Imaging and the ontogeny of brain metabolism.
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Animals↗
Biomedical subjects
A Nehlig
Publications and source records attributed to A Nehlig.
An experimental model of generalized seizures for the measurement of local cerebral glucose utilization in the immature rat. I. Behavioral characterization and determination of lumped constant.
An experimental model of status epilepticus has been developed in the immature rat by administration of pentylenetetrazol (PTZ) using repetitive, timed intraperitoneal injections of subconvulsive doses. The pattern of behavioral signs has been well characterized in each age group, i.e. 10 (P10), 14 (P14), 17 (P17) and 21 postnatal days (P21). In this model, the dose of convulsant could be adjusted as a function of interindividual sensitivity and status epilepticus lated for quite a long duration to allow the measurement of local cerebral metabolic rates for glucose (LCMRglc) by means of the [14C]2-deoxyglucose method [J. Neurochem., 28 (1977) 897-916]. To estimate LCMRglc during status epilepticus, the lumped constant (LC) was re-calculated in controls and PTZ-treated rats. The control LC was 0.54 at P10 and 0.50-0.51 at the three older ages studied (P14, P17 and P21). During status epilepticus, it increased to 0.64 in P10 rats and decreased to 0.42 and 0.40, respectively, in P17 and P21 animals. At P14, LC was not affected by seizures. The measurements of brain lactate levels showed a large 4.5-10-fold increase in PTZ-treated rats as compared to controls at all ages. The results of the present study show that the immature brain responds to sustained seizure activity in a specific way according to its postnatal age. Moreover, our results underscore the necessity of re-calculation of LC to the quantification of LCMRglc in such pathological states, particularly in immature animals.
Aging↗
An experimental model of generalized seizures for the measurement of local cerebral glucose utilization in the immature rat. II. Mapping of brain metabolism using the quantitative [14C]2-deoxyglucose technique.
The quantitative autoradiographic [14C]2-deoxyglucose technique (2DG) was applied to measure the effects of pentylenetetrazol (PTZ)-induced status epilepticus (SE) on local cerebral metabolic rates for glucose (LCMRglc) in 10 (P10)-, 14 (P14)-, 17 (P17)- and 21 (P21)-day-old rats. To produce long-lasting SE (55 min), the animals received repetitive, timed intraperitoneal injections of subconvulsive doses of PTZ until SE was reached. At P10 and P14, SE induced a marked increase in LCMRglc which affected 66 of the 76 structures studied. Increases were especially high (200-400%) in limbic and motor cortices at P10 and in some brainstem areas at these 2 ages. At P17 and P21, average brain glucose utilization was similar in seizing and control rats, but in PTZ-treated rats reflected a redistribution in local metabolic rates with increases in brainstem, midbrain, hypothalamus and septum, decreases in cortex, hippocampus, some sensory areas and white matter and no change in many motor and limbic structures. In a few cerebral regions, such as hippocampus, dentate gyrus and mammillary body, LCMRglc did not increase at P10 and P14 and decreased at P17 and P21 in PTZ- vs. saline-treated rats. The results of the present study show that the immature brain responds to sustained seizure activity in a specific way according to its maturational state. Moreover, these data allow the mapping of the vulnerability of cerebral structures to seizures, according to their metabolic response to convulsions.
Aging↗
Effects of the acute administration of a new trimethylxanthine derivative, S 9977-2, on local cerebral blood flow and glucose utilization in the rat.
S 9977-2 is a new trimethylxanthine derivative with promnesic properties. Its effects on cerebral glucose utilization and blood flow were studied by means of quantitative autoradiography. S 9977-2 was injected intravenously into adult rats at doses of 0.1, 1.0 and 10 mg/kg. At 0.1 mg/kg, S 9977-2 induced a significant increase in cerebral glucose utilization over control values in two white matter areas and in the vestibular nucleus. At 1.0 mg/kg, glucose utilization was affected in 14 areas out of the 63 studied, mainly limbic regions such as the hippocampus, raphe nuclei and locus coeruleus, as well as some posterior areas. Conversely, after the injection of 10 mg/kg S 9977-2, cerebral glucose utilization was similar to that of control rats. At the three doses tested, S9977-2 did not induce any significant variation in local rates of cerebral blood flow compared to those of controls. Likewise, S 9977-2 did not change the level of coupling between cerebral blood flow and metabolism, except at 10 mg/kg, where a relative hypoperfusion at a constant metabolic level was recorded. These data show that, at 1.0 mg/kg, S 9977-2 increased glucose utilization in hippocampal areas, an effect which may be related to the promnesic properties of this compound at the same dose. Moreover, at low doses, the lack of change in the level of coupling between cerebral blood flow and metabolism is indicative of the rather selective action of this compound, compared to that of caffeine. Thus S9977-2 should have therapeutic effects, mainly via its promnesic properties, without having many side effects.
