Susceptibility to neuroleptic malignant syndrome in Parkinson's disease.

OBJECTIVE: To determine susceptibility to neuroleptic malignant syndrome (NMS) in patients with PD in relation to central monoamine metabolism. METHODS: CSF levels of homovanillic acid (HVA), 3-methoxy-4-hydroxy phenyletilene glycol (MHPG), and 5-hydroxyindole acetic acid (5-HIAA) were assayed in 98 PD patients (mean age, 77.2 years), including 11 patients with a prior NMS-like episode, by high-performance liquid chromatography with electrochemical detection. RESULTS: Patients with a previous NMS-like episode had worse parkinsonian disability as measured by Hoehn & Yahr scale (3.7 +/- 0.8 versus 3.0 +/- 1.1; p = 0.038) and lower CSF HVA levels (20.9 +/- 17.3 versus 44.7 +/- 22.2 ng/mL; p = 0.001) compared to those without, despite similar age, disease duration, and daily dosages of antiparkinsonian drugs between groups. Logistic regression analysis showed that the CSF HVA level (p = 0.008), but not 5-HIAA level (p = 0.621), was significantly and independently related to NMS, and that the MHPG level (p = 0.070) was tendentially associated with the disorder. Odds ratios (95% confidence intervals) corresponding to 10 ng/mL increment in CSF HVA, MHPG, and 5-HIAA levels were 0.30 (0.13 to 0.73), 4.03 (0.89 to 18.2) and 1.29 (0.47 to 3.58), respectively. CONCLUSIONS: Central dopaminergic and possible noradrenergic activity contributes to NMS development in an elderly population of PD patients. Measuring CSF levels of monoamine metabolites may provide a means for identifying NMS susceptibility in PD patients.

Hereditary spastic paraplegia with a thin corpus callosum and thalamic involvement in Japan.

The authors examined two Japanese siblings with a recessive hereditary spastic paraplegia (HSP) with dementia and a thin corpus callosum. Both showed thalamic glucose hypometabolism on PET. Recessive HSP with a thin corpus callosum is a rare disorder, with less than 20 reported patients, that may be a Japanese subtype of HSP.

Increased intracellular Ca2+ concentration in the hippocampal CA1 area during global ischemia and reperfusion in the rat: a possible cause of delayed neuronal death.

The crucial role of free cytosolic Ca2+ in ischemic neuronal damage has been studied in recent years. In the present report, changes in the intracellular Ca2+ concentration in the hippocampal CA1 area during transient global ischemia and reperfusion were measured using in vivo Ca2+ fluorometry with fura-2 in the four-vessel occlusion and reperfusion model in halothane-anesthetized rats. Marked changes were seen during 10-min global ischemia, with the intracellular Ca2+ concentration increasing gradually following application of the ischemic insult and rapidly about 2 min after the beginning of ischemia, and continuing to increase until reperfusion. On reperfusion, the intracellular Ca2+ concentration began to decrease and returned to the pre-ischemic level within 15 min. Induction of severe global ischemia was confirmed by the complete suppression of synaptic activity and the decrease in hippocampal temperature in the CA1 area. After seven days, CA1 pyramidal cell loss was observed histopathologically in the same rats which had undergone measurement of the intracellular Ca2+ concentration changes. In the present study, a temporal profile of the free cytosolic Ca2+ dynamics during ischemic and early post-ischemic period was determined in vivo. The results demonstrate that the intracellular Ca2+ concentration in the hippocampal CA1 area is transiently and markedly increased during a brief ischemia-inducing delayed neuronal death, implying that Ca2+ overload during cerebral ischemia is a possible cause of the delayed cell death of CA1 pyramidal neurons.

Effects of simvastatin on serum lipids and atherosclerosis in WHHL rabbits.

