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Cerebral Carbohydrate and Energy Metabolism in Perinatal Hypoxic‐Ischemic Brain Damage

Cerebral Carbohydrate and Energy Metabolism in Perinatal Hypoxic‐Ischemic Brain Damage Department of Pediatrics, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA 17033, U S A . Cerebral hypoxia-ischemia remains a major cause of acute perinatal brain injury. Research in experim ent al animals over t h e past decade has greatly expanded our knowledge of those oxidative events whic h occur during a hypoxic-ischemic insult t o t h e brain, as w e l l as th o s e metabolic alterations which evolve during th e recovery period following resuscitation. The available evidence suggests that hypoxia alone does n o t lead t o brain damage, but rather a combination of hypoxia-ischemia or isolated cerebral ischemia is a necessary prerequisite f or tissue injury t o occur. Furthermore, hypoxiaischemia severe enough t o produce irreversible tissue injury is always associated with major perturbat ions in t h e energy status o f t h e perinatal brain which persists w e l l i n t o t h e recovery period. The lingering energy depletion sets in motion a cascade of biochemical alterations t h a t are initiated during t he course of t h e insult and proceed w e l l into the recovery pe ri o d t o culminate in either neuronal necrosis or infarction. Unlike t h e adult, where glucose supplementation prior t o or during hypoxiaischemia accentuates tissue injury, glucose treatm e n t of perinatal animals subjected t o a similar insult substantially reduces t h e extent of tissue injury. The mechanism for th e age-specific effect of glucose o n hypoxic-ischemic brain damage is discussed in relation t o pathogenetic mechanisms responsible for t h e occurrence of permanent brain damage. acidosis (asphyxia), cerebral ischemia and occlusive vascular disease is a major cause of perinatal mortality and of chronic neurologic morbidity in the survivors of such insults. Research over the past decade has expanded our knowledge of those critical cellular metabolic events that eventually lead to brain tissue injury arising from hypoxia-ischemia. Investigations have shown that hypoxia-ischemia sets in motion a cascade of biochemical alterations that are initiated during the course of the insult and that proceed well into the recovery period after resuscitation. This review will focus on those cellular processes which are perturbed by the tissue oxygen and glucose debt which arises from Hypoxia-ischemia and how these alterations evolve into perinatal brain damage. O x i d a t i v e Metabolism Introduction Brain damage that results from systemic hypoxiaCorresponding author: Dr. R.C. Vannucci, Department of Pediatrics, The Milton S. Tel. +1 (717) 531 8790; Fax Hershey Medical Center, Hershey, PA 17033, U S.A. +1 (717) 531 8985 Tissue hypoxia denotes a cellular oxygen debt, owing typically to inadequate oxygen delivery (CBF x Sa02) via nutrient arteries. When the tissue (mitochondrial) partial pressure of oxygen falls below a critical value ( ~ 0 . mmHg), the cytochrome system of mito1 chondria becomes unsaturated, and reducing equivalents (NADH, FADH) begin to accumulate (1,Z). High energy phosphate (ATP) production by oxidative phosphorylation is curtailed, with concurrent increases in cellular ADP and AMP, as cytosolic ATP hydrolysis continues to drive endergonic reactions (3). The elevations in ADP and AMP serve to stimulate glycolysis, through activation of its key regulatory enzyme, phosphofructokinase (PFK). Unlike oxidative phosphorylation, which produces 36 moles of ATP for every mole of glucose consumed, glycolysis is an inefficient method to generate ATP by substrate phosphorylation, with a net production of only two moles of ATP/mole of glucose consumed. To produce the amount of ATP equivalent to that of oxidative phosphorylation, glycolysis would need to increase to a rate 18 times its basal flux. In reality, glycolysis, even when maximally stimulated by total cerebral ischemia, is capable of increasing only four-fold to five-fold, owing in part to the concurrent accumulation of Hf ions derived from the accumulated NADH, which serves to inhibit PFK activity (4,s). R.C. Vannucci: Cerebral metabolism and perinatal brain damage i \. PaO, (rnmHg) Figure 1 Cerebral blood flow (CBF) and tissue lactate and lactate/pyruvate ratios during graded systemic hypoxia in newborn dogs. Symbols for CBF represent means 1 S.E. for 3-5 animals. Symbols for lactate and lactate/pyruvate represent individual brain tissue. Data of Vannucci and Hernandez (10). Thus, glycolysis can never completely substitute for mitochondria1 oxidation, although its stimulation can supplement oxidative phosphorylation under conditions of partial