Adenovirus-mediated transduction with human glial cell line-derived neurotrophic factor gene prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopamine depletion in striatum of mouse brain

OBJECTIVE: This study assesses intravascular density produced by ionic and nonionic contrast material and its effect on visualization of stenoses by CT angiography. MATERIALS AND METHODS: CT angiography was performed using a 32-vessel phantom to study grades of luminal stenoses (0-100%), three lengths of stenoses (1, 3, and 5 mm), and two angles of inclination into the stenoses (45 degrees and 75 degrees). Scans were obtained with a slice thickness of 2 mm, a slice interval of 1.5 mm, a pitch of 1.0, a voltage of 120 kV, and a current of both 100 and 200 mA. Vessels were oriented parallel to the z-axis, and opacified with ionic and nonionic contrast material that had densities of 100, 150, 200, 250, 300, and 350 H. Cross-sectional luminal diameters were measured in and out of the stenoses. Edge definition and halo artifact for each vessel were graded by an investigator who was unaware of the contrast material density used. RESULTS: A contrast density of 150 H as revealed by CT angiography yielded the most accurate stenosis measurements with ionic contrast material. For nonionic contrast material, attenuation values of 150 and 200 H produced the best results on CT angiography. A density of 100 H or greater than 250 H significantly increased the error of vessel measurement (p = .001) for both types of contrast material. For the two current levels tested (100 and 200 mA), no statistical difference was found. CONCLUSION: The accuracy of CT angiography in measuring carotid stenosis depends on the luminal attenuation value. An optimum contrast density is 150 H for ionic contrast material; for nonionic contrast material, 150-200 H (at the window and level settings of 300 H and 40 H).     

Protective effects of the antiparkinsonian drugs talipexole and pramipexole against 1-methyl-4-phenylpyridinium-induced apoptotic death in human neuroblastoma SH-SY5Y cells

Treatment of human neuroblastoma SH-SY5Y cells with 1 mM 1-methyl-4-phenylpyridinium (MPP+) for 3 days induced production of reactive oxygen species (ROS), followed by caspase-3 activation, cleavage of poly(ADP-ribose) polymerase (PARP), and apoptotic cell death with DNA fragmentation and characteristic morphological changes (condensed chromatin and fragmented nuclei). Simultaneous treatment with 1 mM talipexole slightly inhibited the MPP+-induced ROS production and apoptotic cell death. In contrast, pretreatment with 1 mM talipexole for 4 days markedly protected the cells against MPP+-induced apoptosis. However, this protective effect might not be mediated by dopamine receptors. The talipexole pretreatment induced an increase in antiapoptotic Bcl-2 protein level but had no effect on levels of proapoptotic Bax, Bak, and Bad. It also inhibited MPP+-induced ROS production, p53 expression, and cleavages of caspase-3 and PARP. Similarly, pramipexole pretreatment increased Bcl-2 and inhibited MPP+-induced apoptosis. Although pretreatment with bromocriptine also had a protective effect against MPP+-induced apoptosis, it had no effect on the protein levels of Bcl-2 family members. On the other hand, N6,2'-O-dibutyryl cAMP or calphostin C induced a decreased Bcl-2 level and enhanced MPP+-induced cell death. These results suggest that talipexole has dual actions: (1) it directly scavenges ROS, affording slight protection against MPP+-induced apoptosis, and (2) it induces Bcl-2 expression, thereby affording more potent protection, if it is administrated before MPP+. Pramipexole has similar effects, whereas bromocriptine seems to exhibit the former but not the latter effect.     

Effects of chronic caffeine administration on respiration and schedule-controlled behavior in rhesus monkeys

