Triphenyl Phosphite and Diisopropylphosphorofluoridate Produce Separate and Distinct Axonal Degeneration Patterns in the Central Nervous System of the Rat

This study compared the neurotoxic effects of triphenyl phosphite(TPP) in the rat with those seen after exposure to diisopropylphosphorofluoridate(DFP), a compound known to produce organophosphorus-induceddelayed neurotoxicity (OPIDN). Animals received either threesubcutaneous injections of TPP (1184 mg/kg body wt each dose)administered at 3-day intervals or a single subcutaneous injectionof DFP (4 mg/kg body wt). TPP-induced clinical signs were initiallyobserved 2 to 18 days after the last injection and includedataxia, flaccid paresis, stereotyped alternating side-to-sidemovements, and circling behavior. Axonal and terminal degenerationwere present in the cerebellum, vestibular nuclear complex,cochlear nuclei, and superior and inferior colliculi. The subthalamicnucleus, substantia nigra, septal region, hypothalamus, thalamus,hippocampus, and cerebral cortex also contained degeneratingaxons and terminals. Degeneration was particularly evident inthe sensorimotor cerebral cortex, mediodorsal, ventromedial,and medial geniculate thalamic nuclei and in the magnocellularpreoptic and medial mammillary nuclei of the hypothalamus. Verylight degeneration was present in the gracile fasciculus andnucleus. In contrast, rats injected with DFP showed moderatedegeneration in the gracile fasciculus and nucleus but did notdisplay degeneration in any other brain region. Injections ofDFP did not produce delayed onset clinical signs. The resultsindicate that in the rat, different central nervous system cellgroups are affected by these two organophosphorus compoundsand that TPP affects nuclei and tracts at all levels of theneuraxis, including those associated with higher-order processingand cognitive functions. In addition, the distinct degenerationpatterns produced by these two compounds support the view thatTPP-induced neurotoxicity should not be considered as a typeof OPIDN, but rather as a separate category of organophosphorus-inducedneurotoxicity.     

锂对中枢神经和血液系统的作用（三）

双相抑郁是最严重和最常见的精神病中的一种。全球患病率为1％～5％，如果不治疗，自杀率为15％。在15至24岁的年青人中，囚抑郁自杀列死亡原因的第三位。这是一种终身疾病，有很强的遗传倾向。锂、丙戊酸和卡马西平是目前治疗躁狂抑郁症的主要药物。锂对急性躁狂症效果明显。丙戊酸的疗效不确定，许多病人都不能耐受其体重增加的副作用。卡马西平仅有较弱的作用。近来还有一些其他的药物可供选用，包括奥氮平、     

Effects of Tityustoxin on Central Nervous System

Abstract

Tityustoxin mimics many effects of electrical stimulation causing cell depolarization that increases the uptake of Na⁺ and Ca²⁺ ions and the release of acetylcholine in rat brain cortical slices and synaptosomes. Tityustoxin caused mobilization of acetylcholine from the cytoplasmic and crude vesicular fractions. The release of acetylcholine by tityustoxin is Na⁺ and Ca^{2 +} dependent and is inhibited by tetrodotoxin. Tityustoxin-stimulated release of acetylcholine is blocked by ω-Agatoxin an antagonist of P-type calcium channel. The toxin activates the voltage dependent sodium channel stimulating the turnover of inositol phosphates. Chemical groups in the cell membrane, particularly SH groups, are essential for the tityustoxin-induced release of acetylcholine. Tityustoxin increased the incorporation of ³²P into synapsin I and the effect is blocked by calmodulin inhibitors. Tityustoxin increased the release of norepinephrine, glutamate, γ-aminobutyric and excitatory aminoacids. It is concluded that tityustoxin is an important tool in studies of neurotransmitter release and signal transduction.     