oxygen debt. There is an abundance of experimental data to indicate that hypoxia alone does not acutely damage the perinatal brain and that either ischemia alone, secondary to occlusive vascular disease, or a combination of hypoxia and ischemia is a necessary pre requisite for tissue injury to occur. In experimental animals, and presumably newborn human infants, hypoxemia is associated with an increase in cerebral blood flow (CBF) which serves to maintain adequate tissue oxygenation of the brain unless cerebral ischemia secondary to systemic hypotension or vascular disease is superimposed. Indeed, overt brain damage does not result from acute hypoxemia, even if the insult is severe enough to cause transient alterations in CBF and metabolism (6-8). Vannucci and Duffy (7) subjected term fetal and newborn rats to anoxia (nitrogen breathing) nearly to the point of death and allowed them to recover into adulthood. Pathologic analysis at that time revealed no brain damage, and the brain growth of the previously anoxic animals were comparable to that of agematched controls. In a more recent study, Ting et al. (9) subjected fetaI sheep to hypoxemia, some of which were rendered concurrently hypotensive by partial exsanguination. During hypoxemia, the fetuses developed systemic metabolic acidosis secondary to the accumulation of lactic acid; this was especially apparent in the hypoxic-hypotensive animals. Three days following the experimental manipulation, the fetuses were delivered by cesarean section. Of the survivors, 29% showed evidence of brain damage with moderate to severe hemorrhagic necrosis (infarction) of cerebral cortex, subcortical white matter, and basal ganglia. All the brain damaged animals had been significantly hypotensive during the hypoxic exposure whether or not they were partially exsanguinated, whereas the brains of the fetuses that remained normotensive during hypoxemia were free of tissue injury. The findings of these studies support the notion that acute perinatal brain damage arises not from systemic hypoxia alone but rather from cerebral ischemia occurring alone or superimposed on hypoxemia. To determine the threshold of hypoxemia below which alterations in CBF and metabolism occur, Vannucci and Hernandez subjected newborn dogs to graded hypoxemia with Pa02 values ranging from 11 to 110 mmHg (for review, see Ref. 10). CBF was unchanged at Pa02 tensions above 35 mmHg but increased significantly at oxygen tensions below this value (Fig. 1). Major alterations in cerebral metabolism did not occur until Pa02 fell below 20 mmHg; at these low values, the cerebral metabolic rate for oxygen (CMR02) declined and cerebral lactate and lactate/pyruvate ratios increased progressively, denoting at least a partial shift from aerobic to anaerobic metabolism in cerebral tissue. However, ATP, the primary modulator of energy flux in the brain was not altered until severe systemic hypotension (mean arterial blood pressure <20 mmHg) supervened (Fig. 2). This study suggests that the compensatory increase in CBF which occurs during hypoxemia adequately protects the perinatal brain from injury unless cerebral ischemia due to systemic hypotension supervenes. When cerebral hypoxia-ischemia is severe enough to product irreversible tissue injury, the insult is always R.C. Vannucci: Cerebral metabolism and perinatal brain damage Brain Damage 2.5 - ---4 I 7 E n 2.0 - "c \* 1. o .05- MABP (rnrnHg) Duration of Hypoxia-Ischemia (rnin) Figure 2 Brain tissue concentrations of ATP and ADP in relation to mean arterial blood pressure (MABP) during graded hypoxia in newborn dogs. Symbols represent individual brain tissue concentrations. Data of Vannucci and Voorhies (10); 3 Changes in cerebral high-energy phosphate reserves during hypoxia-ischemia in the immature rat. Seven-day postnatal rats were subjected to unilateral common carotid artery ligation followed by exposure to hypoxia with 8% oxygen at 37°C. Symbols represent means for ATP, phosphocreatine (PCr), and total adenine nucleotides (ATP + ADP + AMP). All values are significantly different from control (zero time point). Histologic brain damage commences between 60 and 90 minutes of hypoxia-ischemia, with increasing severity thereafter. associated with major perturbations in the energy status of the brain (3,11,12). Alterations occur not only in ATP, ADP and AMP, but also in phosphocreatine (PCr), which changes actually precede those of the adenine nucleotides. During the course of the cerebral hypoxia-ischemia, changes in the tissue concentrations of these high-energy phosphate reserves occur early during the course of the insult and persist well into the recovery period (13-15). Greater depletions in PCr occur relativ? to ATP as the cell attempts to maintain optimal levels