Comparison of Brain Maturation among Species: An Example in Translational Research Suggesting the Possible Use of Bumetanide in Newborn

Using neurogenesis as a criterion, it has been shown that E18 and E21 rat brain match with week 8–9 and week 15–16 after fertilization in the human embryo, respectively (Bayer et al., 1993). But the timing of neurogenesis differs substantially across brain regions increasing the challenge to compare brain maturation between species. Moreover, most of the neuronal/astrocytic migration ends at 20 weeks of gestation (WG) in humans while this process is mainly observed between E19 and E21 in rats (Raedler et al., 1980). Other parameters such as functional measures could be used to evaluate postnatal development. As an example, the age at which the ability to move is achieved can be compared. Locomotion in the rat matures during the first few weeks after birth. Rat pups are able to ambulate through the use of their forelimbs, upper torso and head beginning around P3–P4. This ‘‘crawling’’ behavior peaks around P7 and disappears around P15. It is not until around P8–P10 that rat pups can stand with their abdomens completely off the floor. Around P12–P13, rat pups can walk while supporting their full weight, but the hindlimbs are typically rotated outward (Wood et al., 2003). In human infants, the last stage before walking around at 13 months of age typically involves intermittently placing one foot flat on the floor and creeping like a bear on hands and feet. Interestingly, an infant can bear his full weight (i.e., stand) while being held by her hands by 24–28 weeks and can walk while holding onto a piece of furniture by 48 weeks (Wood et al., 2003). The therapeutic need for neurological diseases requires the pursuit of research in this area by the development of new models of brain diseases as well as preclinical drug studies. Among them, the development of medicines for newborns has been identified as an urgent need for both preclinical and clinical research (Silverstein et al., 2008). This would lead to more translational studies on the developing brain. However, there are certain risks involved in this translation from animal models to humans such as the effect on brain maturation, safety, and co-morbidity. Interpretation of results of preclinical drug studies requires a knowledge of brain maturation among species in particular when the efficacy or the safety of a drug may be different. Moreover, the risk benefit ratio of a drug in development should also be considered in the interpretation of translational studies. The use of animal models in experimental studies has led to a dramatic increase in our knowledge. Rodents are the most frequently used species in both experimental and translational studies. In the field of developmental neuroscience several differences between human and laboratory rodent brain maturation are well recognized, but determining the exact equivalences in developmental milestones between species is a multidimensional task and a single answer is not always possible. To put experimental data into clinical context, brain maturation among species is compared using various criteria such as cerebral growth, neurogenesis, synaptogenesis, and other variables (Table 1). These comparisons are done to propose translational Using several criteria, some authors have suggested a 12–13-day-old rat pup cerebral cortex can be compared to a term human newborn (Romijn et al., 1991). Reviewing these data on brain development, we think that the recent data published by Wang and Kriegstein (2011) don’t provide any argument against the use of bumetanide in the human neonate. Wang and Kriegstein used different protocols of bumetanide administration in four different age groups showing that the early life blocking Na+-K+-2Cl− co-transporter (NKCC1) with bumetanide disrupts the balance of excitatory and inhibitory synapses in the cortex of adult mice. These effects were shown in two of the treated groups. These groups received daily systemic injections of 0.2 mg/kg of bumetanide from the 15th day of gestation (E15) to the 7th postnatal day (P7) or from E17 to P7. Interestingly, no difference in the synapse excitability was observed when the mice became adult in the two other groups which were treated with bumetanide after birth (P0-P7 and P7-P14). The altered neurotransmission in adult mice that were exposed to bumetanide early in life (E15-P7 and E17-P7) was correlated with modifications of neuron morphology as well as behavior modifications. Behavior studies were conducted in adult mice from the E15-P7 group. Long-term consequences were observed such as developmental delay and impairment in sensorimotor gating. Similar findings were observed with other antiepileptic drugs (Forcelli et al., 2012a,b). Bumetanide is a loop diuretic with a rapid onset and short duration of action blocking the renal NKCC1 co-transporter. Comparison of brain maturation among species: an example in translational research suggesting the possible use of bumetanide in newborn