Effects of Spider Venom Toxin PWTX-I (6-Hydroxytrypargine) on the Central Nervous System of Rats

The 6-hydroxytrypargine (6-HT) is an alkaloidal toxin of the group of tetrahydro-β-carbolines (THβC) isolated from the venom of the colonial spider Parawixia bistriata. These alkaloids are reversible inhibitors of the monoamine-oxidase enzyme (MAO), with hallucinogenic, tremorigenic and anxiolytic properties. The toxin 6-HT was the first THβC chemically reported in the venom of spiders; however, it was not functionally well characterized up to now. The action of 6-HT was investigated by intracerebroventricular (i.c.v.) and intravenous (i.v.) applications of the toxin in adult male Wistar rats, followed by the monitoring of the expression of fos-protein, combined with the use of double labeling immunehistochemistry protocols for the detection of some nervous receptors and enzymes related to the metabolism of neurotransmitters in the central nervous system (CNS). We also investigated the epileptiform activity in presence of this toxin. The assays were carried out in normal hippocampal neurons and also in a model of chronic epilepsy obtained by the use of neurons incubated in free-magnesium artificial cerebro-spinal fluid (ACSF). Trypargine, a well known THβC toxin, was used as standard compound for comparative purposes. Fos-immunoreactive cells (fos-ir) were observed in hypothalamic and thalamic areas, while the double-labeling identified nervous receptors of the sub-types rGlu2/3 and NMR1, and orexinergic neurons. The 6-HT was administrated by perfusion and ejection in "brain slices" of hippocampus, inducing epileptic activity after its administration; the toxin was not able to block the epileptogenic crisis observed in the chronic model of the epilepsy, suggesting that 6-HT did not block the overactive GluRs responsible for this epileptic activity.     

Combined Effects of Xylene and Alcohol on the Central Nervous System

Abstract Ten healthy male students were exposed to m-xylene alone at concentrations of about 6 and 11.5 μmol/l and given a single dose of alcohol (0.4 and 0.8 g/kg) prior to exposure. The effects of these xylene concentrations and alcohol doses, as well as the combined effects of the two xylene concentrations with the higher alcohol dose on psychophysiological functions, such as body balance and reaction time, were assessed. Xylene alone did not significantly impair these functions, although there was a tendency towards impairment by the exposure to the higher xylene concentration. The impairment caused by alcohol alone was dose-dependent and exceeded that caused by xylene alone. The deleterious effects of xylene combined with alcohol were usually additive, although antagonism of alcohol effects on body balance by the higher xylene concentration was observed. The effects were pharmacodynamic rather than pharmacokinetic in nature.     

木防己碱对中枢神经系统影响的实验观察

本文观察到Tr具有抑制小鼠的自主活动,加强戊巴比妥钠及水合氯醛对中枢的抑制作用,拮抗咖啡因与苯丙胺的兴奋作用,推迟出现戊四氮和士的宁惊厥的潜伏期,延长士的宁致小鼠惊厥后死亡的时间,本品尚有镇痛和降温作用,表明Tr具有镇静、镇痛、降温等中枢抑制作用。     

Pharmacokinetic-Pharmacodynamic Modelling of Zopiclone Effects on Human Central Nervous System

Abstract: The present data shows the pharmacokinetics and concentration-effect relationship of a single 7.5 mg oral dose of zopiclone in ten healthy volunteers. Plasma concentrations and effects of zopiclone on central nervous system as quantified by changes in saccadic peak velocity and digit symbol substitution test were measured for 17 hr after ingestion of zopiclone. Pharmacokinetics was described with a linear one-compartment open model. Maximum effects preceded peak plasma zopiclone concentrations causing a clockwise hysteresis, i.e. proteresis, in concentration versus effect loops. Therefore, pharmacodynamics was described both with a tolerance model and a model with distributional pseudo-tolerance where the concentration in the blood sampling site is assumed to equilibrate slower with arterial blood than the site of action of zopiclone. Both models related the changes in pharmacodynamics linearly to changes in zopiclone concentrations. The median (range) values for clearance, volume of distribution and elimination half-life were 21 (15-53) L/hr, 132 (58-161) L and 3.4 (1.7-5.7) hr, respectively. Both pharmacodynamic models were able to describe the relationship between zopiclone concentrations and changes in psychomotor performance equally well. However, because the pharmacodynamics of zopiclone were studied in a non-steady-state situation, the mechanism for proteresis, i.e. true tolerance versus distributional pseudotolerance cannot be identified.     