of ATP (Fig. 3). With the eventual decline in tissue ATP; ADP and AMP accumulate in proportion to the loss of ATP. Ultimately, the total adenine nucleotide pool (ATP + ADP + AMP) also decreases, as AMP is catabolized slowly to adenosine and further breakdown products. The concentrations of ATP and the total adenylate compounds never completely recover after resuscitatlon (Fig. 4), and their persisting partial depletions reflect the presence and severity of tissue destruction (14,15). As expected, the loss of cellular ATP during hypoxiaischemia severely compromises those metabolic processes that require energy for their completion. Thus, ATP-dependent Na+ extrusion through the plasma membrane in exchange for K+ is curtailed with a resultant intracellular accumulation of Na+ and C1as well as water (cytotoxic edema). Equally vital to cellular function is the prompt restoration of highenergy phosphate reserves during and after resuscitation. Without regeneration of ATP, endergonic reactions cannot resume, especially those involving ion pumping at plasma and intracellular membranes. Intracellular Na+ and C1- ions and water will continue to accumulate, and electro-chemical gradients cannot be re-established. Just how long the cell can survive under this situation is not entirely clear, but other factors are called into play that prominently influence ultimate tissue cellular integrity; including the formation of oxygen free radicals and the associated peroxidation of free fatty acids within cellular membranes, an uncoupling of oxidative phosphorylation, the accumulation of cytotoxic excitatory neurotransmitters (glutamate) and of cytosolic calcium ions, and a lingering cellular acidosis; all of which enhance the process of cellular destruction (for review, see Ref. 16). Glucose and Lactic Acid Metabolism For normal cerebral development and consequent function to proceed, an adequate amount of metabolizable substrate must be supplied to the brain during the perinatal period. It has long been known that glucose is the primary energy substrate for the adult brain, and recent investigations indicate that glucose is also the predominant cerebral fuel in fetal and newborn animals, including probably human infants, under physiologic conditions (17-20). Despite the critical role of glucose in sustaining the energy needs of the brain, other organic substrates are capable of supplementing glucose during periods of starvation, suckling and hypoglycemia (20-22). However, all alternate substrates, including ketone bodies, lactic acid, fatty and amino acids, require oxygen for consumption in order to produce energy R.C. Vannucci: Cerebral metabolism and perinatal brain damage Table 1 Neuropathologic responses of hyperglycemic immature rats to cerebral hypoxia-ischemia Extent of brain damage Hyperglycemia 11 Normoglycemia No damage Mild atrophy Moderate atrophy Atrophy + infarction Seven-day postnatal rats were subjected t o cerebral hypoxia-ischemia, immediately prior t o which they received a injection of 0.1 ml 50% glucose followed by 0.15 ml 25% glucose one hour later. Normoglycemic animals received equivalent volumes of N saline a t the same intervals. Data of Reeves et al. (38). S.C. equivalents. Thus, only glucose is capable of sustaining energy metabolism in brain under conditions of hypoxia-ischemia because of its capacity for consumption via anaerobic glycolysis with the production of lactic acid and ATP (16). Research conducted many years ago demonstrated that pretreatment of perinatal animals with glucose prolongs their survival when subjected to systemic hypoxia, asphyxia or cerebral ischemia (23-25) and may reduce permanent brain damage as well (26,27). Despite the increased hypoxic-ischemic resistance of glucose treated immature animals, more recent experiments in adult animals have shown that glucose supplementation actually accentuates hypoxicischemic brain damage (28-30). Therefore, glucose appears to have a paradoxical role in hypoxiaischemia; prolonging hypoxic survival of immature animals on the one hand while increasing brain damage in adults on the other. Neuropathologic and metabolic studies have been conducted in perinatal animals of several species to resolve the apparent paradox (see below). The pathophysiologic mechanism by which glucose accentuates brain damage in adult animals has been related to an excessive production of tissue lactic acid or to an associated derangement in pH homeostasis (31-35). Some investigators have suggested that brain lactacidosis enhances hypoxic-ischemic injury in vulnerable regions and that a minimum concentration of 15-20mmol lactatekg brain is required for irreversible damage to occur (3 1,32,34). Presumably, excessive lactate production by brain during hyperglycemic cerebral