Watanabe heritable hyperlipidemic rabbits aged three months (young group) or 10 months (adult group) received 10 mg/kg of simvastatin daily for 24 weeks. Serum levels of total cholesterol, triglycerides, and beta-lipoproteins were reduced significantly in the treated animals but not in untreated controls. The decreases were greater in the young than in the adult animals. Levels of high-density lipoprotein cholesterol were not affected by treatment. At 24 weeks, the extent of atheromatous lesions on the thoracic-abdominal aorta was lower in the treated animals than in the controls, but the difference was significant only in the young animals. The results indicate that simvastatin would be effective in the treatment of atherosclerosis.

Effect of nicardipine, a Ca2+ channel blocker, on pyruvate dehydrogenase activity and energy metabolites during cerebral ischemia and reperfusion in gerbil brain.

The purpose of this study was to determine if nicardipine, a calcium ion channel blocker, affects pyruvate dehydrogenase (PDH) activity and improves energy metabolism during cerebral ischemia and reperfusion. Cerebral ischemia was induced, using the bilateral carotid artery occlusion method, for 60 min followed by reperfusion up to 120 min in gerbils. Nicardipine (1 mg/kg) or saline (vehicle-treated) was given to gerbils 30 min prior to the occlusion of the common carotid arteries. PDH activity and metabolites (ATP, PCr, and lactate) were measured in cortex prior to ischemia, immediately following ischemia, and after each reperfusion period. After 60 min ischemia, PDH activity increased in both groups, and was significantly higher in the nicardipine-treated group. After 20 min reperfusion, PDH activity in the nicardipine-treated group recovered to control levels, whereas, the PDH activity in the vehicle-treated group remained elevated, and was higher than the nicardipine-treated animals. At 60 and 120 min reperfusion, the activities in the vehicle-treated group were significantly below control levels, there were no differences, however, between the two groups. ATP and PCr concentrations were markedly depleted immediately after ischemia in both groups. ATP levels at 20 min reperfusion and PCr levels at 60 min reperfusion were significantly higher in the nicardipine-treated group. Lactate concentrations in both groups increased 7-8 fold, similarly, immediately after ischemia. During reperfusion, the lactate remained elevated in both groups, though the levels in the nicardipine-treated group were lower than those in the vehicle-treated group, but not significantly. Nicardipine treatment normalized PDH activity quickly and improved energy metabolism after reperfusion.

Ischemic tolerance phenomenon from an approach of energy metabolism and the mitochondrial enzyme activity of pyruvate dehydrogenase in gerbils.

The objective of this study was to determine if the pretreatment with a sublethal ischemic insult, which has been shown to protect against delayed neuronal death, effects the recovery of energy metabolites or alters the activity of pyruvate dehydrogenase (PDH) following transient cerebral ischemia. Gerbils were pretreated with a sublethal ischemic insult, 2 min of bilateral common carotid artery occlusion, and 24 h later given a 5-min lethal ischemic insult. Animals were reperfused for 0, 10, or 60 min, or 1, 3 or 7 days. Brain metabolites, ATP, PCr, and lactate, and PDH activity were measured in the cortex and the hippocampal CA1 region. The pretreatment had no effect on ATP and PCr depletion or on lactate accumulation after the 5-min insult, nor on their recovery up to 1 day reperfusion, although there was a difference in the lactate levels of the non-pretreated and the pretreated gerbils after 10 min reperfusion. The pretreatment also had no effect on PDH activity during ischemia and reperfusion in either region. However, at 3 days reperfusion the non-pretreated animals exhibited a secondary decrease in ATP levels in the hippocampus. At 7 days reperfusion, ATP levels in the hippocampus of both the pretreated animals and the non-pretreated animals were significantly decreased compared to controls. Additionally, the level of ATP in the non-pretreated group was significantly lower than that in the pretreated group. The pretreatment with a sublethal ischemic insult did not effect the initial recovery of metabolites or the activity of PDH following transient cerebral ischemia. However, it protected against the secondary decrease of ATP levels in the hippocampus. Thus, the induction of ischemic tolerance is not caused by a reduction in metabolic impairment during the secondary insult.

Effect of hyperglycemia on pyruvate dehydrogenase activity and energy metabolites during ischemia and reperfusion in gerbil brain.