Animals↗
Acute hypoxia induces specific changes in local cerebral glucose utilization at different postnatal ages in the rat.
The quantitative autoradiographic 2-[14C]-deoxyglucose technique (2-DG) was applied to measure the effects of an acute hypoxic exposure on local cerebral metabolic rates for glucose (LCMRglcs) in the 10 (P10)-, 14 (P14)-, and 21 (P21)-day-old rat. The animals were exposed to hypoxic (7% O2/93% N2) or control gas mixture (21% O2/79% N2) for 20 min before the initiation and for the duration of the 2-DG procedure. Lumped constants were not affected by hypoxia at any age. At P10, the exposure to the hypoxic gas mixture induced a generalized increase in LCMRglc which affected 41 structures of the 45 studied. At P14, average cerebral glucose utilization was similar in hypoxic and control rats. LCMRglc increased in 5 areas and decreased in 11 regions, mainly brainstem and respiratory areas in hypoxic rats. Finally, at P21, LCMRglc decreased in 11 structures of hypoxic rats. The increase in LCMRglc in the hypoxic 10-day-old rat likely reflects stimulation of anaerobic glycolysis. Conversely, at P14 and P21, when the brain has become more dependent upon oxygen supply for its energy metabolism, levels of LCMRglc are similar in both groups of animals or decreased in a few structures of hypoxic compared to normoxic rats. The results of the present study show that the immature brain responds to an acute hypoxic insult in a specific way according to its maturational state. They are also in good accordance with the higher resistance of the immature animal to oxygen deprivation.
Acute Disease↗
Mapping of cerebral energy metabolism in rats with genetic generalized nonconvulsive epilepsy.
The quantitative 2-[14C]deoxyglucose autoradiographic method was applied to measure local cerebral metabolic rates of glucose (LCMRglc) in a model of genetic petit-mal-like seizures in a strain of Wistar rats. During the experimental period, epileptic rats exhibited synchronous spike-and-wave discharges, whereas the EEG pattern of control animals was normal. Overall, LCMRglc was consistently higher in epileptic rats than in the non-epileptic controls. The increase in LCMRglc was widespread and concerned all cerebral functional systems studied, whether they exhibit spike-and-wave discharges (neocortex and thalamus), or not (limbic system). These results are in good accordance with positron-emission tomography measurements in humans with typical childhood absence epilepsy. There appears to be a lack of anatomical correlation between areas demonstrating hypermetabolism and areas where spike-and-wave discharges are recorded. The administration of 200 mg/kg ethosuximide completely suppressed spike-and-wave discharges in epileptic rats and did not change the EEG pattern in controls. However, LCMRglc were increased to the same extent over control values in epileptic rats whether they were injected with ethosuximide or untreated. By contrast, when epileptic rats were given 2 mg/kg haloperidol, the frequency and the length of spike-and-wave discharges increased, inducing almost a permanent petit-mal status epilepticus. Haloperidol did not change EEG pattern in controls. In haloperidol-treated epileptic rats, LCMRglc decreased to levels comparable to those measured in untreated control rats. In the presence of haloperidol, LCMRglc were similar in both control and epileptic rats. Thus, the diffuse increase in cerebral energy metabolism in epileptic rats as compared to controls is not directly related to the occurrence of spike-and-wave discharges, and may rather be associated with inhibitory mechanisms involved in their termination and suppression, as well as their spread to limbic and motor structures.
Animals↗
Local cerebral glucose utilization during chronic infusion of GABA into the nucleus basalis magnocellularis of rats.
The metabolic effects of gamma aminobutyric acid (GABA) unilaterally infused for 24 h into the nucleus basalis magnocellularis (NBM) of rats were studied using the 2-deoxyglucose method for measuring local cerebral metabolic rates for glucose (CMRglc). These results demonstrated that GABA infusion at the concentration of 100 micrograms.microliters-1 induced a strong ipsilateral depression in glucose utilization in the NBM and in some surrounding structures (e.g., the lateral hypothalamic area, thalamus, and amygdala) as well as in the major cortical targets of NBM neurons (i.e., the frontal, parietal, and temporal cortices). On an other hand, GABA infusion at the concentration of 10 micrograms.microliter-1 had no significant effect on cerebral metabolism compared to the saline-infused rats. Nevertheless, both GABA at the concentration of 10 micrograms.microliter-1 and saline induced a reduction of cerebral metabolism in the infused NBM, compared to the contralateral noninfused NBM. It was also demonstrated that saline pretreatment reduced the metabolic depression induced by GABA infusion at the highest concentration. When GABA was infused at the concentration of 100 micrograms.microliter-1, a slight reduction of CMRglc was observed in the hemisphere contralateral to the infused one, mainly in NBM target areas. In view of our previous behavioral data, these results suggest among others, that there is no necessary relationship between cerebral glucose metabolism and behavioral expression.
