n = 8) vs veh + HI (n = 8) |
– | 6 h and 1 wk | Yes |
| Innate defence regulator proteins | ||||||||||
|
[60]
|
Mouse pups, P9 | LPS, 0.3 mg/kg + HI CAL, 10% O2, 20 min | Innate defence regulator protein (IDR)-1018, 8 µg/g, i.p | 3 h after insult | – |
M + F, Ns not reported |
↓ % White and grey matter tissue loss ↓ Injury scores in hippocampus, striatum, and thalamus LPS + HI + IDR1018 (n = 11) vs. LPS + HI + veh (n = 9) |
– | 1 wk | Yes |
| Lipoxin A4 | ||||||||||
|
[72]
|
Rat pups, P7 | HI, CAL, 8% O2, 2.5 h | LXA4 10 mg/kg, ICV | 1 h after insult | Ambient T: 37.5 °C during HI |
M + F, Ns not reported |
↓% brain infarct area ↓Brain TNF and IL-6 protein HI + LXA4, (n = 3) vs. HI + veh (n = 3) |
↑Motor function and cognition HI + LXA4 (n = 8) vs. HI + veh (n = 8) |
Pathology: 1 day Function: 3 wks |
Yes |
| Cytokine IL-35 targeted therapies | ||||||||||
|
[73]
|
Rat pups, P7 | HI, CAO, 8% O2, 2 h | IL-35, 20 μg/g, i.v | Immediately and 1 d after insult | Ambient T: 37 ℃ during HI | – |
↓Infarct volume ↓IL1β and TNFA mRNA in the cortex ↑Arg1, CD206, and YM-1 gene expression in the cortex of HI + IL-35 (n = 6) vs. HI + veh (n = 6) |
↓Neurological deficit score HI + IL-35 (n = 8) vs. HI + veh (n = 8) | 2 d | Yes |
| Melanocortin receptor 1 agonists | ||||||||||
|
[74]
|
Rat pups, P10 | HI, CAL, 8% O2, 2.5 h | BMS-470539, 50 μg/kg OR 160 μg/kg, OR 500 μg/kg, i.n., | 1 h after insult | Ambient T: 37 ℃ during HI | – | ↓% Infarct area HI + BMS470539 (160 and 500 μg/kg groups, n = 6/group) vs. HI + veh (n = 6) | ↑Sensory motor function HI + BMS470539 (160 and 500 μg/kg groups, n = 6/group) vs. HI + veh (n = 6) | 2 d | Yes |
|
[74]
|
Rat pups, P10 | HI, CAL, 8% O2, 2.5 h | BMS-470539, 160 μg/kg, i.n., | 1 h after insult | Ambient T: 37 ℃ during HI | – | ↓ % tissue loss HI + BMS470539 (n = 8) vs. HI + veh (n = 8) | ↑Sensory motor function HI + BMS470539 (n = 8) vs. HI + veh (n = 8) | 4 wks | Yes |
| COX2 inhibitors | ||||||||||
|
[45]
|
Piglets, P1 | Spontaneous IUGR | Ibuprofen, 20 mg/kg 24 h and 10 mg/kg on days 2 and 3, oral | 1, 2 and 3 d after insult | – | M + F |
↓IBA1 and GFAP + cells in IGWM and SCWM ↑Myelination ↑Neuron survival in cortex IUGR + ibu (n = 6) vs. IUGR + veh (n = 6) |
– | 3 d | Yes |
|
[75]
|
Rat pups, P3 | HI, CAO, 6% O2, 30 min | Ibuprofen, 100 mg/kg, s.c., and 50 mg/kg every 24 h | 2 h after insult | Ambient T: 37 ℃ during HI | – |
↓IBA + activation and IL-1β in frontal cortex and thalamus in HI + ibu (n = 8) vs HI + veh (n = 7) |
– | 1 wk | Yes |
|
[53]
|
Rat pups, P5 | LPS, 2 mg/kg, i.p | Celecoxib, 20 mg/kg, i.p | 5 min after insult | Core T: 29.4–33.1 ℃ |
M + F, Ns not reported |
↑Survival of progenitor OLs in the cingulum ↓Apoptosis, ↓IBA1 and GFAP + cells in cingulum and cortex LPS + Cel (n = 8) vs. LPS + veh (n = 8) |
