Ketogenic Diet for Neonatal Hypoxic–Ischemic Encephalopathy

Abstract

The prevalence of neonatal hypoxic–ischemic encephalopathy (HIE), a devastating neurological injury, is increasing; thus, effective treatments and preventions are urgently needed. The underlying pathology of HIE remains unclear; recent research has focused on elucidating key features of the disease. A variety of diseases can be alleviated by consuming a ketogenic diet (KD) despite differences in pathogenesis and features, given the common mechanisms of KD-induced effects. Dietary modification is the most translatable, cost-efficient, and safest approach to treat acute or chronic neurological disorders and reduces reliance on pharmaceutical treatments. Evidence suggests that the KD can exert beneficial effects in animal models and in humans with brain injuries. The efficacy of the KD in preventing neuronal damage, motor alterations, and cognitive decline varies. Moreover, the KD may provide an alternative source of energy, enhance mitochondrial function, and reduce the expression of inflammatory and apoptotic mediators. Thus, this diet has attracted interest as a potential therapy for HIE. This review examined the role of the KD in HIE treatment and described the mechanisms by which ketone bodies (KBs) exert effects under pathological conditions and protect against brain damage; the evidence supports the implementation of dietary interventions as a therapeutic strategy for HIE. Future research should aim to elucidate the underlying mechanisms of the KD in patients with HIE and determine whether the effect of the KD on clinical outcomes can be reproduced in humans.

Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases

“…KBs attenuate apoptotic cell death by reducing mitochondrial ROS production, mPTP opening, and cytochrome C release in neurons isolated from rat brains [114,118]. KBs and KD may protect neurons from brain damage by improving mitochondrial function during acute cerebral ischemia and chronic neurological disorders, including AD and PD [45,83,120]. KBs have been reported to reduce glutamate-induced cell death and free radical formation by increasing NADH oxidation (resulting in elevated NAD + levels) and enhancing mitochondrial respiration in neocortical neurons [110].…”

Role of integrating cannabinoids and the endocannabinoid system in neonatal hypoxic-ischaemic encephalopathy

“…One of the major causes of impairment in newborns is neonatal hypoxic-ischaemic encephalopathy (HIE), which has serious long-term implications for child development ( Barata et al, 2019 ; Zhou et al, 2023 ). At present, the incidence of perinatal asphyxia ranges between 0.5–1% of all live births, and substantial neurologic damage occurs in as many as 50–75% of these children ( Torfs et al, 1990 ; Ferriero, 2004 ).…”

New Therapeutic Paradigms in Neonatal Hypoxic–Ischemic Encephalopathy

“…These include the supply of alternative sources of energy to glucose with normalization of aberrant cellular energy metabolism in the brain, the occurrence of an anticonvulsant action, a decrease of oxidative stress, inflammation and cellular apoptosis susceptibility, and the epigenetic upregulation of neurotrophic factors production. 4 Moreover, considering that in term neonates, for at least the first week of life, ketone bodies (KBs) production and metabolism are upregulated, and with these organic molecules providing about 10% of cerebral metabolic energy requirements, 4 it is conceivable that a further availability of KBs can potentiate the endogenous response to cerebral hypoxia−ischemia enhancing neuroprotection. 5 Of note, because TH and KBs may both act on the latent period of HIE damage, a synergistic effect of these therapeutic strategies is likely.…”

“…In an issue of ACS Chemical Neuroscience , in their recent review, Zhou et al suggest a therapeutic role of ketogenic diets (KDs) in neonatal HIE and discuss in detail the underlying main biochemical mechanisms likely involved. These include the supply of alternative sources of energy to glucose with normalization of aberrant cellular energy metabolism in the brain, the occurrence of an anticonvulsant action, a decrease of oxidative stress, inflammation and cellular apoptosis susceptibility, and the epigenetic upregulation of neurotrophic factors production .…”

“…In an issue of ACS Chemical Neuroscience , in their recent review, Zhou et al suggest a therapeutic role of ketogenic diets (KDs) in neonatal HIE and discuss in detail the underlying main biochemical mechanisms likely involved. These include the supply of alternative sources of energy to glucose with normalization of aberrant cellular energy metabolism in the brain, the occurrence of an anticonvulsant action, a decrease of oxidative stress, inflammation and cellular apoptosis susceptibility, and the epigenetic upregulation of neurotrophic factors production . Moreover, considering that in term neonates, for at least the first week of life, ketone bodies (KBs) production and metabolism are upregulated, and with these organic molecules providing about 10% of cerebral metabolic energy requirements, it is conceivable that a further availability of KBs can potentiate the endogenous response to cerebral hypoxia–ischemia enhancing neuroprotection .…”