The effects of chronic caffeine administration on ventilation and schedule-controlled behavior were studied in 12 adult rhesus monkeys. In seated subjects prepared with a head plethysmograph, ventilation was measured during exposure to air (normocapnia) and to elevated levels of CO2 (3%, 4% and 5%) mixed in air (hypercapnia). Acute administration of caffeine (10.0-30.0 mg/kg i.m.) produced marked, dose-dependent increases in ventilation during conditions of normocapnia and hypercapnia. However, daily administration of caffeine (10.0 mg/kg i.m.) for 8 consecutive days resulted in tolerance to its respiratory-stimulant effects that was surmountable with higher doses. Caffeine-tolerant subjects also were cross-tolerant to theophylline, an active metabolite of caffeine, and to rolipram and Ro 20-1724, selective phosphodiesterase inhibitors. When chronic administration was terminated and the acute effects of caffeine were redetermined, sensitivity returned to levels obtained before chronic administration within 9 days. Drug effects on behavior were studied in monkeys trained to respond under a fixed-interval schedule of stimulus termination. Acute administration of caffeine (1.0-30.0 mg/kg i.m.) produced significant rate-increasing effects on fixed-interval responding, but chronic administration resulted in tolerance that was insurmountable, such that no dose increased responding above control rates. Although the time course for development and loss of tolerance to the behavioral effects of caffeine corresponded closely with respiration, cross-tolerance did not extend to the behavioral effects of rolipram. Chronic caffeine administration had little effect on caffeine metabolism or clearance, which indicated that caffeine tolerance was pharmacodynamic. The results suggest that different neurochemical mechanisms mediate the effects of caffeine on respiration and behavior, and that inhibition of type IV phosphodiesterase plays a prominent role in caffeine-induced respiratory stimulation.     

Photochromism of an anticonvulsant, 1-diphenylmethyl-4-(6-methyl-2-pyridylmethylene-amino) piperazine, in the solid state

The light-induced color change of 1-diphenylmethyl-4-(6-methyl-2-pyridylmethyleneamino) piperazine in the solid state was investigated. Light in the 420-700-nm visible region had no effect. Elevated temperature, dissolution, or prolonged storage in the dark at room temperatures restored the intrinsic color of the compound. IR, UV (solution), NMR, differential scanning calorimetry, and GC methods showed no detectable difference between the long wave-length UV light-exposed (yellow) and unexposed (colorless) samples of the pure compound. Long wavelength UV light exposure studies with several substituted piperazine analogs revealed a structure-activity requirement for the color conversion process. The data indicated that the transformation process from colorless (or faint yellow) to bright yellow is photochromism (phototropy) and is dependent on the intensity of the "action spectrum" in the 300-400-nm region. Studies in the solid state showed that heat-induced fading of the color followed apparent zero-order kinetics. The energy of activation, Eb, for the photochromic conversion process from the metastable (yellow) to the stable (colorless) state was estimated to be about 19 kcal/mole.     

Synthesis and pharmacological evaluation of 1-methyl-5-[substituted-4 (3H)-oxo-1,2,3-benzotriazin-3-yl]-1H-pyrazole-4-acetic acid derivatives

Several new 1-methyl-5-[substituted-4-oxo-1,2,3-benzotriazin-3-yl] -1H-pyrazole-4-acetic acids and their ethyl ester derivatives were prepared. The compounds were tested for analgesic and antiinflammatory activities, acute toxicity, ulcerogenic effect, and as in vitro inhibitors of 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), since it is claimed that the inhibition of such an enzyme predicts in vivo antiinflammatory activity. Some compounds were more active than phenylbutazone in the phenylbenzoquinone and acetic acid peritonitis tests, and equiactive to the same drug in the carrageenin paw edema test. All the compounds inhibited the 3 alpha-HSD, but no correlation was observed with the paw edema inhibition values. The compounds proved to possess marginal or no ulcerogenic effect, as well as low systemic toxicity.     

Effects of ageing on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxic effects on striatum and brainstem in the rat

In 3- and 18-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), noradrenaline (NA), uric acid, glutathione (GSH) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined by HPLC in the striatum and/or in the brainstem 24 h after single injections of MPTP (12-35 mg/kg i.p.). Aged rats had lower baseline levels of AA and GSH, compared to young rats. In aged rats, MPTP 35 mg/kg induced a 70% death rate and a decrease in striatal DOPAC/DA ratio which was significantly correlated to MPP+ concentrations (r = -0.840, P < 0.005); in addition, MPTP did not increase AA oxidation. In the brainstem, the MPTP-induced decrease in NA levels and increase in uric acid levels were significantly correlated to the MPP+ concentrations (r = -0.709, P < 0.05, and r = +0.888, P < 0.001, respectively). In conclusion, evidence is given of a mechanism of toxicity of MPTP involving oxidative stress produced by xanthine oxidase; in addition, in aged rats the neuronal antioxidant system (levels of AA and GSH) is considerably lower than in young rats and may play an enabling role in the MPTP age-related neurotoxic effects on striatum and brainstem.     