The effects of hyperglycemia on brain pyruvate dehydrogenase (PDH) and metabolites (ATP, PCr, and lactate) were investigated at 20 min ischemia, 0, 20, and 60 min, and 4 h reperfusion. During reperfusion, PDH activities were suppressed corresponding to the poor recovery of ATP and PCr concentrations and the increase in lactate concentration in the hyperglycemic group, suggesting that preischemic hyperglycemia may impair metabolism by suppressing PDH activity.

1H magnetic resonance spectroscopic imaging of permanent focal cerebral ischemia in rat: longitudinal metabolic changes in ischemic core and rim.

The purpose of this study was to determine whether regional differences in metabolites can be seen chronologically in permanent focal cerebral ischemia using 1H magnetic resonance spectroscopic imaging (MRSI), and whether these changes reflect pathological outcome. Regional variation in metabolites after permanent focal ischemia were investigated longitudinally in rats using 1H MRSI for a total of 7 days and then compared to histopathological findings. Four hours after the induction of ischemia, N-acetyl-L-aspartate (NAA) levels in the lateral caudo-putamen and the somatosensory cortex, core ischemic regions, decreased 22 and 40%, respectively. This reduction in NAA was coupled with a marked rise in lactate. In the medial caudo-putamen, the ischemic rim, however, NAA was preserved in spite of a marked increase in lactate. By 24 h post ischemia, the levels of NAA in medial caudo-putamen (ischemic rim in caudate) also decreased significantly. However NAA in cingulated cortex (ischemic rim in cortex) decreased more gradually between 24 and 48 h. This regional difference can reflect the severity of metabolic derangement in the acute stage. After 96 h following ischemia, the levels of all metabolites detected by 1H MRSI had decreased and the levels of NAA decline reflected the severity of histopathological damage. In conclusion, the regional metabolic differences could be assessed by 1H MRSI chronologically, and the depth of NAA decline reflected histopathological changes in the chronic stage.

The effect of duration of cerebral ischemia on brain pyruvate dehydrogenase activity, energy metabolites, and blood flow during reperfusion in gerbil brain.

The objective of this study was to determine whether the duration of an ischemic insult effects the activity of the mitochondrial enzyme pyruvate dehydrogenase (PDH) in relation to the recovery of metabolites and regional cerebral blood flow (rCBF) immediately after ischemia and during reperfusion in gerbil cortex. Cerebral ischemia was induced, using the bilateral carotid artery occlusion method, for 20 or 60 min, followed by reperfusion up to 120 min. Immediately after ischemia PDH activity increased threefold regardless of ischemic duration. In the 60-min ischemic group, PDH remained activated, the recovery of high energy phosphates and the clearance of lactate were poor, and the rCBF was 48% of controls after 20-min reperfusion, decreasing gradually to 26% at 120-min reperfusion. In the 20-min ischemic group, PDH activity normalized quickly, the restoration of energy phosphates was good, there was a quick reduction in lactate within the first 60 min of reperfusion, and the rCBF was 65% of control at 20-min reperfusion, and remained over 48% of control throughout reperfusion. Recovery of metabolism after reperfusion did not parallel the changes in rCBF in either group, most noticeably in the 60-min ischemic group. The slow normalization of PDH activity reflected the poor recovery of metabolites in the 60-min ischemic group, indicating that PDH activity is important in the resynthesis of energy metabolites during reperfusion. In conclusion, prolonging the ischemic insult effected PDH activity during reperfusion, impaired recovery of energy metabolites, and worsened the recovery of rCBF.

Effect of long-term administration of ethyl eicosapentate (EPA-E) on local cerebral blood flow and glucose utilization in stroke-prone spontaneously hypertensive rats (SHRSP).

