Table 2.
Immunomodulatory therapeutic possibilities for perinatal brain injury
| Experimental insult and animal model | Intervention | Outcome |
|---|---|---|
| Corticosteroids (DEX) | ||
| HI, P7 rats | DEX given between P1 and P3 | Exacerbated brain damage, decreased glutamate reuptake; role of microglia not specifically addressed90 |
| HI, P7 rats | DEX given 24 h and 4 h before the insult | Neuroprotection, increased brain VEGF production; role of microglia not specifically addressed139 |
| HI + LPS, P7 rats | DEX given 24 h and 4 h before the insult | Neuroprotection and decreased CXCR4 receptor density140,141 |
| Minocycline | ||
| HI, P7 rats | Minocycline given either immediately before or after the insult | Marked neuroprotection; role of microglia not specifically addressed34 |
| HI, P8 mice | Minocycline given either immediately before or 12 h before the insult | Exacerbated brain damage; role of microglia not specifically addressed142 |
| Ibo, P5 mice | Repeated minocycline injections either before or after Ibo | Protection of GM and WM; reduced microglial density143 |
| LPS (intracerebral), P5 rats | Minocycline given for 3 days, starting 12 h before insults | Protection, reduced microglial activation144 |
| Hyperoxia, P6 rats | Minocycline given during exposure to hyperoxia | Protection, long-lasting reduction in microglial activation145 |
| Melatonin | ||
| Ibo, P5 mice | Melatonin administered immediately after Ibo | Reduced microglial density, beneficial effect on WM146 |
| Experimentally induced stroke, P7 rats | Melatonin given as either a single dose before ischaemia or a double-dose regimen, combining one before ischaemia and one 24 h after reperfusion | Improved myelination, no effect on infarct size, reduced microglial density147 |
| UAL, E18 rats (growth restriction model) | Melatonin given from P0 to P3 | Improved myelination, reduced microglial density148 |
| UCO, E92 sheep | Melatonin infused for 6 h after UCO | Reduced cell death, oxidative stress and microglial density149 |
| UCO, E130 sheep | Melatonin infused to the ewe for 2 h, before and after UCO | Protection, reduced microglial density150 |
| HI (βNTP at 40% baseline for 12.5 min), P0 piglets | Combined melatonin–hypothermia treatment | Neuroprotection, did not affect microglial density151 |
| EPO | ||
| HI, P3 rats | EPO given once a day during the first week after HI (P3 to P10) and then 3 times/week until P25 | Improved WM microstructure, no effect on cortex; role of inflammation not specifically addressed152 |
| HI, P7 rats | EPO was studied as an add-on to hypothermia | No overall protection by EPO or hypothermia, alone or in combination; role of microglia not specifically addressed153 |
| Stroke, P7 rats | EPO given at reperfusion, 24 h, and 7 days after stroke | Lasting decreased brain damage and improved function, neurogenesis enhanced; role of inflammation not specifically addressed154 |
| Ibo, P5 mice | Single dose of EPO 1 h after Ibo | Protection in GM and WM; role of inflammation not specifically addressed155 |
| UCO E165–172, macaques | EPO given on days 1, 2, 3, and 7 after UCO + hypothermia | Improved anisotropy and cognitive functions; role of inflammation not specifically addressed156 |
| Cyclooxygenase inhibitors | ||
| IL-1β P1–P5 and Ibo P5, mice | Nimesulide (COX-2) or indomethacin (COX-1+2) given in combination with IL-1β | Blockade of IL-1β-induced sensitization of brain injury and inflammatory response in the brain91 |
| IL-1β P1–P5 and Ibo P5, mice | Tianeptine given for 5 days before Ibo | Blockade of IL-1β-induced sensitization in GM and WM, no effect in absence of IL-1β; effect on microglia not specifically addressed157 |
| Pifithrin-μ | ||
| HI, P7 rats | Pifithrin-μ given after HI | Protection of GM and WM, reduced microglial density158 |
| Cromolyn | ||
| IL-9 P1-P5 and Ibo P5, mice | Cromoglycate given 1 h before Ibo | Blockade of IL-9-induced sensitization, protection in WM and GM, but no effect in the absence of IL-9; reduced MC density41 |
| HI, P7 rats | Cromoglycate given before and/or following HI | Neuroprotection, inhibition of microglial activation, and MC migration18,42 |
| Innate defence regulatory peptide | ||
| LPS and HI, P8–9 mice | Innate defence regulatory peptide 1018 given 3 h after HI | Reduced injury in WM and GM, microarray analysis demonstrated decrease in proinflammatory and cell-death-related pathways159 |