hypoxia-ischemia relates to a greater acceleration of anaerobic glycolytic flux than that which occurs when the circulating glucose concentration is not increased. To ascertain whether glucose is protective or deleterious to the perinatal brain undergoing hypoxia- ischemia, Voorhies et al. (36) used an experimental model of perinatal hypoxic-ischemic brain damage in the immature rat (37). Seven-day postnatal rats were rendered hyperglycemic to blood glucose concentrations of 180 - 240 mg/dl with 50% glucose, following which they were exposed to hypoxiaischemia produced by the ligation of one common carotid artery followed by exposure to 8% oxygen at 3 7" C. The glucose-supplemented rat pups survived more than twice as long as their normoglycemic, saline-treated littermates. In further experiments, glucose pretreated and control immature rats were exposed to cerebral hypoxia-ischemia for two hours, after which they were reared with their dams until 30 days of postnatal age. Neuropathologic analysis at that time failed to reveal any quantitative difference in the extent of brain damage in the glucose and saline-treated groups. In a more recent investigation by Reeves et al. (38), using the same immature rat model, hyperglycemia to blood glucose levels of 630720 mg/dl were associated with a dramatic improvement in neuropathologic outcome to the extent that the hyperglycemia completely prevented the occurrence of cerebral infarction which occurred in 57% of the normoglycemic controls (Table 1). The findings of the two studies clearly indicate that, unlike adults, glucose supplementation and its associated hyperglycemia in the immature animal does not accentuate the severity of brain damage but rhther protects the immature brain from the deleterious effect of hypoxia-ischemia. The mechanism for the production of more extensive brain damage in glucose treated adults, but not immature animals relates to the age-specific difference in the rate of cerebral glucose uptake and metabolism. In the newborn animal, the carrier that transports glucose from blood into brain is immature. Under normoxic conditions, glucose penetrates R.C. Vannucci: Cerebral metabolism and perinatal brain damage http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Brain Pathology Wiley

Cerebral Carbohydrate and Energy Metabolism in Perinatal Hypoxic‐Ischemic Brain Damage

Brain Pathology , Volume 2 (3) – Jul 1, 1992

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Publisher
Wiley
Copyright
Copyright © 1992 Wiley Subscription Services, Inc., A Wiley Company
ISSN
1015-6305
eISSN
1750-3639
DOI
10.1111/j.1750-3639.1992.tb00696.x
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Abstract

Department of Pediatrics, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA 17033, U S A . Cerebral hypoxia-ischemia remains a major cause of acute perinatal brain injury. Research in experim ent al animals over t h e past decade has greatly expanded our knowledge of those oxidative events whic h occur during a hypoxic-ischemic insult t o t h e brain, as w e l l as th o s e metabolic alterations which evolve during th e recovery period following resuscitation. The available evidence suggests that hypoxia alone does n o t lead t o brain damage, but rather a combination of hypoxia-ischemia or isolated cerebral ischemia is a necessary prerequisite f or tissue injury t o occur. Furthermore, hypoxiaischemia severe enough t o produce irreversible tissue injury is always associated with major perturbat ions in t h e energy status o f t h e perinatal brain which persists w e l l i n t o t h e recovery period. The lingering energy depletion sets in motion a cascade of biochemical alterations t h a t are initiated during t he course of t h e insult and proceed w e l l into the recovery pe ri o d t o culminate in either neuronal necrosis or infarction. Unlike t h e adult, where glucose supplementation prior t o or during hypoxiaischemia accentuates tissue injury, glucose treatm e n t of perinatal animals subjected t o a similar insult substantially reduces t h e extent of tissue injury. The mechanism for th e age-specific effect of glucose o n hypoxic-ischemic brain damage is discussed in relation t o pathogenetic mechanisms responsible for t h e occurrence of permanent brain damage. acidosis (asphyxia), cerebral ischemia and occlusive vascular disease is a major cause of perinatal mortality and of chronic neurologic morbidity in the survivors of such insults. Research over the past decade has expanded our knowledge of those critical cellular metabolic events that eventually lead to brain tissue injury arising from hypoxia-ischemia. Investigations have shown that hypoxia-ischemia sets in motion a cascade of biochemical alterations that are initiated during the course