Nutraceuticals in the Prevention of Neonatal Hypoxia–Ischemia: A Comprehensive Review of their Neuroprotective Properties, Mechanisms of Action and Future Directions

Abstract

Neonatal hypoxia–ischemia (HI) is a brain injury caused by oxygen deprivation to the brain due to birth asphyxia or reduced cerebral blood perfusion, and it often leads to lifelong limiting sequelae such as cerebral palsy, seizures, or mental retardation. HI remains one of the leading causes of neonatal mortality and morbidity worldwide, and current therapies are limited. Hypothermia has been successful in reducing mortality and some disabilities, but it is only applied to a subset of newborns that meet strict inclusion criteria. Given the unpredictable nature of the obstetric complications that contribute to neonatal HI, prophylactic treatments that prevent, rather than rescue, HI brain injury are emerging as a therapeutic alternative. Nutraceuticals are natural compounds present in the diet or used as dietary supplements that have antioxidant, anti-inflammatory, or antiapoptotic properties. This review summarizes the preclinical in vivo studies, mostly conducted on rodent models, that have investigated the neuroprotective properties of nutraceuticals in preventing and reducing HI-induced brain damage and cognitive impairments. The natural products reviewed include polyphenols, omega-3 fatty acids, vitamins, plant-derived compounds (tanshinones, sulforaphane, and capsaicin), and endogenous compounds (melatonin, carnitine, creatine, and lactate). These nutraceuticals were administered before the damage occurred, either to the mothers as a dietary supplement during pregnancy and/or lactation or to the pups prior to HI induction. To date, very few of these nutritional interventions have been investigated in humans, but we refer to those that have been successful in reducing ischemic stroke in adults. Overall, there is a robust body of preclinical evidence that supports the neuroprotective properties of nutraceuticals, and these may represent a safe and inexpensive nutritional strategy for the prevention of neonatal HI encephalopathy.

Movement disorders in patients with Rett syndrome: A systematic review of evidence and associated clinical considerations

“…Neuroprotective agents could be other options to consider. Several candidates such as levetiracetam, melatonin, memantine, omega‐3, topiramate, and vitamin E have been examined for their neuroprotective potential 122,123 . Some of these have been shown to provide neuroprotection in different neurological disorders 122 .…”

“…Several candidates such as levetiracetam, melatonin, memantine, omega‐3, topiramate, and vitamin E have been examined for their neuroprotective potential. 122 , 123 Some of these have been shown to provide neuroprotection in different neurological disorders. 122 These candidate molecules could delay the progression of movement disorders in rare neurodevelopmental syndromes.…”

“… 122 , 123 Some of these have been shown to provide neuroprotection in different neurological disorders. 122 These candidate molecules could delay the progression of movement disorders in rare neurodevelopmental syndromes. Although some of these agents, such as memantine, might offer some promise in RTT, 124 there is at present no robust empirical evidence to suggest whether these molecules would offer any neuroprotective benefit for patients with RTT.…”

Nutrition and Immunity in Perinatal Hypoxic-Ischemic Injury

“…Examples of these can be seen in cytotoxic T cell immune responses to in utero infections such as with Human Immunodeficiency Virus [19], priming by in utero exposure to bacterial pathogens such as Staphylococcus and Lactobacillus [20], development of memory B cells in utero and in adaptations to physiologic and pathological hypoxia [21,22]. There is a fine balance between immune tolerance and the ability to mount a response to stressors such as infection and hypoxia and in this, nutrition plays an important multidirectional role (Figure 2, [18,[23][24][25][26][27]).…”

“…Prophylactic nutraceuticals, specifically those dietary compounds with antioxidant, anti-inflammatory or anti-apoptotic properties are being studied now in the context of PHI [27]. This is a difficult area for research as acute HIE cannot be predicted, so most of the work in this area is being undertaken in rodent models.…”