Cerebral metabolic and circulatory effects of 1,1,1-trichloroethane,a neurotoxic industrial solvent

The effects of inhaled 1,1,1-trichloroethane (3500, 6000, and 7800 ppm) on behavior, local cerebral blood flow, and local cerebral glucose consumption were studied in awake rats. The effect of the solvent inhalation on the EEG pattern and local cerebral blood flow was also studied in paralyzed animals under N₂O analgesia. Exposure of awake animals to 6000 ppm 1,1,1-trichloroethane induced a decrease in motility and exploratory behavior. At 7800 ppm the rats were clearly ataxic. The local cerebral glucose consumption in 23 brain regions was studied by the [¹⁴C]deoxyglucose technique. A decrease was observed ranging from 14 to 55% of control values. The inferior colliculus and substantia nigra displayed the largest reductions. In exposed animals the local cerebral blood flowincreased in 11 brain structures by 28–45%. In animals under N₂O analgesia, 7400 ppm 1,1,1-trichloroethane induced a depression of the EEG activity. In these animals the local cerebral blood flow increased by 12–99%, with a large variability in blood flow between the different structures. It is concluded that exposure of rats to subanesthetic doses of 1,1,1-trichloroethane induces an increase in cerebral blood flow in spite of a concomitant decrease in glucose consumption and depression of cerebral function.     

Cerebral metabolic effects of glycerol infusion in diabetics with stroke

Measurement of cerebral blood flow and metabolism before and after intravenous infusion of 10% glycerol was investigated in 22 patients with acute cerebral ischemia, 10 of whom had diabetes mellitus and 12 of whom did not. In diabetic patients, resulting increases of hemispheric blood flow and reduction of oxygen consumption and CO₂ production were not significant whereas these changes in the non-diabetic group were significant. In diabetics cerebral glucose consumption and glucose:oxygen utilization ratio increased significantly but remained unchanged in non-diabetics. Following glycerol infusion, release of free fatty acids and inorganic phosphate from the infarcted hemisphere was diminished or reversed in both groups. It is postulated that the differences in cerebral metabolic responses to glycerol among an acute stroke population with diabetes compared to a similar group with acute stroke but without diabetes may be accounted for by the depressed cerebral glucose consumption in diabetics resulting from elevated blood levels of β-hydroxybutyrate, which tends to be reversed by the antiketogenic effect of glycerol and/or by the greater rise in blood glucose in diabetics following glycerol administration. Hence glycerol would not reduce cerebral oxygen consumption and CO₂ production in the diabetics as much as in the non-diabetics although the release of cerebral free fatty acids and inorganic phosphate from the infarcted brain would be reduced or reversed in both groups. It is concluded that intravenous glycerol infusion may improve uncoupled cerebral oxidative phosphorylation or provide the brain with an additional source of high energy phosphate bonds (ATP production) such as glycerol phosphate.     

Cerebral metabolic effects of sigma ligands in the rat

The 2-deoxy-D-[1-14C]glucose method was used to study the effects of sigma-type drugs, BMY 14802, (+)-pentazocine and BW 234U (rimcazole), on cerebral metabolism in 44 male Fischer 344 rats. Drug effects were observed in epithalamic, methathalamic, hypothalamic and mesencephalic regions, as well as in cranial nerve nuclei, the cerebellum, and the medulla oblongata. BMY 14802 and (+)-pentazocine increased local cerebral glucose utilization (LCGU) in areas that generally did not overlap; BW 234U administered 30 min before the radiotracer decreased LCGU. Most of the areas that showed changes in LCGU are known to contain sigma receptor sites. Differences in pharmacological properties, including effects on neuronal electrical excitability, may have resulted in the different distributions and effects of the drugs on LCGU. The present findings did not discriminate the compounds as agonists or antagonists for sigma receptor sites. However, the 2-deoxy-D-[1-14C]glucose method appeared useful in delineating the distribution of CNS responses to sigma drugs in the rat.     

