Despite improvements in viability, the long-term neurodevelopmental outcomes of 
preterm babies remain serious concern as a significant percentage of these 
infants develop neurological and/or intellectual impairment, and they are also 
at increased risk of psychiatric illnesses later in life. The current challenge 
is to develop neuroprotective approaches to improve adverse outcomes in preterm 
survivors. The purpose of this review was to provide an overview of the current 
evidence on pharmacological agents targeting the neuroprotection of the preterm 
brain. Among them, magnesium sulfate, given antenatally to pregnant women with 
imminent preterm birth before 30 to 34 weeks of gestation, as well as caffeine 
administered to preterm infants after birth, exhibited neuroprotective effects 
for human preterm brain. Erythropoietin treatment of preterm infants did not 
result in neuroprotection at 2 years of age in two out of three published large 
randomized controlled trials; however, long-term follow-up of these infants is 
needed to come to definite conclusions. Further studies are also required to 
assess whether melatonin, neurosteroids, inhaled nitric oxide, allopurinol, or 
dietary supplements (omega-3 fatty acids, choline, curcumin, etc.) could be 
implemented as neuroprotectants in clinical practice. Furthermore, other 
pharmacological agents showing promising signs of neuroprotective efficacy in 
preclinical studies (growth factors, hyaluronidase inhibitors or treatment, 
antidiabetic drugs, cannabidiol, histamine-H3 receptor antagonists, etc.), as 
well as stem cell- or exosomal-based therapies and nanomedicine, may prove 
useful in the future as potential neuroprotective approaches for human preterm 
brain. KEY POINTS: · Magnesium and caffeine have neuroprotective effects for the 
preterm brain.. · Follow-up of infants treated with erythropoietin is needed.. · 
Neuroprotective efficacy of several drugs in animals needs to be shown in 
humans..