Animals↗
Effects of pentylenetetrazol-induced seizures on dopamine and norepinephrine levels and on glucose utilization in various brain regions of the developing rat.
Levels of dopamine and norepinephrine were measured in seven brain areas after 60 min of sustained seizure activity induced by intraperitoneal repetitive timed administrations of pentylenetetrazol in rats at 10, 14, 17 and 21 days of postnatal life. The tissue levels of norepinephrine were markedly reduced in the majority of brain structures, except for striatum at 10 and 14 days. Conversely, dopamine concentrations increased in many areas and at various ages, except in cerebral cortex at 10 and 14 days and in midbrain between 14 and 21 days. PTZ seizures induced marked increases over control levels in the rates of glucose utilization, measured by the quantitative autoradiographic [14C]2-deoxyglucose method, in all dopamine- and norepinephrine-innervated areas studied at 10 and 14 days, except in cerebellar cortex at both ages and in frontal cortex and anteroventral thalamus at 14 days. At 17 and 21 days, glucose utilization remained increased over control levels in some areas, mainly in catecholaminergic cell groupings such as substantia nigra, ventral tegmental area and locus coeruleus, but was significantly reduced in cortex, caudate nucleus and thalamus, and similar to control rates in other regions. The present results suggest that pentylenetetrazol-induced seizures lead to a simultaneous increase in functional activity of norepinephrine neurons and an inhibition of dopaminergic-mediated neurons. They also confirm the maturation of connections, of metabolic activity and of neurotransmitter interaction within the brain, occurring mainly during the third week of postnatal life, paralleled by an increased selective vulnerability of some regions to this kind of insult.
Animals↗
Quantitative histochemical changes in enzymes involved in energy metabolism in the rat brain during postnatal development. II. Glucose-6-phosphate dehydrogenase and beta-hydroxybutyrate dehydrogenase.
The postnatal maturation of glucose-6-phosphate and beta-hydroxybutyrate dehydrogenase activity was assessed by histochemistry in rats at eight postnatal stages, P0, P5, P10, P14, P17, P21, P35 and the adult stage. Enzyme activities were revealed on cryostat brain sections with nitroblue tetrazolium. Both enzyme activities were low and homogeneous at birth, and increased to reach a peak in all areas studied, at P17 for beta-hydroxybutyrate dehydrogenase and at P21 for glucose-6-phosphate dehydrogenase. Then, glucose-6-phosphate dehydrogenase activity decreased regularly by 20-49% from P21 to adult stage, except in cerebellar white matter where activity did not change after P21. beta-hydroxybutyrate dehydrogenase activity decreased regularly from P17 to adult stage in globus pallidus, hippocampus, thalamus, brainstem, genu of corpus callosum and cerebellar white matter. It sensorimotor cortex, medial geniculate body, caudate nucleus, hypothalamus and inferior colliculus, beta-hydroxybutyrate dehydrogenase activity stayed stable between P17 and P35 and decreased thereafter to adult levels. Finally, in parietal, auditory and cerebellar cortices, beta-hydroxybutyrate dehydrogenase activity either stayed stable or slightly increased after P17. The present study shows that there is a quite good correlation between postnatal changes in cerebral glucose-6-phosphate and beta-hydroxybutyrate dehydrogenase activities and the importance of pentose phosphate pathway and ketone body utilization in the developing brain. Our results also reflect the regional heterogeneity of beta-hydroxybutyrate utilization in the adult rat brain, translating into a remaining high activity of beta-hydroxybutyrate dehydrogenase in cerebral cortex.
Aging↗
Quantitative autoradiographic measurements of functional changes induced by generalized seizures in the developing rat brain: central adenosine and benzodiazepine receptors and local cerebral glucose utilization.
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Age Factors↗
Local cerebral glucose utilization in rats with petit mal-like seizures.