of the insult and that proceed well into the recovery period after resuscitation. This review will focus on those cellular processes which are perturbed by the tissue oxygen and glucose debt which arises from Hypoxia-ischemia and how these alterations evolve into perinatal brain damage. O x i d a t i v e Metabolism Introduction Brain damage that results from systemic hypoxiaCorresponding author: Dr. R.C. Vannucci, Department of Pediatrics, The Milton S. Tel. +1 (717) 531 8790; Fax Hershey Medical Center, Hershey, PA 17033, U S.A. +1 (717) 531 8985 Tissue hypoxia denotes a cellular oxygen debt, owing typically to inadequate oxygen delivery (CBF x Sa02) via nutrient arteries. When the tissue (mitochondrial) partial pressure of oxygen falls below a critical value ( ~ 0 . mmHg), the cytochrome system of mito1 chondria becomes unsaturated, and reducing equivalents (NADH, FADH) begin to accumulate (1,Z). High energy phosphate (ATP) production by oxidative phosphorylation is curtailed, with concurrent increases in cellular ADP and AMP, as cytosolic ATP hydrolysis continues to drive endergonic reactions (3). The elevations in ADP and AMP serve to stimulate glycolysis, through activation of its key regulatory enzyme, phosphofructokinase (PFK). Unlike oxidative phosphorylation, which produces 36 moles of ATP for every mole of glucose consumed, glycolysis is an inefficient method to generate ATP by substrate phosphorylation, with a net production of only two moles of ATP/mole of glucose consumed. To produce the amount of ATP equivalent to that of oxidative phosphorylation, glycolysis would need to increase to a rate 18 times its basal flux. In reality, glycolysis, even when maximally stimulated by total cerebral ischemia, is capable of increasing only four-fold to five-fold, owing in part to the concurrent accumulation of Hf ions derived from the accumulated NADH, which serves to inhibit PFK activity (4,s). R.C. Vannucci: Cerebral metabolism and perinatal brain damage i \. PaO, (rnmHg) Figure 1 Cerebral blood flow (CBF) and tissue lactate and lactate/pyruvate ratios during graded systemic hypoxia in newborn dogs. Symbols for CBF represent means 1 S.E. for 3-5 animals. Symbols for lactate and lactate/pyruvate represent individual brain tissue. Data of Vannucci and Hernandez (10). Thus, glycolysis can never completely substitute for mitochondria1 oxidation, although its stimulation can supplement oxidative phosphorylation under conditions of partial oxygen debt. There is an abundance of experimental data to indicate that hypoxia alone does not acutely damage the perinatal brain and that either ischemia alone, secondary to occlusive vascular disease, or a combination of hypoxia and ischemia is a necessary pre requisite for tissue injury to occur. In experimental animals, and presumably newborn human infants, hypoxemia is associated with an increase in cerebral blood flow (CBF) which serves to maintain adequate tissue oxygenation of the brain unless cerebral ischemia secondary to systemic hypotension or vascular disease is superimposed. Indeed, overt brain damage does not result from acute hypoxemia, even if the insult is severe enough to cause transient alterations in CBF and metabolism (6-8). Vannucci and Duffy (7) subjected term fetal and newborn rats to anoxia (nitrogen breathing) nearly to the point of death and allowed them to recover into adulthood. Pathologic analysis at that time revealed no brain damage, and the brain growth of the previously anoxic animals were comparable to that of agematched controls. In a more recent study, Ting et al. (9) subjected fetaI sheep to hypoxemia, some of which were rendered concurrently hypotensive by partial exsanguination. During hypoxemia, the fetuses developed systemic metabolic acidosis secondary to the accumulation of lactic acid; this was especially apparent in the hypoxic-hypotensive animals. Three days following the experimental manipulation, the fetuses were delivered by cesarean section. Of the survivors, 29% showed evidence of brain damage with moderate to severe hemorrhagic necrosis (infarction) of cerebral cortex, subcortical white matter, and basal ganglia. All the brain damaged animals had been significantly hypotensive during the hypoxic exposure whether or not they were partially exsanguinated, whereas the brains of the fetuses that remained normotensive during hypoxemia were free of tissue injury. The findings of these studies support the notion that acute perinatal brain damage arises not from systemic hypoxia alone but rather from cerebral ischemia occurring alone or superimposed on hypoxemia. To determine the threshold of hypoxemia below which alterations in CBF and metabolism occur, Vannucci and Hernandez subjected newborn dogs to graded hypoxemia with Pa02 values