The objective of this study was to determine the effect of ethyl eicosopentate (EPA-E) on local cerebral blood flow (1-CBF) and local glucose utilization (1-CGU) in specific regions of the brain in stroke-prone spontaneously hypertensive rats (SHRSP). EPA-E (100 mg/kg body weight) or saline was orally administered to 8-week-old SHRSP. L-CBF and 1-CGU in the EPA-E-treated, saline-treated, and 8-week-old control rats were measured autoradiographically using 14C-iodoantipyrine and 14C-deoxyglucose (Sakurada's and Sokoloff's methods). The 1-CBF of the saline-treated group decreased significantly with age in all areas measured. EPA-E treatment alleviated the age-dependent decrease in 1-CBF in all areas, especially those in the basal ganglia. The 1-CGU of the saline-treated group did not change with age, however EPA-E treatment increased 1-CGU in all areas measured, though the changes were not significant. EPA-E ameliorated the decrease in cerebral blood flow and improved glucose metabolism in SHRSP suffering from severe hypertension. These results suggest that EPA-E may be useful in the prevention of stroke.

Effect of long-term administration of JTP-2942, a novel thyrotropin-releasing hormone analogue, on neurological outcome, local cerebral blood flow and glucose utilization in a rat focal cerebral ischemia.

The effect of JTP-2942, a novel thyrotropin-releasing hormone analogue on neurological examination, local cerebral blood flow (l-CBF) and local cerebral glucose utilization (l-CGU) were examined when JTP-2942 was administered for 4 weeks after 1 week reperfusion following ischemia in a rat middle cerebral artery (MCA) occlusion. Left middle cerebral artery ischemia was induced for 90 min followed by reperfusion. JTP-2942 (0.03 or 0.003 mg/kg) or saline (vehicle) were administered for 4 weeks after 1 week ischemia, and then the drug was withdrawn. Neurological symptoms and motor disturbance based on inclined plane test were measured once a week after 1 week ischemia. l-CBF and l-CGU were measured by quantitative autoradiographic technique after 6 weeks ischemia. The adjacent sections subjected to l-CBF or l-CGU measurement were stained with Hematoxylin-Eosin, and the infarction volume was measured. JTP-2942 (0.03 mg/kg) significantly ameliorated neurological symptoms and motor disturbance at 5 weeks after ischemia as compared with vehicle, and then after completion of drug administration, amelioration effect continued. JTP-2942 (0.03 mg/kg) also significantly ameliorated the reduced l-CBF and l-CGU in the peri-infarcted areas such as the frontal cortex, motor cortex and medial caudate-putamen. No significant differences were noted in the infarction volume among MCA occlusion rats. This indicates that activating reduced metabolic turnover associated with synaptic connection changes or the activation of compensation mechanisms may result in improvement of neurological symptoms and motor disturbances. It is therefore expected that JTP-2942 may be a possible therapeutic agent for motor disturbance during the subacute or chronic cerebral infarction.

Influences of supplementary dietary tungsten on methionine metabolism in rabbits fed a low-cholesterol plus methionine diet.

Hyperhomocysteinemia results from an impaired methionine metabolism. Sulfite oxidase, which is an important enzyme in methionine metabolism, contains molybdenum. In contrast, tungsten has a molybdenum-antagonistic effect. Thus, we hypothesized that dietary tungsten may decrease plasma homocysteine levels and influence methionine metabolism. Male New Zealand White rabbits (n=15) were fed a low-cholesterol basal diet and then placed on three different diets: 0.1% cholesterol (Chol), Chol plus 1% methionine (Met), and Chol plus Met plus 0.1% tungsten (W). The animals received these diets for 20 weeks. Biochemical tests of blood and urine were performed. Plasma homocysteine levels were significantly lower in the Chol+Met+W group than in the Chol+Met group. Plasma levels of total cholesterol, triglyceride, lipid peroxide, and urinary 24-h taurine concentrations were higher in the Chol + Met + W group than in the Chol + Met group. In comparison, concentrations of 2, 3-diphosphoglycerate (2, 3-DPG), reduced glutathione (GSH) in erythrocytes, and urinary 24-h SO4(2) were lower in the Chol+Met+W group than in the Chol+Met group. From these results, tungsten could be expected to exhibit an antiatherogenic effect. Conversely, it may have effects on atherogenic factors. Thus, tungsten may play a number of roles in the methionine metabolism.

