TABLE 1.

Summary of neuroprotective agents for neonatal brain injury in pre-clinical studies and in clinical trials.

Agent	Preclinical evidence	Clinical trials	Negative results
Cannabinoids	• Decreases inflammation, excitotoxicity, oxidative stress in the rat (Pazos et al., 2013). • In the mouse and piglet, reduced astroglia activation and tissue loss (Martínez-Orgado et al., 2007; Mohammed et al., 2016).	–	• In a piglet model.
Quercetin	• Decreases microglial, astroglial activation, apoptotic markers in the rat (Wu et al., 2019). • Increases oligodendrocytes proliferation. Improves spatial and memory learning and cognitive ability in the rat (Huang et al., 2012; Qu et al., 2014).	–	–
Pentoxifylline	• Decreases hippocampal atrophy, apoptotic markers, inflammation markers in the rat (Kalay et al., 2013). • Improves spatial learning and memory in the rat (Halis et al., 2019).	–	–
Oxymatrine	• Reduces infarct volume, apoptosis, and oxidative stress in the rat (Zhao et al., 2015; Liu et al., 2019). • Ameliorates morphology of injured hippocampal neurons in the rat (Zhao et al., 2015).	–	–
Resveratrol	• Decreases infarct volume, cerebral edoema, apoptosis, elevates anti-oxidative enzymes activity, reduces pro-inflammatory markers in the rat (Pan et al., 2016; Gao et al., 2018). • Reduces astrogliosis and improves behavioural outcomes (anxiety and neophobia) (Arteaga et al., 2015).	–	–
Pterostilbene	• Decreases infarct volume, apoptosis, and pro-inflammatory markers; improves motor coordination, working memory deficit in the rat (Li D. et al., 2016).	–	–
Erythropoietin	• Improves synaptogenesis, reduces apoptosis, improves spatial memory in the rat (Zhang L. et al., 2017; Huang et al., 2019; Xiong et al., 2019).	• Successful phase I, II, and III clinical trials completed as monotherapy application (Zhu et al., 2009; Elmahdy et al., 2010; Malla et al., 2017). • Active phase II clinical trial as augmentation with TH (Wu et al., 2016). • Active phaseIII clinical trial as augmentation with TH (Sheldon et al., 2017).	• In severe HI injury EPO worsens the outcome because it interferes with endogenous repair responses (Sheldon et al., 2017).
Allopurinol	• Decreases acute brain edoema and sub-acute brain atrophy in the rat (Palmer et al., 1993). • Decreases caspase-3 mediated apoptosis in the rat (Rodríguez-Fanjul et al., 2017).	• Successful postnatal clinical trials I–III as monotherapy (Gunes et al., 2007; Kaandorp et al., 2012). • Active postnatal phase III trial as augmentation with TH. • Successful phase III trial on antenatal administration (Kaandorp et al., 2015).	–
Indomethacin	• Reduced caspase mediated apoptosis, glutathione depletion, and lipid peroxidation in the rat (Taskin et al., 2009).	–	–
Topiramate	• The acute administration reduces histopathological brain injury and improves behavioural outcomes (Jiang et al., 2014; Landucci et al., 2018) in rodents. • Reduces infarct volume in augmentation with TH in the piglet (Noh et al., 2006).	• Successful safety phase I trial as monotherapy. • Successful phase I and II trials as augmentation with TH. • Active further augmentation phase I and II trials (Filippi et al., 2010).	–
Curcumin	• Decreased microglia, astroglia activation, cell death, and tissue loss if administered up to 2 h after HI insult in the mouse (Rocha-Ferreira et al., 2019). • Improved myelination and reduced iNOS levels in the mouse (Rocha-Ferreira et al., 2019). • Increased expression of nuclear factor erythroid-2-related factor 2 (Nrf2), attenuation of the increased expression of inducible NOS, and caspase-3 activity in the rat (Cui et al., 2017).	–	–
Melatonin	• If administered with TH, decreased tissue loss and improved learning in the Morris Water-Maze test in the rat (Carloni et al., 2014). • Reduction of cell death if administered in augmentation with TH in the piglet (Robertson et al., 2019, 2020). • If administrated with topiramate reduced infarct volume and cell death in the rat (Ozyener et al., 2012).	• Successful phase II augmentation trial with TH. • Active phase I augmentation trial with TH (NCT02621944).	• Only subtle neuroprotective effect but not long-term brain injury improvement in the rat (Berger et al., 2019). • No protection of neuronal mitochondria as shown by GABA-A and lactate levels (Berger et al., 2016).
Hydrogen	• Reduces cell death via reduction of caspase-3 and 12 activity, infarct volume, inflammation via AIF-1 expression reduction in the rat (Cai et al., 2008). • Improves spatial learning measured via Morris Water maze and locomotor activity in the rat (Wang et al., 2020) and piglet (Htun et al., 2019).	• Clinical study showed reduction of IL-6 and TNF-α cytokines (Domoki, 2020).	• Not associated with decreased infarct volume or decreased concentration of malondialdehyde (MDA), an end-product of lipid peroxidation in the rat (Matchett et al., 2009).