ranging from 11 to 110 mmHg (for review, see Ref. 10). CBF was unchanged at Pa02 tensions above 35 mmHg but increased significantly at oxygen tensions below this value (Fig. 1). Major alterations in cerebral metabolism did not occur until Pa02 fell below 20 mmHg; at these low values, the cerebral metabolic rate for oxygen (CMR02) declined and cerebral lactate and lactate/pyruvate ratios increased progressively, denoting at least a partial shift from aerobic to anaerobic metabolism in cerebral tissue. However, ATP, the primary modulator of energy flux in the brain was not altered until severe systemic hypotension (mean arterial blood pressure <20 mmHg) supervened (Fig. 2). This study suggests that the compensatory increase in CBF which occurs during hypoxemia adequately protects the perinatal brain from injury unless cerebral ischemia due to systemic hypotension supervenes. When cerebral hypoxia-ischemia is severe enough to product irreversible tissue injury, the insult is always R.C. Vannucci: Cerebral metabolism and perinatal brain damage Brain Damage 2.5 - ---4 I 7 E n 2.0 - "c \* 1. o .05- MABP (rnrnHg) Duration of Hypoxia-Ischemia (rnin) Figure 2 Brain tissue concentrations of ATP and ADP in relation to mean arterial blood pressure (MABP) during graded hypoxia in newborn dogs. Symbols represent individual brain tissue concentrations. Data of Vannucci and Voorhies (10); 3 Changes in cerebral high-energy phosphate reserves during hypoxia-ischemia in the immature rat. Seven-day postnatal rats were subjected to unilateral common carotid artery ligation followed by exposure to hypoxia with 8% oxygen at 37°C. Symbols represent means for ATP, phosphocreatine (PCr), and total adenine nucleotides (ATP + ADP + AMP). All values are significantly different from control (zero time point). Histologic brain damage commences between 60 and 90 minutes of hypoxia-ischemia, with increasing severity thereafter. associated with major perturbations in the energy status of the brain (3,11,12). Alterations occur not only in ATP, ADP and AMP, but also in phosphocreatine (PCr), which changes actually precede those of the adenine nucleotides. During the course of the cerebral hypoxia-ischemia, changes in the tissue concentrations of these high-energy phosphate reserves occur early during the course of the insult and persist well into the recovery period (13-15). Greater depletions in PCr occur relativ? to ATP as the cell attempts to maintain optimal levels of ATP (Fig. 3). With the eventual decline in tissue ATP; ADP and AMP accumulate in proportion to the loss of ATP. Ultimately, the total adenine nucleotide pool (ATP + ADP + AMP) also decreases, as AMP is catabolized slowly to adenosine and further breakdown products. The concentrations of ATP and the total adenylate compounds never completely recover after resuscitatlon (Fig. 4), and their persisting partial depletions reflect the presence and severity of tissue destruction (14,15). As expected, the loss of cellular ATP during hypoxiaischemia severely compromises those metabolic processes that require energy for their completion. Thus, ATP-dependent Na+ extrusion through the plasma membrane in exchange for K+ is curtailed with a resultant intracellular accumulation of Na+ and C1as well as water (cytotoxic edema). Equally vital to cellular function is the prompt restoration of highenergy phosphate reserves during and after resuscitation. Without regeneration of ATP, endergonic reactions cannot resume, especially those involving ion pumping at plasma and intracellular membranes. Intracellular Na+ and C1- ions and water will continue to accumulate, and electro-chemical gradients cannot be re-established. Just how long the cell can survive under this situation is not entirely clear, but other factors are called into play that prominently influence ultimate tissue cellular integrity; including the formation of oxygen free radicals and the associated peroxidation of free fatty acids within cellular membranes, an uncoupling of oxidative phosphorylation, the accumulation of cytotoxic excitatory neurotransmitters (glutamate) and of cytosolic calcium ions, and a lingering cellular acidosis; all of which enhance the process of cellular destruction (for review, see Ref. 16). Glucose and Lactic Acid Metabolism For normal cerebral development and consequent function to proceed, an adequate amount of metabolizable substrate must be supplied to the brain during the perinatal period. It has long been known that glucose is the primary energy substrate for the adult brain, and recent investigations indicate that glucose is also the predominant cerebral fuel in fetal and newborn animals, including probably human infants, under physiologic conditions (17-20). Despite the critical role of glucose in