Some Effects of Cassia italica on the Central Nervous System in Mice

This work examines some effects of the crude ethanolic extract of the medicinal plant Cassia italica, given at single oral doses of 0.25, 0.5 or 1 g kg^?1, on the central nervous system in mice. Several models of nociception have been used to examine the analgesic effect of the extract. HPLC fingerprinting of the extract was performed to ensure uniformity of the extract material used. In treated mice, the extract caused dose-related inhibition of acetic acid-induced abdominal constriction, and in the formalin test of antinociception the extract reduced formalin-induced pain in the second (late) but not in the first (early) phase of the pain. Treatment with the extract at doses of 0.5 and 1 g kg^?1 significantly increased the reaction time in the hot-plate and warm-water tail-flick tests. Naloxone was ineffective in antagonizing the analgesic effect of C. italica on tail-flick and abdominal constriction tests, possibly indicating that the effect occurs via non-opiate pathways. The C. italica extract caused slight dose-related impairment of motor control which was significant only at a dose of 1 g kg^?1. Treatment at the three doses used did not affect the rectal temperature of normothermic mice, but was effective in significantly reducing the rectal temperature of hyperthermic rats, 0.5 and 1 h (but not 6 h) after administration of the extract at doses of 0.5 and 1 g kg^?1. The extract also produced progressive diminution in the ambulatory and total activity of treated mice for up to 2 h after administration. It is concluded that the crude ethanolic extract of C. italica has CNS depressant properties, manifested as antinociception and sedation.     

A time-course analysis of chick (Gallus domesticus) response during aflatoxicosis

Body weights, packed cell volumes and plasma protein concentrations among nonsurviving chicks receiving 5·0 μg of aflatoxin per g of diet were significantly less than in surviving chicks. Over the last 14 days of life, changes in plasma protein concentrations among nonsurvivors were significantly greater than among surviving chicks.     

The effect of diethyldithiocarbamate on passive avoidance learning by chicks (Gallus domesticus)

Diethyldithiocarbamate (DDC), a competitive inhibitor of dopamine-B-hydroxylase, produced a dosage-related depletion of neural NE and impairment of passive avoidance learning in young chicks. Retention was not impaired, however, as shown by normal relearning of the task a day later, when the drug was no longer active. Perhaps, neural NE depletion impairs ability to inhibit responding and, thus, impairs passive or inhibitory avoidance learning indirectly. Alternatively, NE depletion may slow down learning by interfering with consolidation, but if the task is well learned, it is remembered.     

Influence of some serotoninergic agents on nitrazepam-induced sleep in the domestic fowl (Gallus domesticus)

The influence of some serotoninergic agents on nitrazepam-induced sleep was studied in 5-8-day-old chicks. Nitrazepam (0.4-51.2 mg/kg) induced behavioural sleep in chicks dose-dependently. 5-Hydroxytryptamine (5-HT; 10-20 mg/kg) hypnotised young chicks. Similarly, 5-HT (5-20 mg/kg) shortened the onset and significantly prolonged the duration of nitrazepam-induced sleep in chicks and increased the proportion of chicks that were hypnotized by nitrazepam; these effects were dose-dependent. 5-Hydroxytryptophan (5-HTP; 2-8 mg/kg) did not induce sleep but dose-dependently shortened the onset and profoundly prolonged the duration of nitrazepam (1.6 mg/kg)-induced sleep. Cyproheptadine (0.5-2 mg/kg) delayed the onset of nitrazepam sleep and reduced the proportion of chicks that were hypnotized by nitrazepam. Parachlorophenylalanine (PCPA, 200 mg/kg) completely blocked nitrazepam-induced sleep. Nitrazepam sleep was associated with synchronization of the electroencephalogram (EEG) of the hyperstriatum, optic tectum and pontine reticular formation. 5-HT synchronized the EEG of the hyperstriatum and the pontine reticular formation while the electromyograph (EMG) activity was profoundly reduced. These behavioural and electrocortical data suggest that 5-HT may be involved in nitrazepam-induced sleep in young chicks.     

The concentration of catecholamines in the brain of the domestic fowl (Gallus domesticus)

1. The concentrations of adrenaline and noradrenaline in the brains of chickens (Gallus domesticus) have been determined using two different methods of fluorimetric analysis.2. The concentrations of adrenaline, noradrenaline and also dopamine were found to increase with age, as did the relative amount of adrenaline present in the chicken brain.3. It was observed that the differential assay of adrenaline by the trihydroxyindole method often underestimated the amount of adrenaline present.     