Effects of clonidine, dexmedetomidine and xylazine on thermal antinociception in rhesus monkeys

The antinociceptive effects of the s.c. administration of the alpha-2 agonists clonidine (0.0032-1.0 mg/kg), dexmedetomidine (0.001-0.032 mg/kg) and xylazine (0.1-3.2 mg/kg) were examined in the warm-water tail withdrawal assay in rhesus monkeys. The three agonists were dose-dependently effective in this assay; their potency order being dexmedetomidine > clonidine > xylazine. The alpha-2 antagonist idazoxan (0.1-3.2 mg/kg) caused dose-dependent and roughly parallel rightward shifts in the dose-effect curves for the three agonists. Apparent pA2 analysis with idazoxan yielded homogeneous values for the three agonists, supporting the notion that similar receptors mediate their antinociceptive effects. The opioid antagonist quadazocine (1.0 mg/kg) did not antagonize the antinociceptive effects of clonidine and xylazine, indicating that opioid receptors do not participate in the effects of the compounds in this assay. At dose ranges found to be effective in the antinociceptive assay, clonidine, dexmedetomidine and xylazine also dose-dependently caused sedation, muscle relaxation, bradycardia and moderate respiratory depression. The sedative, muscle relaxant and respiratory depressant effects of xylazine could be antagonized by idazoxan, suggesting that these effects may be mediated through alpha-2 receptors. These data indicate that the three imidazoline alpha-2 agonists, clonidine, dexmedetomidine and xylazine are effective s.c. in the warm-water tail withdrawal assay in rhesus monkeys, but only at doses that produce other behavioral and physiological effects.     

Implication of dopamine transporter system on 1-methyl-4-phenylpyridinium and rotenone effect in striatal synaptosomes

Absorption and endogenous excretion of P by male broiler chicks (14-29 d old) were quantitatively evaluated at different Ca:P ratios (1, 1:1; 2, 1.5:1; 3, 2:1; 4, 2.5:1) in four groups given experimental diets ad lib. The P content was the same in all diets. An isotope-dilution technique was used to determine endogenous faecal and renal excretion. Ca and P retentions in the whole body were estimated according to the comparative slaughter technique. P absorption was calculated from retention and endogenous excretion. Absorption and endogenous excretion of P amounted to (mg P/d per chick): 304, 270, 160 and 158; and 135, 109, 31 and 30 in groups 1, 2, 3 and 4 respectively. Widening of the Ca:P ratio in the feed limited the P absorption. Availability of feed P amounted to (%): (1) 66, (2) 57, (3) 32 and (4) 30, and the amounts of absorbed P retained were (%): (1) 56, (2) 60, (3 and 4) 81. The increasing Ca concentration in the feed showed a greater effect on P absorption than on P retention. The ratios of relative retention to relative endogenous excretion of absorbed P were: (1) 1.27, (2) 1.50, (3 and 4) 4.26.     

Effects of triazolam, 8-OH-DPAT, and buspirone on repeated acquisition in squirrel monkeys.

The nonserotonergic benzodiazepine, triazolam, was compared with two 5-HT1A receptor agonists, 8-OH-DPAT and buspirone, in squirrel monkeys responding under a repeated-acquisition procedure. In each session, subjects acquired a 4-response sequence by responding sequentially on 3 keys in the presence of 4 discriminative stimuli (colors). Response sequences for each session were maintained by food presentation under a second-order fixed-ratio schedule. Errors produced a brief time-out but did not reset the sequence. In general, all of the drugs produced dose-dependent decreases in overall response rate and increases in the percentage of errors as the cumulative dose was increased. Together, these results indicate that 5-HT1A receptor agonists disrupt learning in squirrel monkeys by producing rate-decreasing and error-increasing effects in a manner comparable with the nonserotonergic benzodiazepine triazolam. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of reversible inactivation of the supplementary motor area (SMA) on unimanual grasp and bimanual pull and grasp performance in monkeys