↑ Motor function LPS + Cel (n = 8) vs. LPS + veh (n = 8) | 1 d | Yes |
| Colony stimulating factors | ||||||||||
|
[76]
|
Rat pups, P10 | HI, Right CAL, 8% O2, 2.5 h | Granulocyte stimulating factor (G-CSF), 50 µg/kg, i.p | 1 h after insult | Ambient T: 37 °C during HI |
M + F, Ns not reported |
↑Blood brain barrier integrity ↓NF- κB in whole brain HI + GCSF (n = 6) vs. vs. HI + veh (n = 6) |
– | 2 d | Yes |
|
[77]
|
Rat pups, P10 | HI, CAL, 8% O2, 2.5 h | Colony stimulating factor-1 (CSF-1), 80 μg/kg, i.n., | 1 and 24 h after insult | Core T: 37 °C during HI | – |
↓%Infarct area ↓Brain oedema HI + CSF-1 (n = 4) vs. HI + veh (n = 4) |
– | 2 d | Yes |
|
[77]
|
Rat pups, P10 | HI, Right CAL, 8% O2, 2.5 h | CSF-1, 80 μg/kg, i.n | 1 and 24 h after insult | Core T: 37 °C during HI | – | ↓Tissue loss HI + CSF-1 (n = 8) vs. HI + veh (n = 8) | ↑Sensorimotor function and ↑cognition HI + CSF-1(n = 6) vs. HI + veh (n = 6) | 4 wks | Yes |
| Cytokine TNF-targeted therapies | ||||||||||
|
[52]
|
Rat pups, P3 | LPS, 2 mg/kg, i.p | Etanercept, 5 mg/kg, i.p | Immediately after insult | Ambient T: 22 °C |
M + F, Ns not reported |
↑NG2 and O4 + cells and MBP ↓TUNEL and IBA1 + cells in cingulum LPS + etan (n = 6) vs. LPS + veh (n = 6) |
– | 1 d | Yes |
|
[56]
|
Fetal sheep, 0.7 GA | i.v. LPS infusion + i.v. LPS boluses at 2, 3, and 4 d | Etanercept, 2 doses, 5 mg/kg infused over 30 min, 48 h apart, i.v | Immediately after insult | – | M + F | ↓Iba1, GFAP, and TNF + cells and ↑ % mature oligodendrocytes in white matter LPS + etan (n = 8) vs. LPS + veh (n = 8) | ↑EEG power in LPS + etan (n = 8) vs. LPS + veh (n = 8) | 10 d | Yes |
|
[40]
|
Fetal sheep, 0.7 GA | Umbilical cord occlusion, 25 min, | Etanercept, 1 mg, ICV | 3 d after insult | – | M + F |
↑ Olig2 and CC1 + cells ↑ MBP density in white matter HI + etan (n = 9) vs. HI + veh (n = 9) |
– | 3 wks | Yes |
| Cytokine IL-1-targeted therapies | ||||||||||
|
[49]
|
Fetal mice, E15 | Maternal LPS, 200 μg, i.u | Anakinra, 10 mg/kg, maternal i.p | 30 min before insult | – | – |
↑Phos-nNOS ↑NMDA R1mRNA in the cortex LPS + IL-1Ra v LPS + veh (ns not reported) |
– | 4–6 h | Yes |
|
[46]
|
Fetal mice, E16 | Maternal IL-1β, 1 μg, i.u | Anakinra, 4 mg/kg, maternal s.c | 30 min before insult | – | M + F | ↓Microvascular degeneration vs. control in cortex, cingulum and hippocampus IL-1Ra + IL-1β (n = 8) vs veh + IL-1β (n = 8) | ↑Visual evoked potentials IL-1Ra + IL-1β (n = 6) vs veh + IL-1β (n = 6) | Pathology: 15 d Function: 30 d | Yes |
|
[46]
|
Fetal mice, E16 | Maternal IL-1β, 1 μg, i.u., | 101.10, 1 mg/kg, maternal s.c | 30 min before insult | – | M + F | ↓ Cortical microvascular degeneration vs. control in cortex, cingulum and hippocampus IL-1Ra + IL-1β (n = 8) vs veh + IL-1β (n = 8) | Visual evoked potentials 101.10 + IL-1β (n = 6) vs veh + IL-1β (n = 6) | Pathology: 15 d Function: 30 d | Yes |