Cerebral metabolic and circulatory changes in the rat during sustained seizures induced by DL-homocysteine

Sustained, generalized seizure activity was induced in anaesthetized (70% N2O), paralyzed and artifically ventilated rats by i.p. DL-homocysteine thiolactone in a dose of 11 mmol/kg. Epileptic discharges in the EEG were accompanied by marked perturbation of tissue metabolites. There was a fall in phosphocreatine concentration to 40% of control but only moderate changes in adenine nucleotides, a marked rise in lactate concentration, and a pronounced increase in the lactate/pyruvate ratio. Excessive amounts of dihydroxyacetone phosphate (and glyceraldehyde phosphate) accumulated, indicating that depletion of NAD+ occurred. There was marked accumulation of ammonia, glutamine and alanine, and reduction in glutamate and aspartate concentrations. Administration of a subconvulsive dose of homocysteine (7.5 mmol/kg) gave rise to changes in ammonia and amino acids, qualitatively similar to those occurring during seizures. It is concluded that although changes in the metabolites of the energy reserve were mainly caused by the induced seizures, those affecting amino acid concentrations were significantly influenced by accumulation of ammonia, secondary to metabolism of injected homocysteine. Cerebral blood flow (CBF) and oxygen utilization (CMRO2) were measured during sustained seizures. CMRO2 rose to 150% of control, with a corresponding increase in CBF.     

Cerebral circulatory and metabolic effects of hypotension produced by deep halothane anaesthesia

Hypotension to a mean blood pressure of 33 mmHg for periods of 70 to 187 minutes was induced by increasing the inspired halothane concentration in 11 baboons which were already anaesthetized with 0·5% halothane, nitrous oxide, and oxygen. During hypotension, cerebral blood flow, measured by Xenon clearance and by a carotid electromagnetic flowmeter, decreased by more than half, and sagittal sinus oxygen saturation was 46%. Cerebral oxygen uptake fell from 5·15 to 3·56 ml./100 g/min at this deeper level of halothane anaesthesia. Cerebral hyperaemia developed after hypotension in those animals which regained a mean blood pressure greater than 70 mmHg. Acidbase measurements on CSF from the cisterna magna revealed no metabolic acidosis during or after hypotension. In all four animals with intact autoregulation before hypotension, this was absent or impaired afterwards.     

Cerebral metabolic and circulatory changes in the rat during sustained seizures induced bydl-homocysteine

Sustained, generalized seizure activity was induced in anaesthetized (70%N₂O), paralyzed and artificially ventilated rats by i.p.dl-homocysteine thiolactone in a dose of 11 mmol/kg. Epileptic discharges in the EEG were accompanied by marked perturbation of tissue metabolites. There was a fall in phosphocreatine concentration to 40% of control but only moderate changes in adenine nucleotides, a marked rise in lactate concentration, and a pronounced increase in the lactate/pyruvate ratio. Excessive amounts of dihydroxyacetone phosphate (and glyceraldehyde phosphate) accumulated, indicating that depletion of NAD⁺ occurred. There was marked accumulation of ammonia, glutamine and alanine, and reduction in glutamate and aspartate concentrations.Administration of a subconvulsive dose of homocysteine (7.5 mmol/kg) gave rise to changes in ammonia and amino acids, qualitatively similar to those occuring during seizures. It is concluded that although changes in the metabolites of the energy reserve were mainly caused by the induced seizures, those affecting amino acid concentrations were significantly influenced by accumulation of ammonia, secondary to metabolism of injected homocysteine.Cerebral blood flow (CBF) and oxygen utilization (CMR_O2) were measured during sustained seizures. CMR_O2 rose to 150% of control, with a corresponding increase in CBF.     

Metabolic heat production and cardiovascular responses to an incremental intravenous infusion of adrenaline in healthy subjects