The supplementary motor area (SMA) was reversibly inactivated by muscimol microinfusion in two monkeys while they were performing two motor tasks: (1) a delayed conditional bimanual drawer pulling and grasping sequence which was initiated on a self-paced basis; (2) a unimanual reach and grasp task (modified Kluver board task). Unilateral or bilateral inactivation of the SMA induced a prominent deficit in trial initiation of bimanual sequential movements, affecting the hand contralateral to the inactivated side or both hands, respectively. The deficit was a long lasting (10-15 min or more) inability of the monkey to place its hand (s) in the ready position on start touch-sensitive pads, a condition required to initiate the drawer task. However, if after such a deficit period, the experimenter put his hand on the start touch-sensitive pad to initiate the trial, then the monkey executed the drawer task without obvious motor deficit. SMA inactivation did not affect unimanual reaching and grasping movements in the board task. In contrast to the SMA, inactivation of other motor areas (primary, premotor dorsal, anterior intraparietal area) did not affect the initiation of movement sequences in the drawer task. These data thus indicate that the SMA plays a crucial and specific role in initiation of self-paced movement sequences. However, SMA inactivation did not prevent the monkeys to perform coordinated movements of the two forelimbs and hands, indicating that SMA is not necessary for bimanual coordination.     

Prenatal exposure to alcohol, caffeine, tobacco, and aspirin: Effects on fine and gross motor performance in 4-year-old children.

Fine and gross motor performance in 4-year-old children was examined in relation to prenatal exposure to alcohol, caffeine, tobacco, and aspirin in a longitudinal prospective population-based study. Multiple regression analyses of data from 449 children indicated statistically significant relationships between moderate levels of prenatal alcohol exposure and increased errors, increased latency, and increased total time on the Wisconsin Fine Motor Steadiness Battery and poorer balance on the Gross Motor Scale, even after adjustment for relevant covariates. Most of these alcohol-related motor findings were linear, suggesting no safe level of exposure. Alcohol scores from the period prior to pregnancy recognition were the most predictive of decrements in motor performance. Although moderate prenatal alcohol exposure was also related to lower IQ scores in this same cohort, the motor effects were independent of IQ. Some relationships with aspirin and caffeine were also found, but they were difficult to interpret. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nullification of a positive correlation between urinary contents of alpha1-microglobulin and ulinastatin with intracerebroventricularly administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) in mice

BACKGROUND: Wolff-Parkinson-White syndrome is thought to be a congenital disease, however, its exact prevalence is not known. This may be because of the intermittent activity of accessory pathways in some cases and fluctuations in autonomic tone. AIMS: To investigate the prevalence of ventricular preexcitation by electrocardiography and reported symptoms in each school age child in Yamanashi prefecture. METHODS: From 1994 to 1996, answers to a questionnaire, results of physical examination, and electrocardiography were obtained from all schoolchildren in Yamanashi prefecture (n = 92,161; total population 880,000) on admission to elementary school (age 6 to 7 years, n = 28,395), junior high school (age 12 to 13 years, n = 31,206), and high school (age 14 to 15 years, n = 32,837). RESULTS: Elementary and junior high school students had a significantly lower prevalence of preexcitation than high school students (0.073% and 0.070% v 0.174%, p < 0.001). The prevalence of left free wall pathway was highest in high school students (n = 27) compared with elementary (n = 6) and junior high school students (n = 5) (p < 0.005). The only symptom noted in the answers to the questionnaire was palpitations. The symptomatic cases were more frequent in high school (n = 13) than in elementary (n = 1) and junior high school (n = 2) children, but not significantly. No student with preexcitation had associated heart disease or family history of Wolff-Parkinson-White syndrome or sudden death. CONCLUSIONS: The prevalence of preexcitation in younger schoolchildren was less frequent than previously reported. The prevalence of preexcitation and left free wall pathways increased with age. The symptoms were few and there was no significant morbidity.     

Effects of phencyclidine, pentobarbital, and d-amphetamine on the acquisition and performance of conditional discriminations in monkeys

In each of two components of a multiple schedule, monkeys were required to respond on a right or left lever depending upon the stimulus combination (a color and a geometric form) presented. Reinforcement of a response in the presence of one stimulus (the form) was therefore conditioned upon the other stimulus (the color). The completion of a two-member chain of discriminations produced a food pellet. Errors produced a brief timeout. One composition of the multiple schedule was a repeated-acquisition task where the discriminative stimuli for left- or right-lever responses changed each session (learning). In the other component, the discriminative stimuli for left- or right-lever responses were the same each session (performance). Phencyclidine, pentobarbital, and d-amphetamine each produced dose-related decreases in the overall rate of responding in both components of the multiple schedule. At high doses each drug increased the percent errors in each component. At lower doses, however, the three drugs produced selective effects on accuracy. Errors were increased in the learning component at lower doses than those required to disrupt the discrimination in the performance component. A signal detection analysis of the data revealed that none of the drugs tested increased errors by selectively affecting either discriminability or bias.     