|
[50]
|
Fetal rats, E20 | Maternal LPS, 200 μg, i.p | Anakinra, 10 mg/kg, every 12 h from P1-9 | Immediately after insult | – | M + F |
↑Myelin density in the internal capsule ↑DCX + cells in hippocampal dentate gyrus ↓IBA1 + cells in CC and cingulum LPS + IL-1Ra (n = 10–13) vs LPS + veh (n = 10–13) |
↑Motor function ↓Anxiety-like behaviour in LPS + IL-1Ra (n = 10–13) vs LPS + veh (n = 10–13) |
40 d | Yes |
|
[50]
|
Rat pups, P1 | HI, CAL, 8% O2, 3.5 h | Anakinra, 10 mg/kg, every 12 h from P1-9 | Immediately after insult | Ambient T: 37 °C during HI | M + F |
↑Myelin density in the internal capsule ↑DCX + cells in hippocampal dentate gyrus ↓IBA1 + cells in CC and cingulum HI + IL-1Ra (n = 12–16) vs HI + veh (n = 12–16) |
↑Motor function and ↓Anxiety-like behaviour in HI + IL-1Ra (n = 12–16) vs HI + veh (n = 12–16) |
40 d | Yes |
|
[50]
|
Fetal rats, E20, | Maternal LPS, 200 μg, i.p., + HI, CAL, 8% O2, 3.5 h | Anakinra, 10 mg/kg, every 12 h from P1-9 | Immediately after insult | Ambient T: 37 °C during HI | M + F |
No improvement in myelin density in the internal capsule ↑DCX + cells in hippocampal dentate gyrus in LPS + HI + IL-1Ra (n = 10–13) vs LPS + HI + veh (n = 10–13) |
↑Motor function and ↓Anxiety-like behaviour in LPS + HI + IL-1Ra (n = 10–13) vs LPS + HI + veh (n = 10–13) | 40 d | Yes |
|
[51]
|
Rat pups, P3 | LPS, 16 µg/µL, i.c | Anakinra, 2 mg/kg, i.p | 5 min, then 6 and 22 h after insult | – | M |
↓Hippocampal markers of neuronal integrity, excitatory amino acids, and membrane integrity LPS + veh (n = 16) vs. sham (n = 17) ↓ AD in corpus callosum and cingulum LPS vs. sham. ↓Fractin in corpus callosum and cingulum LPS + veh (n = 16) vs. sham (n = 17). No differences between LPS + IL-1Ra (n = 15) and sham |
– | 1 d | Yes |
|
[39]
|
Fetal sheep, 0.85 GA | HI, bilateral CAO, 30 min | Anti- IL-1β monoclonal antibody, 7.7 mg/kg, i.v | 15 min and 4 h after insult | – | – | ↑Anti IL-1β mAb in brain parenchyma HI + IL-1β mAb (n = 5) vs. HI + veh (n = 5) | – | 1 d | Yes |
|
[38]
|
Fetal sheep, 0.85 GA | HI, bilateral CAO, 30 min | Anti- IL-1β monoclonal antibody, 5.1 mg/kg, i.v | 15 min after insult | – | – |
↓ ApopTag in non-neuronal cells ↓Caspase-3 activity ↓Global pathology score in the cortex of HI + IL-1β mAb (n = 10–12) vs. HI + veh (n = 10–14) |
– | 1 d | Yes |
|
[55]
|
Fetal sheep, 0.85 GA | LPS, 400 µg, 800 µg, and 1200 µg, i.v | Anakinra, 13 mg/kg, i.v, | 1 h after insult | – | M + F |
↑Olig2 + cells ↓Caspase + cells ↓IBA1 + cells in white matter of LPS + IL-1Ra (n = 9) vs. LPS + veh (n = 8) |
↑EEG power LPS + IL-1Ra (n = 9) vs. LPS + veh (n = 8) | 4 d | Yes |
