Neonatal hypoxia-ischemia is a leading cause of neonatal death in both developed and developing countries. The consequences of hypoxic-ischemic injury affect the rest of the child’s life, often resulting in intellectual or motor disability that persists into adulthood. To date, therapeutic hypothermia (TH) appears to be the only available intervention aimed at limiting brain injury and is recognized as the “gold standard” in neonatal intensive care. The basic mechanisms of neuroprotection achieved by temporal cooling involve the reduction of free radical activity, suppression of the inflammatory response after reperfusion and increased neuronal cell survival. However, the protective effects of hypothermia need to be enhanced by additional therapies that can enhance neuroprotection and support neuroregenerative processes. The components derived from the umbilical cord are thought to confer the above-mentioned beneficial effects. This review summarizes the clinical trials based on stem cell transplantation or umbilical cord milking and presents their effects when supported by official data. The great promise associated with the application of stem cells to neonates suffering from perinatal asphyxia is discussed in the context of the results of their clinical use. Graphical abstract

A developing nervous system is particularly vulnerable to the influence of pathophysiological clues and injuries in the perinatal period. Astrocytes are among the first cells that react to insults against the nervous tissue, the presence of pathogens, misbalance of local tissue homeostasis, and a lack of oxygen and trophic support. Under this background, it remains uncertain if induced astrocyte activation, recognized as astrogliosis, is a friend or foe for progressing neonatal neurodevelopment. Likewise, the state of astrocyte reactivity is considered one of the key factors discriminating between either the initiation of endogenous reparative mechanisms compensating for aberrations in the structures and functions of nervous tissue or the triggering of neurodegeneration. The responses of activated cells are modulated by neighboring neural cells, which exhibit broad immunomodulatory and pro-regenerative properties by secreting a plethora of active compounds (including interleukins and chemokines, neurotrophins, reactive oxygen species, nitric oxide synthase and complement components), which are engaged in cell crosstalk in a paracrine manner. As the developing nervous system is extremely sensitive to the influence of signaling molecules, even subtle changes in the composition or concentration of the cellular secretome can have significant effects on the developing neonatal brain. Thus, modulating the activity of other types of cells and their interactions with overreactive astrocytes might be a promising strategy for controlling neonatal astrogliosis.

Despite significant progress in preclinical research aimed at developing effective therapies for the acute and long-term consequences of perinatal asphyxia, there is still a lack of clinical protocols to regenerate the neonatal brain damaged by hypoxic-ischemic (HI) injury. To date, only therapeutic hypothermia is routinely used in neonates who have experienced perinatal asphyxia. It has been shown to be effective only in limiting the spread of brain damage caused by a cascade of molecular and biochemical events triggered by limited blood supply to the body’s organs, including the fragile, developing brain. Ongoing clinical trials are exploring pharmacological approaches aimed at promoting neurogenesis and gliogenesis to repair damaged neural tissue, as well as modulating the neuroinflammation that results from the cellular response to HI injury. Among promising therapeutic agents, erythropoietin, and melatonin have emerged as major drugs with potential neuroprotective effects in neonatal hypoxic-ischemic encephalopathy. Erythropoietin is recognized for its anti-apoptotic, anti-oxidative, and anti-inflammatory properties, supporting neural cell survival and regeneration. Melatonin acts as a potent antioxidant and anti-inflammatory agent, helping to reduce oxidative stress and inflammation triggered by HI injury. As clinical trials on suffering neonates are highly demanding, the ethical and practical concerns of therapeutic approaches are discussed. An urgent need to develop a safe, feasible, and effective clinical approach to promote the restoration of appropriate neurodevelopment in the near future is highlighted. This review summarizes the clinical trials conducted to date, discusses their outcomes and limitations, and considers translational potential of the tested treatment strategies.