Increased circulating adrenaline causes a rise in metabolic heat production and well characterized cardiovascular changes. To further characterize these responses we measured metabolic heat production and cardiovascular responses during an incremental infusion of adrenaline (A) in ten healthy subjects (five male; aged 21 to 27 years) and in a placebo controlled (C) study. Plasma adrenaline was unchanged during C, but increased during A (baseline 0.2 nmol/l and low, intermediate and high dose 1.0, 1.9 and 3.1 nmol/l respectively). There was a stepwise increase in metabolic heat production during A (from baseline +0.19, +0.51 and +0.77 kJ/min) with a fall during C (–0.25 kJ/min). During high dose A, plasma adrenaline correlated with increments in metabolic heat production (p < 0.05). Heart rate increased (p < 0.01) and diastolic blood pressure decreased (p < 0.01) at low dose A, and systolic blood pressure increased during intermediate dose A (p < 0.01). Forearm blood flow increased during A and C, with a greater increase in the former during high dose A (p < 0.01). Toe blood flow and toe pulp blood velocity decreased during high dose A (p < 0.05), whereas, skin capillary blood velocity increased at low (p < 0.05) and fell at high (p < 0.01) dose A. In summary, adrenaline increases metabolic heat production and limb blood flow in a dose-dependent fashion. A small increment in plasma adrenaline causes a rise in skin capillary blood flow; and at higher plasma levels blood flow in skin capillaries and arteriovenous anastomoses falls.     

Continuous intravenous infusion of TRH-T: clinical, cardiovascular and endocrinological effects

Seven patients, six suffering from amyotrophic lateral sclerosis (ALS) and one from Friedreich ataxia, were treated with a placebo i.v. infusion during the first day and with TRH-T i.v. infusion at a rate of 2 mg/h for 8 h daily (total daily dosage 16 mg) on the 2 consecutive days. Continuous blood pressure (BP) and EKG monitorings were performed during 3 days infusion. Blood samples were collected for endocrinological evaluations. The neurological evaluation after acute TRH-T treatment showed an objective improvement in 3 of the 8. We found significantly higher values of systolic (max. difference of 10.1 mm Hg) and diastolic (max. difference of 8.8 mm Hg) BP than during placebo, beginning from the 5th h of the infusion (p less than 0.05). A trend in progressive increase of the heart rate (HR) reached statistical significance (p less than 0.01) at the 8th h of the second TRH-T infusion. The cardiovascular changes during the i.v. continuous TRH-T infusions were clinically irrelevant and never required the interruption of the treatment.     

The effects of intravenous theophylline infusion versus intravenous sodium bicarbonate infusion on lithium clearance in normal subjects

Ten normal subjects ingested lithium carbonate (600 mg p.o. b.i.d.) for three 1-week intervals. At the end of each weekly interval, subjects' lithium clearances were randomly perturbed for 12 hours with the subject in a supine position by infusing either normal saline (308 mEq), sodium bicarbonate (350 mEq) in normal saline (308 mEq), or theophylline (mean = 14.0 micrograms/ml) in normal saline (308 mEq). Subjects were placed on a 200 mEq/day sodium diet during the lithium clearance perturbation stages of the study. When each patient's normal saline lithium clearance was used as a control, it was found that the theophylline produced a significantly greater % increase in lithium clearance than did the sodium bicarbonate. Theophylline infusions increased patients' individual lithium clearances by 51 +/- 52%, while sodium bicarbonate infusions increased lithium clearances by 0.6 +/- 33%. Theophylline infusions ought to be investigated as an alternative to hemodialysis in lithium intoxications requiring the immediate reduction of lithium concentrations.     

Cerebral physiological and metabolic effects of hyperventilation in the neonatal dog

To clarify the changes that occur during marked hypocarbia in the neonate, we measured brain blood flow and metabolite levels after 90 minutes of hyperventilation in neonatal dogs. Brain blood flow decreased significantly in diencephalon, brainstem, and spinal cord but not in cerebral cortex or white matter. There was no substantial change in the electroencephalogram. Lactate concentrations, both in telencephalon and in superior sagittal sinus blood, increased significantly, although there was no alteration in levels of ATP or phosphocreatine. Marked hypocarbia in the neonatal dog produces an elevated brain lactate level that may be related to changes in glycolytic rate rather than to tissue ischemia or hypoxia.     