The quantitative 2-[14C]deoxyglucose autoradiographic method was applied to the measurement of local cerebral metabolic rates for glucose in a model of genetic petit mal-like seizures in a strain of Wistar rats. During the experimental period, epileptic rats exhibited synchronous spike-and-wave discharges recorded from the cerebral cortex, whereas the electroencephalographic pattern of control animals was normal. An overall consistent increase in local cerebral metabolic rates for glucose was observed in epileptic rats as compared to nonepileptic control rats. This increase was statistically significant in 52 of the 59 cerebral structures studied and concerned all cerebral functional systems. These results are in accordance with positron emission tomography measurements in humans with typical childhood absence epilepsy. There is a lack of anatomical correlation between areas demonstrating hypermetabolism and areas where spike-and-wave discharges are recorded. Thus, the diffuse increase in cerebral energy metabolism in epileptic rats as compared to controls is not directly related to the occurrence of spike and wave discharges.
Animals↗
Physiological and pharmacological properties of adenosine: therapeutic implications.
Adenosine is a nucleoside which has been shown to participate in the regulation of physiological activity in a variety of mammalian tissues, and has been recognized as a homeostatic neuromodulator. It exerts its actions via membrane-bound receptors which have been characterized using biochemical, electrophysiological and radioligand binding techniques. Adenosine has been implicated in the pharmacological actions of several classes of drugs. A number of studies strongly suggest that the nucleoside may regulate cellular activity in many pathological disorders and, in that respect, adenosine derivatives appear as promising candidates for the development of new therapeutic compounds, such as anticonvulsant, anti-ischemic, analgesic and neuroprotective agents.
Adenosine↗
Quantitative autoradiographic study of the postnatal development of adenosine A1 receptors and their coupling to G proteins in the rat brain.
Adenosine is now considered as a major regulatory agent in the mammalian central nervous system. Its actions are mediated by specific receptors which are coupled with an adenylate cyclase system via a G protein. The postnatal development of adenosine A1 receptors was studied by quantitative autoradiography using [3H]N6-cyclohexyladenosine, a potent receptor agonist in 42 rat brain structures. The coupling of these sites to G proteins was examined by measuring the effects of in vitro addition of guanylyl-5'-imidodiphosphate, a stable analogue of guanosine triphosphate, on N6-cyclohexyladenosine binding. [3H]N6-Cyclohexyladenosine-specific binding was quite low at birth, around 10% of adult levels, and exhibited a rather homogeneous distribution pattern, except in thalamic nuclei. Data showed a sequential development of adenosine A1 receptors in relation to the time course of maturation of cerebral structures with a proliferation peak which paralleled rapid brain growth. The time period by which adult levels are reached differed according to the cerebral region studied. N6-Cyclohexyladenosine-specific binding sites appeared to be functionally linked to G proteins in all structures and at all postnatal stages. However, the potency of guanylyl-5'-imidodiphosphate to displace N6-cyclohexyladenosine binding was significantly lower before 5 days of age, suggesting functional changes during postnatal maturation in cerebral pathways modulated by adenosine.
Adenosine↗
Autoradiographic measurement of local cerebral beta-hydroxybutyrate uptake in the rat during postnatal development.
An autoradiographic method has been developed for the regional assessment of cerebral tracer levels after the acute intravenous injection of [3-14C]beta-hydroxybutyrate in developing rats. The animals were studied at five postnatal stages, i.e. postnatal day 10 (P10), P14, P17, P21 and P35. Tracer levels were high from P10 to P17, reaching peak values at P14, which were two- to threefold higher than those at P10. At P17, tracer concentrations were about twice as low as at P14. Between P17 and P21, regional 14C concentrations were again reduced by about twofold in all areas studied and decreased further by about 50% after weaning reaching quite low levels by P35. The distribution of 14C inside sections appeared to be rather homogeneous throughout the brain at all stages studied, never exceeding a ratio higher than 2 at any stage studied. These results are in good agreement with previous data on the rate of uptake and utilization of beta-hydroxybutyrate by the immature rat brain.
3-Hydroxybutyric Acid↗
Quantitative histochemical changes in enzymes involved in energy metabolism in the rat brain during postnatal development. I. Cytochrome oxidase and lactate dehydrogenase.
