Na+, K+ ATPase activity is markedly reduced by cis-4-decenoic acid in synaptic plasma membranes from cerebral cortex of rats

We have previously demonstrated that octanoic (OA) and decanoic acids (DA) inhibit Na+, K+ ATPase activity in synaptic plasma membranes from rat brain. The objective of the present study was to investigate the in vitro effects of the other metabolites that accumulate in tissues of medium-chain acyl-CoA dehydrogenase (MCAD)-deficient patients, namely cis-4-decenoic acid (cDA), octanoylcarnitine (OC), hexanoylcarnitine (HC), hexanoylglycine (HG), phenylpropionylglycine (PPG) and suberoylglycine (SG), on Na+, K+ ATPase activity in synaptic plasma membrane from cerebral cortex of 30-day-old rats. cDA, the pathognomonic compound found in this disorder, provoked the strongest inhibition on this enzyme activity at concentrations as low as 0.25 mM, whereas OC inhibited this activity at 1.0 mM and higher concentrations in a dose-dependent manner. In contrast, HC, HG, PPG and SG did not affect Na+, K+ ATPase activity. Furthermore, pre-treatment of cortical homogenates with the antioxidant enzymes catalase plus superoxide dismutase totally prevented cDA-induced Na+, K+ ATPase inhibition. We also provided evidence that cDA, as well as OA and DA, caused lipid peroxidation, which may explain, at least in part, the inhibitory properties of these compounds towards Na+, K+ ATPase. Considering that Na+, K+ ATPase is a critical enzyme for normal brain development and functioning, it is presumed that these findings, especially those regarding to the marked inhibitory effect of cDA, may be involved in the pathophysiology of the neurological dysfunction of MCAD-deficient patients.     

Evidence for a synergistic action of glutaric and 3-hydroxyglutaric acids disturbing rat brain energy metabolism

Glutaric acidemia type I is an inherited metabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase activity leading to accumulation of predominantly glutaric and 3-hydroxyglutaric acids in the brain tissue of the affected patients. Considering that a toxic role was recently postulated for quinolinic acid in the neuropathology of glutaric acidemia type I, in the present work we investigated whether the combination of quinolinic acid with glutaric or 3-hydroxyglutaric acids or the mixture of glutaric plus 3-hydroxyglutaric acids could alter brain energy metabolism. The parameters evaluated in cerebral cortex from young rats were glucose utilization, lactate formation and (14)CO(2) production from labeled glucose and acetate, as well as the activities of pyruvate dehydrogenase and creatine kinase. We first observed that glutaric (5 mM), 3-hydroxyglutaric (1 mM) and quinolinic acids (0.1 microM) per se did not alter these parameters. Similarly, no change of these parameters occurred when combining glutaric with quinolinic acids or 3-hydroxyglutaric with quinolinic acids. In contrast, co-incubation of glutaric plus 3-hydroxyglutaric acids increased glucose utilization, decreased (14)CO(2) generation from glucose, inhibited pyruvate dehydrogenase activity as well as total and mitochondrial creatine kinase activities. The glutaric plus 3-hydroxyglutaric acids-induced inhibitory effects on creatine kinase were prevented by the antioxidants glutathione and catalase plus superoxide dismutase, indicating the participation of reactive oxygen species. Our data indicate a synergic action of glutaric and 3-hydroxyglutaric acids disturbing energy metabolism in cerebral cortex of young rats.     

Normalization of short-chain acylcoenzyme A dehydrogenase after riboflavin treatment in a girl with multiple acylcoenzyme A dehydrogenase-deficient myopathy