Efficacy of stiripentol in the intravenous pentylenetetrazol infusion seizure model in the rat

The potential effectiveness of stiripentol, a new allylic alcohol anticonvulsant, against generalized epilepsy of the absence type was evaluated in the intravenous pentylenetetrazol (PTZ) infusion seizure model in the rat. The ability of stiripentol to elevate the threshold dose of PTZ in eliciting clonic seizure (i.e., ratio of the post-drug threshold dose to the baseline threshold dose) was measured. Dose-response studies were performed after acute intraperitoneal injection and subacute oral drug treatment. Concentrations of stiripentol in plasma and whole brain were determined. Significant elevation in PTZ threshold dose was observed at a single 300 mg/kg intraperitoneal dose of stiripentol or at plasma levels exceeding 35 micrograms/ml. Maximal anticonvulsant response (i.e., a dose ratio of 3) was reached with doses at or above 450 mg/kg (or plasma concentration greater than or equal to 120 micrograms/ml), along with the appearance of neurotoxicity. Subacute treatment consisted of 9 consecutive oral doses of stiripentol over a 3 day period, until steady-state plasma stiripentol concentration was attained. Response data were obtained at dosage levels of 150, 400 and 800 mg/kg with respective mean steady-state levels of 33.2 +/- 7.8, 61.4 +/- 20.7, and 116 +/- 14 micrograms/ml. Maximal anticonvulsant effect was not reached even at the highest dose of 800 mg/kg. Correlation of threshold dose ratio with plasma and brain stiripentol concentrations showed an approximate 40% loss in anticonvulsant potency during subacute treatment. However, the animals also became more resistant to drug-induced neurotoxicity; about 40% higher plasma or brain stiripentol concentrations had to be reached for a given degree of neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular effects of lisuride continuous intravenous infusion in fluctuating Parkinson's disease

The cardiovascular effects of a continuous intravenous infusion of lisuride plus oral domperidone were studied in 16 fluctuating parkinsonian patients as compared to their usual oral therapy with levodopa plus carbidopa. The study was performed using a 24-h ambulatory recording and an automatic noninvasive device for blood pressure monitoring. During lisuride infusion, a significant increase of systolic blood pressure was observed; however, in three patients, a decrease of systolic-diastolic blood pressure occurred; furthermore, a mild increase of atrial arrhythmias and, in two patients, a short run of atrial fibrillation were noted. Asymptomatic orthostatic hypotension, observed in seven patients during levodopa therapy, disappeared during lisuride infusion. Paradoxical hypertensive effects and disappearance of orthostatic hypotension observed in our patients seem related to the concurrent administration of domperidone.     

Effects of adrenaline infusion on platelet number, volume and release reaction

At the end of a diagnostic right heart catheterization ten patients received an intravenous infusion of l-adrenaline which gradually increased the arterial plasma adrenaline concentration from resting physiological values to high values as seen during myocardial infarction, pheochromocytoma and hypoglycemia. Blood was sampled from the brachial artery, femoral vein and hepatic vein. During the adrenaline infusion venous beta-thromboglobulin concentrations increased 23% from 61 +/- 5 to 80 +/- 7 micrograms/l (mean +/- SE), arterial platelet counts 20% from 212 +/- 17 to 253 +/- 25 X 10(9)/l and arterial platelet volume 4% from 7.25 +/- 0.20 to 7.56 +/- 0.21 femtoliter. All changes were significant at the 5% level. Thus, acute increments of arterial plasma adrenaline significantly stimulated the blood platelet parameters studied.     

Modeling cerebral arteriovenous lactate kinetics after intravenous lactate infusion in the rat.

Venous-arterial lactate differences across the brain during lactate infusion in rats were studied, and the fate of lactate was described with a mathematical model that includes both cerebral and extracerebral kinetics. Ultrafiltration was used to sample continuously and simultaneously arterial and venous blood. Subsequent application of flow injection analysis and biosensors allowed the measurement of glucose and lactate concentrations every minute. Because of the high temporal resolution, arteriovenous lactate kinetics could be modeled in individual experiments. The existence of both a cerebral lactate sink and a lactate exchangeable compartment, representing approximately 24% of brain volume, was thus modeled.     

