Development of Enzymes of Energy Metabolism in the Neonatal Mammalian Brain

Abstract

The metabolic capability for the complete oxidation of glucose, i.e. aerobic glycolysis, is highly developed in the brains of neurologically mature (precocial) species at birth, whereas this activity is severely limited in the brains of neurologically immature (non-precocial) species such as the rat and human. The latter utilize a mixture of glucose and ketone bodies for synthetic and energetic activities and the advent of neurological competence associated with the capability for complete dependence on and oxidation of glucose must await the development of key enzymes such as the pyruvate dehydrogenase complex (PDHC). A similar relationship appears to exist with respect to the development of neurological maturity of different brain regions in a single species, the rat. The development of the enzymes of energy metabolism of neonatal rat brain will be discussed with respect to the energy fuels available to the neonatal brain. In particular mechanisms by which the PDHC develops in neonatal brain will be evaluated. Evidence suggests that this is due to a specific increase in enzyme protein in contrast to a general increase in mitochondrial activity.

A Preferential Role for Glycolysis in Preventing the Anoxic Depolarization of Rat Hippocampal Area CA1 Pyramidal Cells

“…However, when mitochondria are inhibited, ATP production by glycolysis is increased, by the Pasteur effect, by a factor of 4 -5 because of increased activity of phosphofructokinase, hexokinase, and glucose transport (Lowry et al, 1964;Drewes and Gilboe, 1973;Depré et al, 1998), and thus there should be much more ATP production than is normally generated by glycolysis. Although P12 animals may rely less on oxidative phosphorylation than older animals and maintain membrane potentials and neuronal excitability through glycolysis alone (Clark et al, 1993;Nabetani et al, 1995), we found identical results in older (P28) rat slices when the oxidative phosphorylation system is mature; i.e., external glucose was sufficient to prevent the AD.…”

“…In case the protective effect of external glucose was caused by ATP production in the young (P12) animals used here being more dependent on glycolysis than is the case in older animals (Clark et al, 1993;Nabetani et al, 1995), we repeated this experiment in slices from P28 rats (in which enzymes of aerobic metabolism are at adult levels) (Clark et al, 1993). The same abolition of the AD by 10 mM glucose was obtained: in the absence of glucose, the latency to the AD in N 2 -bubbled solution containing rotenone, antimycin, and iodoacetate was ϳ4 min (230 Ϯ 8 s; n ϭ 7; i.e., approximately one-half of the latency seen in P12 slices), but in the presence of 10 mM glucose and in the absence of iodoacetate, no AD was seen for Ͼ1 h in six cells (recording time with no AD was 3 h for one cell and had a mean value of 4890 Ϯ 1230 s) (Fig.…”

“…6 D). In case this lack of effect of lactate was caused by ATP production in the young (P12) animals used here being more dependent on glycolysis than is the case in older animals (Clark et al, 1993;Nabetani et al, 1995), we repeated this experiment in slices from P28 rats (in which the enzymes of aerobic metabolism are at adult levels) (Clark et al, 1993). Again, neither 5 nor 20 mM lactate significantly delayed the AD (Fig.…”

Postnatal Development of the Complexes of the Electron Transport Chain in Isolated Rat Brain Mitochondria

“…The activity of the enzymes involved in the metabolism of glucose [3][4][5][6][7], ketone bodies [7,8], and fatty acids [9,10] have all been measured. These data in combination with measured arteriovenous differences in concentration of glucose, lactate and ketone bodies in vivo have demonstrated the fact that the neonatal brain unlike the adult brain is not solely dependant on glucose as its major source of energy, but can obtain a significant proportion of its energy requirements from the metabolism of ketone bod ies (2,11], lactate (12,13] and in the case of astrocytes also from free fatty acids [ 14].…”

Depolarizing Actions of GABA in Immature Neurons Depend Neither on Ketone Bodies Nor on Pyruvate

“…Therefore, depolarizing actions of GABA are not attributable to the absence of DL-BHB or lactate/pyruvate in the ACSF. dehydrogenase that metabolize it (Page et al, 1971;De Vivo et al, 1975;Leong and Clark, 1984;Bilger and Nehlig, 1991;Clark et al, 1993), peak during development well after the GABA shift. Fatty acid oxidation supports gluconeogenesis (Pégorier et al, 1977), and ketosis acts to "spare glucose for the emergence of audition, vision and more integrated behavior whose appearance during brain maturation seems to critically relate upon active glucose supply" (Nehlig, 2004).…”