Magnesium	• If administered prior HI insult it reduces ROS production, IL-1α and IL-1β, and overall cell metabolism in the rat (Koning et al., 2019). • If administered in adjunction with melatonin, it reduces infarct volume of hippocampus and cell death in the rat (Cetinkaya et al., 2011). • If administered with TH reduces infarct volume of hippocampus, cell death and increases oligodendrocytes survival in hippocampus and thalamus in the piglet. • Inconsistent neuroprotection in rodent models.	• Clinical study showed lower incidence of cerebral palsy in infants (Doyle et al., 2009). • An open-label pilot study showed that combination of MgSO4, erythropoietin and TH was found to be safe (Nonomura et al., 2019).	• Not neuroprotective when administrated to rat after severe HI (Galinsky et al., 2014). • Post-injury treatment did not improve neural survival in striatum in rat (Galvin and Oorschot, 1998). • Post-HI treatment did not show any difference in the severity of damage on hippocampus, cerebellum, cerebral cortex, caudate nucleus, thalamus, and striatum and the white matter tracts in the piglet (Greenwood et al., 2000).
Coumestrol	• Pre-treatment prevents mitochondrial failure, improved spatial reference and working memory, reduced tissue loss and long-term astrogliosis in the rat (Anastacio et al., 2019).	–	–
Xenon	• Upregulaition of Bcl-2 and Bcl-xL improving apoptosis, reduction TNF-α and VEGF enhancing cell repair and reducing inflammation in the rat (Amer and Oorschot, 2018). • Improves motor function in the staircase test in the rat in augmentation with TH (Osredkar et al., 2014).	• Successful augmentation trial with TH in reducing apoptosis and cerebral abnormalities (Dingley et al., 2014). • Failed to show improvement compared to TH in moderate and severe cases (Azzopardi et al., 2013).	• Xenon combined with TH is not neuroprotective after severe HI in a P7 rat model since brain area loss and neuronal cell count were similar in all experimental groups (Sabir et al., 2016).
UCBs/MSCs	• Reduce iba-1, CD4+ T cells and improve locomotor activity measured with open field test, cylinder test, and negative geotaxis tests in the rat (Penny et al., 2019). • Reduced microglia, cell death, tissue loss in the mouse (Sisa et al., 2019b). • Prevention of cortical loss and function measured via EEG and reduced white matter injury in ewes (Ophelders et al., 2016).	• Small open label clinical study showed safety and feasibility as augmentation with TH (Tsuji et al., 2020).	–
Diabetes drugs	• Metformin reduced TNF-α, IL-1β, IL-18, microglia, astroglia activation, cell death, and tissue loss in the mouse (Fang et al., 2017). • Glibencalmide improves neuromotor activity in the rat (Zhou et al., 2009). • Liraglutide attenuated the infarct volume and cell oedema, decreased the inflammatory response at TNF-α levels, reduced tissue, neuronal loss, enhanced axonal repair, and accelerated remyelination (Zeng et al., 2020).	–	–
Osteopontin	• Increased cell proliferation, oligodendrogenesis; Decreases infarct volume, cell death; improves behavioural outcomes in the mouse (Van Velthoven et al., 2011), • Decrease infarct volume, reduced cell death and improve memory via MWM in the rat (Chen et al., 2011),	–	• TAT-OPN peptide did not exert neuroprotective effects on neonatal HI-induced brain injury or sensorimotor behavioural deficits in a mouse (Bonestroo et al., 2015b).
C-Jun N-terminal kinases	• Reduces neuronal loss, cell death, apoptosis in the mouse (Pirianov et al., 2007). • Enhances cognitive and sensorimotor function, reduces apoptosis, reduces brain infarct volume in the rat (Nijboer et al., 2013; Hao et al., 2016).	–	–
Edaravone	• Pre-treatment in the rat and the mouse down-regulates cell death, oxidative stress, apoptosis markers, lipid-peroxidation by-products (Yasuoka et al., 2004; Takizawa et al., 2009).	–	• Post-HI treatment is neuroprotective only to the acute phase after HI but not 5–10 days after insult in a rat (Takizawa et al., 2009). • Intravenous administration in combination with TH did not improve neurological outcomes in the newborn HI piglet as indicated by grey, white matter, and hippocampal brain damage (Yamato et al., 2020).
Granulocyte-colony stimulating factor	• Decreases cell death, tissue loss, apoptosis, inflammation in the mouse and rat (Yata et al., 2007; Dumbuya et al., 2020). • Improves long-term cognitive function and exploratory behaviour in the rat (Yang et al., 2013d).	–	–
Anti-inflammatory cytokines	• IL-10 increases cell survival and restores neurotransmission in neuronal cell cultures in ischaemic conditions (Tukhovskaya et al., 2014; Turovsky et al., 2017).