A 12-year-old girl was shown to have carnitine-deficient lipid storage myopathy and organic aciduria compatible with multiple acylcoenzyme A (acyl-CoA) dehydrogenase deficiency. In muscle mitochondria, activities of both short-chain acyl-CoA dehydrogenase (SCAD) and medium-chain acyl-CoA dehydrogenase (MCAD) were 35% of normal. Antibodies against purified SCAD, MCAD, and electron-transfer flavoprotein were used for detection of cross-reacting material (CRM) in the patient's mitochondria. Western blot analysis showed absence of SCAD-CRM, reduced amounts of MCAD-CRM, and normal amounts of electron-transfer flavoprotein-CRM. The patient, who was unresponsive to treatment with oral carnitine, improved dramatically with daily administration of 100 mg oral riboflavin. Increase in muscle bulk and strength and resolution of the organic aciduria were associated with normalization of SCAD activity and "reappearance" of SCAD-CRM. In contrast, both MCAD activity and MCAD-CRM remained lower than normal. These results suggest that in some patients with multiple acyl-CoA dehydrogenase deficiency riboflavin supplementation may be effective in restoring the activity of SCAD, and possibly of other mitochondrial flavin-dependent enzymes.     

Medium-chain acyl coenzyme A dehydrogenase deficiency: occurrence in an infant and his father

BACKGROUND: Autosomal recessive inborn errors of metabolism often present as life-threatening disease in infancy and have adverse effects on the nervous system. Parents are usually heterozygotes. This is true of most disorders of fatty acid oxidation, which are rare and present with hypoketotic hypoglycemia. However, the gene for medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency is common in white people, raising the possibility that a parent may be homozygous. OBJECTIVE: To document the occurrence of MCAD deficiency in a 12-month-old boy and his father, both of whom were homozygous for the A985G mutation. DESIGN: Clinical observations and definitive biochemical testing. SETTING: Children's hospital and university laboratory. PARTICIPANTS: One child and one adult. INTERVENTIONS: Diagnosis and treatment. MAIN OUTCOME MEASURES: Clinical outcome; analysis results of plasma and urine for carnitine and organic acids. RESULTS: An infant admitted with an acute illness requiring intensive care was found to have carnitine deficiency and dicarboxylic aciduria; MCAD deficiency was diagnosed by assay of his DNA for the common mutation. Test results of the father revealed him also to be homozygous. CONCLUSION: In MCAD deficiency, as opposed to the usual rare autosomal recessive metabolic disease, a parent may also be an affected homozygote.     

Changes in regional cerebral catecholamines following middle cerebral artery occlusion in the rat

Ischemic brain injury affects the content and metabolism of brain monomines. Our aim was to know the time course of changes in regional cerebral catecholamines during focal cerebral ischemia, and whether focal cerebral ischemia may affect the metabolism of catecholamines in distant area of the brain. Methods Fifty-five rats were subjected to occlusion of the middle cerebral artery (MCA) on the olfactory tract, under halothane anesthesia. Fourteen animals were sham-operated group. Animals were decapitated at 1/2, 1,2,3,6,12 and 24 hours post-occlusion (PO), respectively. The brains were removed, and the brain structures dissected out include bilateral corpus striatum, cerebral cortex (MCA territory) and cerebellar hemisphere. Catecholamines were extracted by alumina procedure, and determined by high-performance liquid chromatography with electrochemical detection. Results Dopamine (DA) contents, in ipsilateral corpus striatum and cerebral cortex to the ischemia, decreased at 1 hour PO, and reached, at 6 hours PO, to 40% of control value in corpus striatum and 30% in cerebral cortex, respectively. After 6 hours PO, DA remained low. Norepinephrine (NE) content in the ipsilateral corpus striatum gradually reduced and reached to 60% of control value at 24 hours PO. NE in the ipsilateral cerebral cortex decreased to 50% of control at 1 hour PO, and thereafter remained reduced. In the contralateral corpus striatum and cerebral cortex, either DA or NE showed no significant changes, except 1/2 hour PO. NE contents in bilateral cerebral cortex showed a transient increase at 1/2 hour PO. Cerebellar NE content, bilaterally, reduced slowly to 70% of control at 24 hours PO.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glycine Intracerebroventricular Administration Disrupts Mitochondrial Energy Homeostasis in Cerebral Cortex and Striatum of Young Rats