sustaining the energy needs of the brain, other organic substrates are capable of supplementing glucose during periods of starvation, suckling and hypoglycemia (20-22). However, all alternate substrates, including ketone bodies, lactic acid, fatty and amino acids, require oxygen for consumption in order to produce energy R.C. Vannucci: Cerebral metabolism and perinatal brain damage Table 1 Neuropathologic responses of hyperglycemic immature rats to cerebral hypoxia-ischemia Extent of brain damage Hyperglycemia 11 Normoglycemia No damage Mild atrophy Moderate atrophy Atrophy + infarction Seven-day postnatal rats were subjected t o cerebral hypoxia-ischemia, immediately prior t o which they received a injection of 0.1 ml 50% glucose followed by 0.15 ml 25% glucose one hour later. Normoglycemic animals received equivalent volumes of N saline a t the same intervals. Data of Reeves et al. (38). S.C. equivalents. Thus, only glucose is capable of sustaining energy metabolism in brain under conditions of hypoxia-ischemia because of its capacity for consumption via anaerobic glycolysis with the production of lactic acid and ATP (16). Research conducted many years ago demonstrated that pretreatment of perinatal animals with glucose prolongs their survival when subjected to systemic hypoxia, asphyxia or cerebral ischemia (23-25) and may reduce permanent brain damage as well (26,27). Despite the increased hypoxic-ischemic resistance of glucose treated immature animals, more recent experiments in adult animals have shown that glucose supplementation actually accentuates hypoxicischemic brain damage (28-30). Therefore, glucose appears to have a paradoxical role in hypoxiaischemia; prolonging hypoxic survival of immature animals on the one hand while increasing brain damage in adults on the other. Neuropathologic and metabolic studies have been conducted in perinatal animals of several species to resolve the apparent paradox (see below). The pathophysiologic mechanism by which glucose accentuates brain damage in adult animals has been related to an excessive production of tissue lactic acid or to an associated derangement in pH homeostasis (31-35). Some investigators have suggested that brain lactacidosis enhances hypoxic-ischemic injury in vulnerable regions and that a minimum concentration of 15-20mmol lactatekg brain is required for irreversible damage to occur (3 1,32,34). Presumably, excessive lactate production by brain during hyperglycemic cerebral hypoxia-ischemia relates to a greater acceleration of anaerobic glycolytic flux than that which occurs when the circulating glucose concentration is not increased. To ascertain whether glucose is protective or deleterious to the perinatal brain undergoing hypoxia- ischemia, Voorhies et al. (36) used an experimental model of perinatal hypoxic-ischemic brain damage in the immature rat (37). Seven-day postnatal rats were rendered hyperglycemic to blood glucose concentrations of 180 - 240 mg/dl with 50% glucose, following which they were exposed to hypoxiaischemia produced by the ligation of one common carotid artery followed by exposure to 8% oxygen at 3 7" C. The glucose-supplemented rat pups survived more than twice as long as their normoglycemic, saline-treated littermates. In further experiments, glucose pretreated and control immature rats were exposed to cerebral hypoxia-ischemia for two hours, after which they were reared with their dams until 30 days of postnatal age. Neuropathologic analysis at that time failed to reveal any quantitative difference in the extent of brain damage in the glucose and saline-treated groups. In a more recent investigation by Reeves et al. (38), using the same immature rat model, hyperglycemia to blood glucose levels of 630720 mg/dl were associated with a dramatic improvement in neuropathologic outcome to the extent that the hyperglycemia completely prevented the occurrence of cerebral infarction which occurred in 57% of the normoglycemic controls (Table 1). The findings of the two studies clearly indicate that, unlike adults, glucose supplementation and its associated hyperglycemia in the immature animal does not accentuate the severity of brain damage but rhther protects the immature brain from the deleterious effect of hypoxia-ischemia. The mechanism for the production of more extensive brain damage in glucose treated adults, but not immature animals relates to the age-specific difference in the rate of cerebral glucose uptake and metabolism. In the newborn animal, the carrier that transports glucose from blood into brain is immature. Under normoxic conditions, glucose penetrates R.C. Vannucci: Cerebral metabolism and perinatal brain damage

Journal

Brain PathologyWiley

Published: Jul 1, 1992

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