Table 1 Studies of immunomodulatory therapies for treatment of perinatal inflammation-induced brain injury

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