High tissue levels of glycine (GLY) are the biochemical hallmark of nonketotic hyperglycinemia (NKH), an inherited metabolic disease clinically characterized by severe neurological symptoms and brain abnormalities. Considering that the mechanisms underlying the neuropathology of this disease are not fully established, the present work investigated the in vivo effects of intracerebroventricular administration of GLY on important parameters of energy metabolism in cerebral cortex and striatum from young rats. Our results show that GLY reduced CO₂ production using glucose as substrate and inhibited the activities of citrate synthase and isocitrate dehydrogenase in striatum, whereas no alterations of these parameters were verified in cerebral cortex 30 min after GLY injection. We also observed that GLY diminished the activities of complex IV in cerebral cortex and complex I–III in striatum at 30 min and inhibited complex I–III activity in striatum at 24 h after its injection. Furthermore, GLY reduced the activity of total and mitochondrial creatine kinase in both brain structures 30 min and 24 h after its administration. In contrast, the activity of Na⁺, K⁺-ATPase was not altered by GLY. Finally, the antioxidants N-acetylcysteine and creatine, and the NMDA receptor antagonist MK-801 attenuated or fully prevented the inhibitory effects of GLY on creatine kinase and respiratory complexes in cerebral cortex and striatum. Our data indicate that crucial pathways for energy production and intracellular energy transfer are severely compromised by GLY. It is proposed that bioenergetic impairment induced by GLY in vivo may contribute to the neurological dysfunction found in patients affected by NKH.     

Origin of extracellular dopamine from dopamine and noradrenaline neurons in the medial prefrontal and occipital cortex

Our recent studies suggest that extracellular dopamine (DA) in the cerebral cortex not only originates from dopaminergic terminals but is also coreleased with noradrenaline (NA) from noradrenergic terminals [Devoto et al. (2001) Mol Psychiatry 6:657-664]. To further clarify this issue, the concentrations of extracellular DA, its deaminated metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), and NA were compared by microdialysis in the medial prefrontal cortex (mPFC), an area densely innervated by NA and DA neurons, and in the occipital cortex (OCC), equally innervated by NA but receiving scarce DA projections. Moreover, the effect of the alpha(2)-adrenoceptor agonist clonidine locally perfused into the locus coeruleus (LC) on extracellular NA, DA, and DOPAC in the mPFC, OCC, and ventral striatum was investigated. Consistent with the homogeneous NA innervation, extracellular NA concentration was similar in both cortices, while extracellular DA in the OCC, in spite of the scarce DA afference in this area, was only 37% lower than in the mPFC; extracellular DOPAC in the OCC was 81% lower than in the mPFC. Consistent with its ability to inhibit NA neurons, clonidine (10 microM) reduced extracellular NA by about 65 and 80% in the OCC and the mPFC, respectively, but also reduced extracellular DA by 70 and 50% in the OCC and the mPFC, respectively. Clonidine reduced DOPAC in the OCC (by about 40%) but not in the mPFC. In the ventral striatum clonidine reduced NA (by 30%) but not DA and DOPAC. After inhibition of the DA and NA transporter, by perfusing 100 microM desmethyl-imipramine into the mPFC, clonidine perfusion into the LC reduced extracellular NA and DA in the mPFC by about 50%. The results indicate that most of extracellular DA in the OCC and a significant portion in the mPFC reflect the activity of NA neurons and support the hypothesis that extracellular DA in the cerebral cortex may originate not only from DA but also from NA neurons.     

Basal levels of metabolic activity are elevated in Genetic Absence Epilepsy Rats from Strasbourg (GAERS): measurement of regional activity of cytochrome oxidase and lactate dehydrogenase by histochemistry

The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are considered an isomorphic, predictive, and homologous model of human generalized absence epilepsy. It is characterized by the expression of spike-and-wave discharges in the thalamus and cortex. In this strain, basal regional rates of cerebral glucose utilization measured by the quantitative autoradiographic [(14)C]2-deoxyglucose technique display a widespread consistent increase compared to a selected strain of genetically nonepileptic rats (NE). In order to verify whether these high rates of glucose metabolism are paralleled by elevated activities of the enzymes of the glycolytic and tricarboxylic acid cycle pathways, we measured by histochemistry the regional activity of the two key enzymes of glucose metabolism, lactate dehydrogenase (LDH) for the anaerobic pathway and cytochrome oxidase (CO) for the aerobic pathway coupled to oxidative phosphorylation. CO and LDH activities were significantly higher in GAERS than in NE rats in 24 and 28 of the 30 brain regions studied, respectively. The differences in CO and LDH activity between both strains were widespread, affected all brain systems studied, and ranged from 12 to 63%. The data of the present study confirm the generalized increase in cerebral glucose metabolism in GAERS, occurring both at the glycolytic and at the oxidative step. However, they still do not allow us to understand why the ubiquitous mutation(s) generates spike-and-wave discharges only in the thalamocortical circuit.     