Delayed administration of ethyl eicosapentate improves local cerebral blood flow and metabolism without affecting infarct volumes in the rat focal ischemic model.

The objective of this study was to assess whether delayed administration of ethyl eicosapentate has a favorable effect on cerebral blood flow and metabolism in rats suffering from cerebral infarction. Adult male Sprague-Dawley rats weighing 250-300 g were used. Left middle cerebral artery occlusion was induced for 2 h. After 24-h reperfusion, rats were treated with ethyl eicosapentate (100 mg kg(-1); ethyl eicosapentate treated) or saline (saline treated) by gavage, once a day for 4 weeks. After 4 weeks, local cerebral blood flow and local cerebral glucose utilization were measured autoradiographically, and infarction size was measured. In the ischemic side, the local cerebral blood flow and local cerebral glucose utilization values in the parietal cortex and the lateral caudoputamen, which constituted the ischemic core, were equivalent to zero in both groups. The peri-infarcted areas, i.e., the frontal cortex and medial caudoputamen, were significantly higher in the ethyl eicosapentate treated group than the saline treated group. In the non-ischemic side, ethyl eicosapentate treated group had a tendency to improve local cerebral blood flow and local cerebral glucose utilization values in a medial caudoputamen. These results suggest that ethyl eicosapentate treatment may be beneficial for maintaining cerebral circulation and metabolism except for infarction area after cerebral infarction.

Cortical potentials preceding voluntary finger movement in patients with focal cerebellar lesion.

OBJECTIVE: To elucidate influences of the dentate nucleus on the generation of the related cortical potentials (MRCPs) preceding voluntary movement, Bereitschaftspotential (BP) and negative slope (NS). DESIGN AND METHODS: MRCPs preceding self-paced voluntary finger movement were recorded in 5 cases with localized cerebellar lesions due to stroke or tumor. Comparing 3 of them involving the dentate nucleus and 2 others sparing it, as judged from CT or MRI findings. RESULTS: BP and NS preceding voluntary finger movement ipsilateral to the lesion were absent or markedly reduced in amplitude in those 3 cases with the dentate nucleus lesion, whereas those negative components were present in the 2 cases with no evidence of dentate lesion. CONCLUSION: The dentate nucleus has a facilitatory effect on the generation of BP and NS.

CSF beta-endorphin, HVA and 5-HIAA of dementia of the Alzheimer type and Binswanger's disease in the elderly.

Cerebrospinal fluid (CSF) concentration of beta-endorphin (beta-Ep), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) was measured in 15 patients with dementia of the Alzheimer type (DAT) and in 16 patients suspected of having Binswanger's disease (BD) by MRI, which sometimes resembles DAT clinically. These were classified into three stages according to severity of dementia, Stage 1 (mild dementia)-Stage 3 (severe dementia). CSF levels of HVA decreased significantly in severe dementia, but the level of 5-HIAA did not correlate with dementia severity in both dementia groups. beta-Ep levels did not differ significantly between any stages of DAT, and among controls. beta-Ep levels, however, in BD Stage 1 (27.5 +/- 5.9 pg/ml) were significantly higher (p less than 0.05), but level in Stage 3 (6.7 +/- 2.0) was significantly lower (p less than 0.001) than in the controls (19.2 +/- 4.5). These results suggest that CSF beta-Ep may depend on the cause of dementia rather than severity of dementia, and could possibly distinguish the closely resembling BD from true DAT.

Pyruvate dehydrogenase activity and energy metabolite levels following bilateral common carotid artery occlusion in rat brain.

The influence of chronic cerebral hypoperfusion on cerebral energy metabolism was studied. The bilateral common carotid arteries of Wistar rats were occluded for 0, 2, 7, and 28 days. Cerebral energy metabolism was evaluated by assaying adenosine triphosphate (ATP), phosphocreatine (PCr), and lactate levels and measuring pyruvate dehydrogenase (PDH) activity (each time point, n = 6). Pathological changes were assessed light-microscopically by Klüver-Barrera staining and immunohistochemical labeling for astroglia (each time point, n = 3). There were no changes in ATP and PCr levels or PDH activity; there was slight but significant transient lactate accumulation at 2 days. Myelin pallor and increase in immuno-reactive astroglia were only observed at 28 days. These results indicate that chronic cerebral hypoperfusion induces delayed white matter changes in the corpus callosum of rat brain, but does not affect energy production.