| NAC | ||
| Maternal LPS, E19, rat NAC | in drinking water from E17 to birth | Prevented oxidative stress and restored long-term potentiation in the hippocampus and spatial recognition performance (effects found only in males)160 |
| Newborn piglets, hypoxia | NAC given as bolus + 24 h infusion, started 5 min after reoxygenation | Attenuated caspase-3 and lipid hydroperoxide in the cortex, short (48 h) recovery period161 |
| HI, P7 rats | NAC, daily until sacrifice, hypothermia for 2 h post HI | Reduced brain infarct volume and improved behavioural outcome, assessed up to 4 weeks after HI162 |
| Intrauterine LPS, E28 rabbit | NAC administered in dendrimers as a single dose within 6 h after birth | D-NAC taken up by astroglia and microglia; reductions in motor deficits, oxidative injury, expression of proinflammatory genes, microglial activation, and loss of WM and GM163 |
| TNF receptor blockade (etanercept) | ||
| HI, P7 rats | Etanercept given immediately after HI | Etanercept detectable in the brain after intraperitoneal administration, reduced the neuroprotective effect of NF-κB inhibition164 |
| IL-1b + Ibo, P1–P5, mice | Etanercept given before or after Ibo | Reduced brain damage by 50%; protective only when given after combined insult165 |
| IL-1ra | ||
| HI, P7 rats | IL-1ra, intracerebroventricular, before or after HI | Improved brain wet weight, but neuropathology not assessed28 |
| LPS, P5 rats | Co-administration of IL-1ra with LPS | Improved myelination, reduction of lateral ventricle enlargement; neuroinflammation not investigated166 |
| HI, P7 rats | Intracerebroventricular injection of IL-1ra 2 h after HI | Reduced cell death and caspase 3 activity in the hippocampus and cortex; reduced NF-κB activity, iNOS and COX-2167 |
| LPS (E20–E22) + HI (P1), rats | IL-1ra treatment every 12 h from P1 to P9 | Normalized motor function, exploratory behaviour, and density of immature neurons and astrocytes29 |
| TAT-NBD | ||
| HI, P7 rats | TAT-NBD given up to 12 h after HI | Neuroprotection, including improved long-term motor and cognitive outcome when given within 6 h after HI; effect independent of cytokines168 |
| LPS + HI, P7 rats | Intranasal delivery of TAT-NBD 10 min after HI | Prevents brain injury after LPS + HI, blocks NF-κB signalling; not neuroprotective in HI alone169 |
| Simvastatin | ||
| HI, P7 rats | Pre-HI treatment | Neuroprotective, improved behaviour; effect on microglia not addressed; only male rats investigated170 |
| HI, P7, rats | Pre-HI treatment | Improved GM and WM injury, reduced microglial activation171 |
| PTB mice | Pravastatin or simvastatin given 24 h before and 2 h after LPS intravaginal administration | Protected cortical neurons in the fetus, protection mediated by Akt/PKB signalling pathways; effect on microglia not addressed172 |
| Histone deacetylase inhibitors (TSA, valproate) | ||
| Hippocampal Ibo, P7 rats | Injected daily from day after surgery until adulthood | Improved some behavioural characteristics, but not anxiety; did not protect against hippocampal lesions; neuroinflammation not specifically addressed173 |
| LPS + HI, P8–9 mice | TSA or valproate given at the same time as LPS | Valproate increased mortality; TSA reduced GM and WM injury and improved learning in the fear conditioning test in females, but did not affect number of microglia after injury174 |
| Unilateral carotid artery ligation, P12 rats | Treatment with valproate, TSA or vehicle for 2 weeks after insult | Both TSA and valproate increased neurogenesis, but valproate also increased mortality and impaired weight gain; neuroinflammation not specifically addressed175 |
Abbreviations: βNTP, β-nucleotide triphosphate; Akt/PKB, protein kinase B; COX, cyclooxygenase; DEX, dexamethasone; d-NAC, dendrimer NAC; E, embryonic day; EPO, erythropoietin; GM, grey matter; HI, hypoxia–ischaemia; Ibo, ibotenate; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; MC, mast cells; NAC, N-acetylcysteine; NF-κB, nuclear factor-κB; P, postnatal day; PTB, preterm birth; TAT-NBD, Tat-NEMO-binding domain; TSA, trichostatin A; UAL, uterine artery ligation; UCO, umbilical cord occlusion; VEGF, vascular endothelial growth factor; WM, white matter. Chemokines and their receptors are named and abbreviated according to the international classification.