Changes in Local Cerebral Glucose Utilization and Dopamine Metabolism in the Rat Brain Following Acute Administration of Haloperidol

Abstract: The effects of acute administration of haloperidol on local cerebral glucose utilization (LCGU) in 26 discrete regions of the rat brain were examined by the quantitative autoradiographic [¹⁴C] 2-deoxy-D-glucose technique and compared with the changes in dopamine (DA) metabolism in 13 brain regions examined by a high performance liquid chromatographic assay. A moderate dose (0.25 mg/kg) of acute haloperidol significantly reduced LCGU in a few brain regions; a high dose (1.0 mg/kg) reduced LCGU in 11 regions including the prefrontal cortex, thalamus and other subcortical structures, but not in the caudate putamen or accumbens nucleus. However, the levels of DA metabolite in the caudate-putamen, accumbens nucleus, prefrontal cortex, and medial thalamus were strikingly elevated with both doses of haloperidol. Thus, the changes in LCGU did not parallel presynaptic DA metabolism in terms of direction or distribution, and they might represent mainly the activities of postsynaptic sites.     

Monoamine, amino acid and cholinergic interactions in slices of rat cerebral cortex

Interactions of monoamine, amino acid and cholinergic transmitter systems were studied in slices of rat cerebral cortex using a superfusion procedure and measuring release of endogenous dopamine (DA), norepinephrine (NE), serotonin (5-HT), GABA, glutamate (GLU) and aspartate (ASP). Depolarizing concentrations of K+ were used to induce a Ca2+-dependent, Mg2+-inhibited release of the monoamines and amino acids. Submaximal release of the monoamines and amino acids was observed at 35 mM K+, which permitted studies of possible excitatory or inhibitory actions of the added agents. The 35 mM K+-stimulated, Ca2+-dependent release of GABA was inhibited 40, 30 and 25% by 100 microM NE, DA and 5-HT, respectively. The release of GLU was potentiated by NE and reduced by DA. Both DA and 5-HT inhibited the release of ASP. The Ca2+-dependent, K+-stimulated release of endogenous NE, DA and 5-HT was not altered by 100 microM GABA, GLU or ASP. However, 100 microM GLU did enhance the stimulated release of GABA. The cholinergic agonist, carbachol, enhanced the stimulated release of NE, 5-HT and GLU 10, 60 and 40%, respectively. On the other hand, carbachol attenuated the release of DA and GABA approximately 20%. One interpretation of the data is that the amino acid transmitter pathways in slices of the cerebral cortex of the rat can be controlled by monoaminergic and cholinergic systems while the monoamine afferents appear to have a cholinergic regulation but not a major direct amino acid transmitter influence.     

Local uptake of (14)C-labeled acetate and butyrate in rat brain in vivo during spreading cortical depression.

Spreading depression severely disrupts ion homeostasis, causes sensory neglect and motor impairment, and is associated with stroke and migraine. Glucose utilization (CMR(glc)) and lactate production rise during spreading depression, but the metabolic changes in different brain cell types are unknown. Uptake of (14)C-labeled compounds known to be preferentially metabolized by the glial tricarboxylic acid cycle was, therefore, examined during unilateral KCl-induced spreading cortical depression in conscious, normoxic rats. [(14)C]Metabolites derived from [(14)C]butyrate in K+ -treated tissue rose 21% compared to that of untreated contralateral control cortex, whereas incorporation of H(14)CO(3) into metabolites in K+ -treated tissue was reduced to 86% of control. Autoradiographic analysis showed that laminar labeling of cerebral cortex by both (14)C-labeled acetate and butyrate was elevated heterogeneously throughout cortex by an average of 23%; the increase was greatest (approximately 40%) in tissue adjacent to the K+ application site. Local uptake of acetate, butyrate, and deoxyglucose showed similar patterns, and monocarboxylic acid uptake was highest in the structures in which apparent loss of labeled metabolites of [6-(14)C]glucose was greatest. Enhancement of net uptake of acetate and butyrate in cerebral cortex during spreading depression is tentatively ascribed to increased astrocyte metabolism.     