Role of arachidonic acid metabolism on ischemic brain edema and metabolism.

Arachidonic acid is liberated from damaged cell membranes during ischemia and is the source of vasoactive prostanoids. In this study, specific drugs that influence AA metabolism were investigated for their effects on brain edema and energy metabolites during ischemia. The agents tested were: methylprednisolone (phospholipase A2 inhibition), indomethacin (cyclooxygenase inhibitor), trapidil (TXA2 synthetase inhibitor), and OP-41483 (prostacyclin derivative). Cerebral ischemia was produced using bilateral common carotid artery occlusion in spontaneously hypertensive rats. Brain water content and concentrations of ATP, pyruvate, and lactate were determined 3 hr after occlusion. Compared with its vehicle, methylprednisolone significantly reduced water content and lactate concentration and maintained high levels of ATP. Indomethacin had no effect on brain water content nor metabolite levels. Trapidil decreased water content and lactate levels and increased levels of ATP and pyruvate. OP-41483 had no effect on water content and lactate, but maintained ATP and pyruvate at high levels. These results indicate that some of the AA metabolites may play an important role in the development of brain edema and in the impairment of energy metabolism.

Effects of fluosol-DA on brain edema, energy metabolites, and tissue oxygen content in acute cerebral ischemia.

Perfluorochemicals were developed as a blood substitute and were reported to have an advantage in oxygen transport compared with blood. The present study was undertaken to investigate the therapeutic effects of a perfluorochemical, FDA, on brain edema and metabolites in acute cerebral ischemia. Cerebral ischemia was induced in SHR by BLCO followed by recirculation. The FDA administration resulted in (a) the significant inhibition of brain edema as shown by brain water content in the treated group, and (b) significant amelioration of metabolic impairments as shown by lesser degree of ATP and pyruvate decrease and lactate accumulation. The TpO2 was compared between FDA-infused and nontreated group during ischemia. The FDA-infused group had significantly higher TpO2 than nontreated group. These results indicate that the improvement of brain edema and metabolite levels were due to alleviation of ischemic hypoxia by FDA under the same ischemic insult.

Bilateral representation of language function. Agenesis of corpus callosum by Wada and PET activation.

A 33-year-old right-handed man with intermittent headache was found to have agenesis of the corpus callosum. He underwent magnetic resonance imaging, positron emission tomography (PET), and detailed neuropsychologic tests, including a Wada test. There was bilateral representation of language, and a PET activation study with word repetition revealed bilateral areas of activation that were not completely symmetric. These findings and the literature concerning agenesis of the corpus callosum are discussed as is the possible compensatory mechanism for absence of the corpus callosum, which is important for cross-communication.

T-cell activation modified by parathyroid hormone (PTH) in patients with end-stage renal disease.

We studied the effect of parathyroid hormone (PTH) on the proliferation of T cells from patients with end-stage renal disease (ESRD) (n = 16) and normal subjects (n = 20). In patients with ESRD, T-cell proliferation expressed as stimulation index (SI) was significantly decreased from 99.2 +/- 31.2 to 46.3 +/- 10.8, when 10 ng/ml of recombinant PTH (rPTH) was added in vitro. The reduction of SI with rPTH was dose dependent. However, in normal subjects, the SI was increased from 56.2 +/- 13.6 to 67.9 +/- 16.5 (p < 0.01) by addition of rPTH. These findings were also shown by allo or specific antigen-induced T-cell stimulation. When T cells from normal subjects were pretreated with 10 ng/ml of PTH, with 100 mg/dl of urea or with a condition of pH 7.0, the effect of rPTH was changed to decrease the T-cell proliferation induced by anti-CD3 antibody. These data suggested that uremic state, including hyperparathyroidism, changed the response of T cells against PTH.