Assessing Creatine Supplementation for Neuroprotection against Perinatal Hypoxic-Ischaemic Encephalopathy: A Systematic Review of Perinatal and Adult Pre-Clinical Studies

Abstract

There is an important unmet need to develop interventions that improve outcomes of hypoxic-ischaemic encephalopathy (HIE). Creatine has emerged as a promising neuroprotective agent. Our objective was to systematically evaluate the preclinical animal studies that used creatine for perinatal neuroprotection, and to identify knowledge gaps that need to be addressed before creatine can be considered for pragmatic clinical trials for HIE. Methods: We reviewed preclinical studies up to 20 September 2021 using PubMed, EMBASE and OVID MEDLINE databases. The SYRCLE risk of bias assessment tool was utilized. Results: Seventeen studies were identified. Dietary creatine was the most common administration route. Cerebral creatine loading was age-dependent with near term/term-equivalent studies reporting higher increases in creatine/phosphocreatine compared to adolescent-adult equivalent studies. Most studies did not control for sex, study long-term histological and functional outcomes, or test creatine post-HI. None of the perinatal studies that suggested benefit directly controlled core body temperature (a known confounder) and many did not clearly state controlling for potential study bias. Conclusion: Creatine is a promising neuroprotective intervention for HIE. However, this systematic review reveals key knowledge gaps and improvements to preclinical studies that must be addressed before creatine can be trailed for neuroprotection of the human fetus/neonate.

Creatine supplementation reduces the cerebral oxidative and metabolic stress responses to acute in utero hypoxia in the late‐gestation fetal sheep

“…Creatine supplementation is proposed as a prophylactic treatment in pregnancy for preventing hypoxia‐mediated brain to the fetal brain during labour and birth (Ellery et al., 2016; Ireland et al., 2011; Muccini et al., 2021; Tran et al., 2021). Creatine in its phosphorylated form, phosphocreatine, acts physiologically in vertebrates as an ATP buffer through the creatine kinase circuit to maintain ATP‐dependent cellular metabolism (Wyss & Kaddurah‐Daouk, 2000).…”

The role of nutrients in human neurodevelopment and their potential to prevent neurodevelopmental adversity

“…In addition to the use of dietary creatine supplements to correct deficiencies, the capacity of creatine to maintain ATP turnover, acid-base balance, and mitochondrial function, along with its antioxidant, vasodilator, and anti-excitotoxic properties, make creatine a candidate for the treatment of ischemic-reperfusion brain injuries ( 125 ). Indeed, a 2021 systematic review by Tran et al ( 134 ) of pre-clinical (small animal and rodent) studies assessing creatine supplementation to protect the perinatal brain from hypoxic-ischemic encephalopathy concluded that creatine supplementation during pregnancy showed promise as a prophylactic therapy. Further studies in a large translational sheep model of fetal hypoxia-ischemia have detailed the benefits of high creatine concentration in the fetal circulation before hypoxia on reducing systemic hypoxaemia and interstitial cerebral pyruvate, lactate and reactive oxygen species accumulation in the 72 h after oxygen deprivation ( 135 – 137 ).…”

Back to the beginning: can we stop brain injury before it starts?

“…Furthermore, the extent of brain injury with prophylactic creatine treatment has not yet been assessed extensively in this or any other large animal translational model of perinatal hypoxia–ischaemia. Nevertheless, as recently reviewed (Tran et al., 2021), multiple preclinical rodent studies of perinatal hypoxic–ischaemic brain injury have shown neuroprotection with creatine supplementation. For example, maternal dietary creatine supplementation in spiny mice was associated with a profound reduction in apoptosis in the cortical subplate, piriform cortex and thalamus after birth asphyxia (Ireland et al., 2011).…”

“…Nevertheless, as recently reviewed (Tran et al, 2021), multiple preclinical rodent studies of perinatal hypoxic-ischaemic brain injury have shown neuroprotection with creatine supplementation. For example, maternal dietary creatine supplementation in spiny mice was associated with a profound reduction in apoptosis in the cortical subplate, piriform cortex and thalamus after birth asphyxia (Ireland et al, 2011).…”

“…For example, maternal dietary creatine supplementation in spiny mice was associated with a profound reduction in apoptosis in the cortical subplate, piriform cortex and thalamus after birth asphyxia (Ireland et al, 2011). Administration of creatine both before and after hypoxia-ischaemia in postnatal day 7 rats was also associated with a significant increase in cerebral hemisphere volume and reduced neuronal necrosis in the cortex and hippocampus (see Tran et al, 2021). An advantage of the proposed prophylactic creatine treatment strategy is that it might also protect other organs prone to injury after global hypoxia-ischaemia.…”