A comparison of the effects of carbon monoxide intoxication and low-oxygen gas mixtures on cerebral biogenic amine metabolism

The effects of 1% CO on cerebral biogenic amine metabolism was studied by measurement of cerebral hemisphere contents of 5-hydroxytryptophan (5-HTP), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dihydroxyphenylalanine (DOPA) and dopamine (DA). The results indicated that 1% CO is associated with an increased cerebral hemisphere content of DA. In CO-exposed animals treated with the decarboxylase inhibitor, 3-hydroxybenzyl hydrazine, the rate of tryptophan hydroxylation was reduced. When the duration of exposure to a given range of arterial oxygen content was matched to that of a group exposed to a low-oxygen gas mixture (5% O2) the rates of tryptophan hydroxylation were equivalent. This suggests that at a given arterial total oxygen content the tissue oxygen tension and supply are equivalent in low O2 or CO hypoxia. Assessment of the effects of 1% CO on tyrosine hydroxylation indicated no significant effect on this enzyme step.     

Effect of l-Tyrosine In Vitro and In Vivo on Energy Metabolism Parameters in Brain and Liver of Young Rats

Tyrosinemia is a rare disease caused by a single mutation to the gene that code for the enzyme responsible for tyrosine catabolism. Because the mechanisms underlying the neurological dysfunction in hypertyrosinemic patients are poorly understood, we evaluated the in vitro and in vivo effect of l-tyrosine on the activities of the enzymes citrate synthase, malate dehydrogenase, succinate dehydrogenase and complexes of the mitochondrial respiratory chain in the brains and livers of young rats. Thirty-day-old Wistar rats were killed by decapitation, and the brains and livers were harvested. l-Tyrosine (0.1, 1.0, 2.0 or 4.0 mM) was added to the reaction medium. For in vivo studies, Wistar rats were killed 1 h after a single intraperitoneal injection of either tyrosine (500 mg/kg) or saline. The activities of energy metabolism enzymes were evaluated. In this research, we demonstrated in vitro that l-tyrosine inhibited citrate synthase activity in the posterior cortex and that succinate dehydrogenase was increased in the posterior cortex, hippocampus, striatum and liver. The complex I activity was only inhibited in the hippocampus, whereas complex II activity was inhibited in the hippocampus, cortex and liver. Complex IV activity decreased in the posterior cortex. The acute administration of l-tyrosine inhibited enzyme malate dehydrogenase, citrate synthase and complexes II, II–III and IV in the posterior cortex and liver. The enzyme succinate dehydrogenase and complex I activity were inhibited in the posterior cortex and increased in the striatum. These results suggest impairment in energy metabolism that is likely mediated by oxidative stress.     

Neonatal lesions of the ventral tegmental area affect monoaminergic responses to stress in the medial prefrontal cortex and other dopamine projection areas in adulthood.

A mean decrease of dopamine (DA) to 20% and serotonin to 25-30% of control levels was found in the medial prefrontal cortex (mPFC) and amygdala/piriform cortex (A/PC) of adult rats with neonatal lesions of the ventral tegmental area (VTA). The metabolites were less decreased suggesting an increased activity of the remaining terminals. Moderate decreases to 30-75% were detected for DA and serotonin in the nucleus accumbens, olfactory tubercle and striatum. Footshock stress in control animals resulted in a strong increase (200% of control) in DA metabolites in mPFC and A/PC. The noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in A/PC was strongly increased to 240%. When stress was given to the neonatally VTA-lesioned animals these neurochemical responses were reduced compared to the nonlesioned rats. In the case of DA in the mPFC this was clearly due to a loss of stress response in the severe lesion group where DA is depleted to less than 20% of control. The stress-induced small increases in DA metabolism in tubercle, accumbens and striatum and serotonin metabolism in the striatum (20-40%) were entirely lost, while the MHPG increase in the A/PC was blunted. The present results suggest that moderate and severe lesions of DA and serotonin alter or prevent the normal activation of these transmitter systems and even of the noradrenergic system to stress.     