The postnatal maturation of cytochrome oxidase and lactate dehydrogenase activity was assessed by histochemistry in rats at 8 postnatal stages, P0, P5, P10, P14, P17, P21, P35 and the adult stage. Enzyme activities were revealed on cryostat brain sections with diaminobenzidine for cytochrome oxidase and nitroblue tetrazolium for lactate dehydrogenase. Lactate dehydrogenase activity remained unchanged between P0 and P10, significantly increased in 8 areas of the 14 studied between P10 and P14 and in 6 structures from P14 to P17. These were mainly parietal, auditory and cerebellar cortices, hippocampus, thalamus, hypothalamus and medial geniculate body. There was no further change until P35 and lactate dehydrogenase activity increased then significantly to reach higher adult levels in hippocampus and medial geniculate body. Cytochrome oxidase activity was low from P0 to P10 and increased in 8 regions between P10 and P14. These were all cortices, caudate nucleus, hippocampus, inferior colliculus and genu. Enzyme activity further increased between P14 and P17 in auditory cortex, medial geniculate body and brainstem, did not vary from P17 to P21 but increased by 92 to 371% in all areas between P21 and P35. Cytochrome oxidase activity rose further from P35 to adult stage in hippocampus and medial geniculate body. From birth to adulthood, cytochrome oxidase activity increased 5 to 19 fold and lactate dehydrogenase activity 1.8 to 3.0. The present study shows that there is a quite good correlation between postnatal changes in regional cerebral glucose utilization and activity of enzymes involved in glycolytic and oxidative glucose metabolism in the rat.
Aging↗
Influence of early chronic phenobarbital treatment on cerebral arteriovenous differences of glucose and ketone bodies in the developing rat.
The influence of an early chronic phenobarbital treatment on cerebral arteriovenous differences of glucose, lactate, pyruvate, beta-hydroxybutyrate and acetoacetate was studied in suckling rats. The animals were treated from day 2 to 21 after birth by a daily injection of 50 mg/kg phenobarbital or by saline and were studied at 10, 14 and 21 days. Phenobarbital treatment induced a decrease in cerebral arteriovenous difference of glucose at P14 and no change at P10 and P21. The barbiturate did not have any influence on cerebral arteriovenous difference of lactate and pyruvate at the three stages studied. Cerebral uptake of beta-hydroxybutyrate was unchanged at P10 and increased by two-fold at P14 and by threefold at P21 by phenobarbital. Cerebral arteriovenous difference of acetoacetate was low and did not change with the pharmacological treatment. At P14 and P21, the calculated amount of oxygen used by the brain for the oxidation of ketone bodies was twice as high in barbiturate- as in saline-treated rats and reached values of 47 and 16% respectively in phenobarbital-exposed animals. In addition, the barbiturate seemed to affect the carrier process of beta-hydroxybutyrate from blood to brain. The results of the present study are in good agreement with previous data from our laboratory showing that an early chronic phenobarbital treatment is able to induce a shift in the cerebral energy metabolism balance in favor of ketone bodies.
3-Hydroxybutyric Acid↗
Quantitative autoradiographic study of the postnatal development of benzodiazepine binding sites and their coupling to GABA receptors in the rat brain.
The postnatal development of benzodiazepine binding sites in the rat brain was studied by quantitative receptor autoradiography using [3H]flunitrazepam. The coupling of these sites to GABA receptors was assessed in 43 cerebral structures by examining the effects of in vitro addition of GABA on flunitrazepam specific binding. Benzodiazepine-specific binding was relatively high at birth and exhibited an heterogeneous distribution pattern, anatomically different from the adult one. Data showed a sequential development of benzodiazepine receptors in relation to the time course of maturation of cerebral structures. A proliferation peak which paralleled rapid brain growth was noticed. High levels of benzodiazepine sites were transiently observed in some areas, e.g. thalamus and hypothalamus, and might be related to maturational events. In every brain structure examined, benzodiazepine binding sites were linked to GABA receptors. However, enhancement of flunitrazepam specific binding by exogenous GABA differed according to the structures studied and decreased during development, suggesting some changes in the control of GABA/benzodiazepine regulation during postnatal maturation.
Aging↗
[Application of quantitative autoradiography to the measurement of brain function activity in rats during post-natal development].
Quantitative autoradiographic techniques for the measurement of local cerebral functional activity have been set up in the rat during postnatal development and applied to the measurement of local cerebral glucose and beta-hydroxybutyrate utilization as well as of local cerebral blood flow from 10 to 35 days after birth. These techniques have shown transient peaks of cerebral activity for both energy metabolism, expressed in terms of glucose plus beta-hydroxybutyrate utilization, and blood flow from 14 to 17 days of postnatal age. These methods which allow the mapping of functional activity simultaneously in all cerebral regions of conscious animals represent a tool of choice for the study of metabolism and blood flow regional changes, particularly in pathological situations.
3-Hydroxybutyric Acid↗