热挤压工艺对Ti-6Al-4V钛合金组织与性能的影响

研究了挤压温度和挤压比对Ti-6Al-4V钛合金挤压型材显微组织、织构及力学性能的影响.挤压温度在相变点T_β以上150~350℃、挤压比λ为25~85范围内时,型材动态再结晶均已完成,形成均匀的魏氏组织.型材的晶粒随挤压温度的降低和挤压比的提高而细化.型材织构在挤压比较低(λ=25)时强度较弱且为随机分布;当挤压比增加时,织构增强并有形成(相似文献   

Induction of cytochrome P450 1A1 in rat liver slices by 7-ethoxycoumarin and 4-methyl-7-ethoxycoumarin

7-Ethoxycoumarin (EC) is widely used as a model substrate for monooxygenase function, its O-deethylation representing cytochrome P450 (P450) activity mainly of 1A but also of 2B isoforms. Reports on investigations of its own capacity to induce or suppress P450 activities, however, have not been found in biomedical literature. To avoid the influence of in vivo pharmacokinetics, studies can well be undertaken with liver slice incubation. Therefore in the present investigation precision-cut rat liver slices from male 43-63-day-old male HAN:Wistar outbred rats were incubated at 30 degrees C in carbogen saturated William's Medium E for 24 h. EC was added previously to final concentrations of 10, 25, 50, 75 or 100 microM. After incubation, homogenate was prepared from slices and used for model reactions (7-ethoxyresorufin O-deethylation [EROD] and 7-pentoxyresorufin O-depentylation [PROD]). EROD, indicating activities of 1A isoforms, was enhanced by incubation with EC at 25 and 50 microM to about doublefold but showed control or lower values at 75 and 100 microM. Incubation with beta-naphthoflavone in comparison led to variable increases (3-5-fold of controls). For PROD as an indicator of the phenobarbital inducible P450 isoforms 2B1 and 2B2 no enhancement was found, but a decrease by incubation with 75 and 100 microM EC. To further investigate the correlation between enzyme activity and gene expression after slice incubation, P450 1A1 mRNA content was measured by RT-PCR. Induced gene expression for 1A1 was seen with different EC concentrations to a variable extent, though not as strong as with BNF. Similar incubation with 4-methyl-7-ethoxycoumarin revealed an even stronger induction of EROD activity with maxima at about 10-32 microM, reaching BNF values. In contrast incubation with 7-benzyloxycoumarin had no evident inducing or suppressing effect, neither on EROD nor on PROD activity.     

Tyrosine-533 of rat dopamine transporter: involvement in interactions with 1-methyl-4-phenylpyridinium and cocaine

To improve our understanding of structure-function relationships for neurotransmitter transporters, we performed site-directed mutagenesis of the rat dopamine transporter (DAT) and assessed the functions of the mutants in transiently-expressing COS cells. Tyrosine-533 of rat DAT lies in the 11th transmembrane region, where the corresponding amino acid of human DAT is phenylalanine. Alanine substitution of tyrosine-533 (Y533A) conferred an increased affinity for 1-methyl-4-phenylpyridinium (MPP+). Phenylalanine substitution of tyrosine-533 (Y533F) increased the velocity of MPP+ uptake but decreased DAT's affinity for MPP+. Cocaine's potency in inhibiting dopamine uptake was unchanged with Y533A, but increased with Y533F. Differences in the uptake kinetics and inhibitory potency of cocaine between rat and human DATs were similar to the differences observed between the wild-type and Y533F mutants DATs. Tyrosine-533 may be important for the DAT function and for species differences in transporter functions, including differential sensitivities to cocaine and 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) in humans and rats.     

Effects of AF102B and tacrine on delayed match-to-sample in monkeys

1. Object working memory, a function which declines in aging and dementia, was tested in young and aged pretrained monkeys using a delayed match-to-sample task. 2. During drug treatment, monkeys were given the m 1 muscarinic agonist AF102B (0.1-2.1 mg/kg i.m.), the cholinesterase inhibitor tacrine (0.5-2.0 mg/kg p.o.), or vehicle controls in a repeated measures design to assess putative cognitive enhancement. 3. Both agents improved task performance in both young and aged monkeys, AF102B yielding equivalent or greater, and less variable, improvement than tacrine. 4. AF102B may represent a low-toxicity alternative to tacrine for the treatment of age-related memory disorders.