Acute renal failure potentiates brain energy dysfunction elicited by methylmalonic acid

The influence of acute renal failure induced by gentamicin administration on the effects of MMA on mitochondrial respiratory chain complexes, citrate synthase, succinate dehydrogenase and creatine kinase activities in cerebral cortex and kidney of young rats were investigated. Animals received one intraperitoneal injection of saline or gentamicin (70 mg/kg). One hour after, the animals received three consecutive subcutaneous injections of MMA (1.67 μmol/g) or saline (11 h interval between injections) and 60 min after the last injection the animals were killed. Acute MMA administration decreased creatine kinase activity in both tissues and increased complexes I–III activity in cerebral cortex. Creatine kinase activity was also inhibited by gentamicin administration. Simultaneous administration of MMA and gentamicin increased the activities of citrate synthase in cerebral cortex and kidney and complexes II–III in cerebral cortex. The other enzyme activities in cerebral cortex and kidney of animals receiving MMA plus gentamicin did not significantly differ from those observed in animals receiving only MMA. Our present data is line with the hypothesis that MMA acts as a toxin in brain and kidney of rats and suggest that renal injury potentiates the toxicity of MMA on the Krebs cycle and respiratory chain in brain and peripheral tissues.     

Lesions of the basal forebrain in rat selectively impair the cortical vasodilation elicited from cerebellar fastigial nucleus

We sought to determine in rat, whether interruption of the major extrathalamic projections to the cerebral cortex originating in and projecting through the basal forebrain (BF), will impair the increase in regional cerebral blood flow (rCBF), but not metabolism, elicited in the cerebral cortex by electrical stimulation of the cerebellar fastigial nucleus (FN). Studies were conducted in anesthetized, paralyzed, ventilated rats, with blood gases controlled and AP maintained in the autoregulated range. Electrolytic lesions were placed unilaterally in the BF at the level of the lateral preoptic region lying in rostral portions of the medial forebrain bundle and resulted in a reduction of up to 47% of the choline acetyltransferase activity in the ipsilateral cerebral cortex. rCBF was measured in homogenates of 9 paired brain regions by the 14C-iodoantipyrine technique. In unlesioned rats, FN stimulation symmetrically and significantly (P less than 0.05) increased rCBF in all brain regions with the greatest increase (to 180%) in the frontal cortex. Two days following a unilateral BF lesion, FN stimulation failed to increase rCBF in the ipsilateral cerebral cortex distal to the BF lesion. In contrast, rCBF was increased to an almost comparable degree in the remainder of the brain. BF lesions alone resulted in a 18-23% reduction in cortical rCBF ipsilaterally (P less than 0.025). BF lesions did not alter the cerebrovascular vasodilation elicited by CO2 nor perturb autoregulation. The cortical vasodilation elicited by FN stimulation is mediated by intrinsic neuronal pathways and depends upon the integrity of neurons, possibly cholinergic, originating in, or passing through, the BF.     

