Summary of preclinical and clinical trial studies on seven promising adjunct neuroprotective agents
| Adjunct therapy | Mode of action | Examples of recent preclinical trials | Clinical RCTs |
|---|---|---|---|
| Melatonin | Endogenous hormone which entrains the circadian rhythm at physiological doses. At high pharmacological doses melatonin is a powerful antioxidant and antiapoptotic agent. | Systematic review and meta-analysis of 400 adult rodents showed a 43% reduction in stroke infarct size with melatonin.74 A piglet study showed augmentation of brain protection with high dose melatonin at 10 min and cooling versus cooling alone.75 | Oral melatonin (10 mg/kg/day 5 doses) tablets crushed in 5 mL distilled water. n=15 cooled, n=15 cooled plus melatonin, n=15 controls.76 |
| Erythropoietin (Epo) | Acute actions: neurotrophic, anti-inflammatory, antiapoptotic, antioxidant Chronic actions: erythropoiesis, angiogenesis, oligodendrogenesis, neurogenesis. | Non-human primate model—hypothermia+Epo treatment improved outcomes in non-human primates exposed to umbilical cord occlusion.77 | NEAT trial—safety and PK.78 Phase II trial of hypothermia and Epo showed less MRI injury and better short-term outcome.79 Phase III trial is now underway in the USA. |
| Xenon | Inhibits NMDA signalling, antiapoptotic. | Preclinical piglet studies showed benefit of combined cooling and xenon compared with no treatment.80 81 | No evidence of short-term benefit with xenon and cooling above cooling alone, using MRS lactate/NAA as a surrogate outcome.82 |
| Argon | GABA agonist and oxygen type properties. Antiapoptotic. | Preclinical piglet study showed brain protection on MRS and histology with 50% argon and cooling compared with cooling alone.83 | Phase II trials pending regulatory approval. |
| Allopurinol | Reduces free radical production and in high doses acts as a free radical scavenger and free iron chelator. | Improved 31P MRS metabolites and MRI values with allopurinol in piglets.84 | ALBINO trial to start in Europe 2017—to assess benefit of early allopurinol at 30 min plus cooling versus cooling alone. |
| Stem cells | Paracrine signalling—not cellular integration or direct proliferative effects. | Evidence of improved neurological outcome and reduced histological injury.85 | Autologous umbilical cord cells in HIE demonstrated feasibility.86 |
| Magnesium | Prevention of excitatory injury by stabilisation of neuronal membranes and blockade of excitatory neurotransmitters, for example, glutamate. | Magnesium alone has not been protective in piglet models of hypoxia.87 Combinations of magnesium with cooling has shown benefit.88 | Recent meta-analysis shows no evidence of benefit.88 A multicentre pilot RCT reported safety but no outcome data, larger RCT to follow89 |
HIE, hypoxic-ischaemic encephalopathy; GABA, gamma-aminobutyric acid; MRS, magnetic resonance spectroscopy; NAA, N-acetylasparate; NMDA, N-methyl-D-aspartate; PK, pharmacokinetics; RCT, randomised controlled trials.