Effect of nimodipine on cerebral functional and metabolic recovery following ischemia in the rat brain

Whether the calcium entry blocker, nimodipine, prevents the increase in the concentration of free fatty acids and metabolic disturbances during ischemia and promotes functional and metabolic recovery after recirculation were examined. Severe forebrain ischemia in rats was induced by four-vessel occlusion with mild hypotension. After 30 minutes of ischemia, recirculation was started by removal of the arterial clamps and by increasing blood pressure to the preischemic level. Recovery of EEG activity following recirculation was better in the nimodipine-treated group than in the control group. During the ischemic period, there were no significant differences in accumulation of free fatty acids or in depletion of ATP between treated and control groups. At 120 minutes following recirculation, recovery of the ATP level was significantly better in the treated group than in the control group. Therefore, the promotion of functional and metabolic recovery by nimodipine-treatment is suggested to be not due to the prevention of an accumulation of free fatty acids nor to the depletion of ATP during the ischemic period, but to either improvement of postischemic hypoperfusion or a direct action on metabolic processes during reperfusion period.     

Time-course and regional distribution of the metabolic effects of bromocriptine in the rat brain

Local cerebral glucose utilization (LCGU) and motor behavior were examined in awake Fischer-344 rats after administration of the dopaminergic agonist bromocriptine (BROMO). LCGU was measured using the [14C]2-deoxyglucose technique in 63 brain regions at 1,2,3 or 4 h after BROMO 20 mg/kg, and at 4 h after BROMO 100 mg/kg i.p. At 2 h, LCGU was reduced significantly in 13% of the 63 regions examined. The affected regions are related to the topographical distribution of dopaminergic innervation in the brain. At 3-4 h, LCGU remained depressed in some of the above dopaminergic regions, but was elevated significantly in regions which are involved in sensorimotor function. BROMO also produced two behavioral effects depending on time after administration. Locomotor activity was depressed at 1-2 h, and stereotyped behavior appeared at 3-4 h. The time-dependent effects of BROMO may reflect progressively increasing brain concentrations of the drug or of its active metabolites. The coincidence of locomotor depression and reduction of LCGU in dopaminergic regions suggests a role of dopamine autoreceptors in regulation of motor function. Metabolic stimulation of many non-dopaminergic regions when stereotypy is evident suggests that circuit(s) involving these areas may contribute to stereotypy.     

Distribution of dopamine, noradrenaline and adrenaline in coronal sections of the rat lower brainstem

The concentration of the three major catecholamines (CAs) were determined in 500 micron thick coronal sections of the rat medulla oblongata dissected into microcubes. Noradrenaline (NA) concentrations were always found much higher than the levels of the two other CAs in the same microcube. The highest concentrations of the three CAs were found in the dorso-medial region of the lower brainstem, more exactly in the more caudally located parts of the nucleus tractus solitarii (NTS). In the ventro-lateral region, the CA concentrations were lower and, except for adrenaline (A), did not exhibit any substantial change in their rostro-caudal distribution. Conversely, in the dorso-medial region, there was a clear rostro-caudal pattern of distribution of the three CAs. This distribution was similar for the three amines, since only a small difference (about 500 micron) was found between the maximal NA and A concentrations. Since the three CAs are present in highest concentrations within the same dorso-medial or ventro-lateral groups of microcubes, a microdissection of these two areas seems suitable to study simultaneously the metabolism of the three CAs in the rat lower brainstem. These data also suggest a microdissection procedure to study A metabolism within the C2-C3 A cell bodies and within a region more caudally located, rich in A terminals.     

Cerebral metabolism, cognition, and functional abilities in Alzheimer disease

Patients with Alzheimer disease (AD) exhibit profound difficulties in completing instrumental activities of daily living (IADLs), such as managing finances, organizing medications, and food preparation. It is unclear which brain areas underlie IADL deficits in AD. To address this question, we used voxel-based analysis to correlate the performance of IADLs with resting cerebral metabolism as measured during [(18)F] fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging in 44 patients with AD. Poorer ability to complete IADLs was associated with hypometabolism in right-sided cortical regions, including the parietal lobe, posterior temporal cortex, dorsolateral prefrontal cortex, and frontal pole. Follow-up path analyses examining anatomically defined regions of interest (ROI) demonstrated that the association between metabolism and IADLs was mediated by global cognition in frontal ROIs, and partially mediated by global cognition in the parietal ROI. Findings suggest that hypometabolism of right sided brain regions involved in executive functioning, visuospatial processing, attention, and working memory underlie functional impairments in patients with AD.