The effects of neonatal thyroid deficiency on acetylcholine synthesis and glucose oxidation in rat corpus striatum

The effects of propylthiouracil (PTU)-induced thyroid deficiency on [14C]acetylcholine synthesis and 14CO2 production from [U-14C]glucose in vitro, by fine prisms of the corpus striatum were investigated in developing rats. Consistent with deficits in choline uptake and choline acetyltransferase activity (Kalaria et al.17), PTU-treatment from two days after birth significantly impaired (27-39%) [14C]acetylcholine synthesis in striatal tissue taken from 3- or 6-week-old animals. In the thyroid-deficient (Tx) animals, 14CO2 production from [14C]glucose was unchanged in incubations in the presence of 5 mM K+ but was significantly reduced (33%) in medium with 31 mM K+ concentration. The addition of 10 mM DL-3-hydroxybutyrate in incubations with 5 mM K+ persistently inhibited 14CO2 production by striatal samples from the Tx rats. The fraction acetylated of [3H]choline accumulated by striatal prisms was unaffected by the PTU-induced thyroid deficiency. These findings suggest the development of fewer cholinergic nerve terminals in striatum during neonatal thyroid deficiency. Cholinergic nerve terminals that develop seem unaffected in their capacity for K+-stimulation and in their ability to acetylate transported [3H]choline.     

Diffuse prolonged depression of cerebral oxidative metabolism following concussive brain injury in the rat: a cytochrome oxidase histochemistry study.

Utilizing a lateral fluid percussion injury as a model of cerebral concussion, rats were studied histochemically measuring the degree of cytochrome oxidase activity present within different structures at different times following injury. After concussion, the cerebral cortex ipsilateral to the site of injury exhibited a diffuse decrease in its level of chromotome oxidase (CO) activity beginning at as soon as one day and lasting for up to 10 days after the insult. The ipsilateral dorsal hippocampus also exhibited an injury-induced decrease in CO activity, however, it was not as severe as in the cortex. These results indicate that oxidative metabolism is depressed primarily within the cerebral cortex and hippocampus for several days following a cerebral concussion. We propose that this period of metabolic depression may delineate a period of time during which the injured brain is unable to function normally and thus would be vulnerable to a second insult.     

Changes in limbic dopamine metabolism following quinolinic acid lesions of the left entorhinal cortex in rats

To examine the effects of lesions of the entorhinal cortex on limbic dopamine (DA) metabolism, DA and its metabolites were assayed in five brain regions (the medial prefrontal cortex, anterior cingulate cortex, caudate-putamen, accumbens nucleus, and lateral amygdala), 14 and 28 days after quinolinic acid or sham lesions of the left entorhinal cortex in rats. Concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) on day 14 in the medial prefrontal cortex, accumbens nucleus, and lateral amygdala of the entorhinal cortex lesioned animals were significantly decreased compared with the controls, but they returned to control levels on day 28. The concentration of DA in the lateral amygdala and spontaneous locomotion to a novel environment were significantly increased on day 28 after the lesion. These results suggest that entorhinal cortex lesions alter mesolimbic dopamine metabolism, particularly in the amygdala.     

Effects of CDP-choline on neurologic deficits and cerebral glucose metabolism in a rat model of cerebral ischemia

The effects of cytidine 5'-diphosphocholine (CDP-choline) on neurologic deficits and cerebral glucose metabolism were studied in a rat model of transient cerebral ischemia. Cerebral ischemia was induced by occluding both common carotid arteries for 20 or 30 minutes 24 hours after the vertebral arteries were permanently occluded by electrocautery. CDP-choline was administered intraperitoneally twice daily for 4 days after reestablishing carotid blood flow. CDP-choline at two dosages (50 and 250 mg/kg) shortened the time required for recovery of spontaneous motor activity in a dose-related manner; recovery time was measured early after reperfusion. Neurologic signs were observed for 10 days. High-dose CDP-choline improved neurologic signs in the rats within 20-30 minutes of ischemia. When cerebral glucose metabolism was assessed on Day 4, increases in the levels of glucose and pyruvate were accompanied by decreases in the synthesis of labeled acetylcholine from uniformly labeled [14C]glucose measured in the cerebral cortex of rats with 30 minutes of ischemia. High-dose CDP-choline also attenuated changes in these variables. CDP-[1,2-14C]choline injected intravenously 10 minutes after reperfusion was used for membrane lipid biosynthesis. These results indicate that CDP-choline has beneficial effects on brain dysfunction induced by cerebral ischemia, which may be due in part to the restorative effects of CDP-choline on disturbed cerebral glucose metabolism, probably by stimulating phospholipid biosynthesis.