Influence of some GABAergic agents on nitrazepam-induced sleep in the domestic fowl (Gallus domesticus)

The effects of gamma amino butyric acid (GABA), bicuculline and amino-oxyacetic acid (AOAA) on nitrazepam-induced sleep were studied in young chicks. GABA (200-3200 mg/kg) induced a marked sedation in young chicks. It also potentiated nitrazepam (1.6 mg/kg)-induced sleep. Bicuculline (1.25-5.00 mg/kg) effectively antagonized nitrazepam-induced sleep. In addition, it effectively antagonized GABA (1600 mg/kg)-induced potentiation of nitrazepam sleep. AOAA (2.5-7.5 mg/kg) delayed the onset of nitrazepam sleep, but significantly prolonged its duration. Nitrazepam (1.6 mg/kg) synchronized the electroencephalogram (EEG) of the hyperstriatum, optic tectum and reticular formation. Similarly, the electromyograph (EMG) activity was markedly reduced. GABA (1600 mg/kg) synchronized the EEG of the hyperstriatum, optic tectum and reticular formation while the EMG activity was reduced. Administration of GABA (1600 mg/kg) into nitrazepam (1.6 mg/kg)-pretreated chicks induced desynchronization of the EEG of the hyperstriatum, while the EEG of the reticular formation was synchronized. In addition, the EMG activity was reduced. Bicuculline (5 mg/kg) activated the EEG of the hyperstriatum; this effect was antagonized by GABA (1600 mg/kg). Similarly, GABA (1600 mg/kg)-induced decrease in EMG activity, synchronization of the EEG of the optic tectum and reticular formation was antagonized by bicuculline. The present data suggest that GABA potentiated nitrazepam-induced behavioral and electroencephalographical sleep.     

Age-Related Effects of Triphenyl Phosphite-Induced Delayed Neuropathy on Central Visual Pathways in the European Ferret (Mustela putorius furo)

The objective of this study was to investigate the relationshipbetween the maturation of visual system neurons and the onsetof their susceptibility to triphenyl phosphite (TPP)-induceddelayed neurotoxicity in the European ferret. We administeredsingle subcutaneous doses of TPP (1184 mg/kg body wt) to 1-to 10-week-old ferret kits to assess the effects on connectionsand neurons of the developing lateral geniculate thalamic nucleus(LGN) and primary visual cortex. Brains were processed witha modified Fink-Heimer silver-impregnation method. Axonal andterminal degeneration were first noted in the LGN of kits injectedat 5 weeks of age. The severity of the degeneration increasedin kits injected at later ages and reached adult densities andconfigurations in ferrets injected at 10 weeks of age. Degeneratingneuronal cell bodies were also present in the LGN of kits injectedat 7 weeks of age and older. In the visual cortex, axonal andterminal degeneration were consistently present in kits injectedat 8 weeks of age and attained adult-like densities in kitsinjected at 10 weeks of age. Previous studies have reportedthat the ferret visual system appears to reach anatomical maturity(as defined by mature LGN lamination patterns, the locationand density of axon terminals originating from neurons in theretina and LGN, and the migration and synaptic connections ofcortical neurons) by 4–5 weeks of age. A temporal comparisonof these normal developmental data with the degeneration dataobtained in the present study suggests that immature neuronsin the visual system of the ferret are not susceptible to TPP-in-duceddelayed neurotoxicity but only become so after they have achievedsome degree of maturity. Whether the LGN neurons undergoingdegeneration are directly affected by TPP or are showing a transneuronalresponse to loss of afferent input remains Unresolved.     

Effects of Mulberry on The Central Nervous System: A Literature Review

Background Mulberry, including several species belonging to genus Morus, has been widely used as a traditional medicine for a long time. Extracts and active components of mulberry have many positive neurological and biological effects and can become potential candidates in the search for new drugs for neurological disorders.Objectives We aimed to systematically review the medical literature for evidence of mulberry effects on the central nervous system.Methods We conducted a systematic search in nine databases. We included all in vivo studies investigating the effect of mulberry on the central nervous system with no restrictions.Results We finally included 47 articles for quality synthesis. Our findings showed that mulberry and its components possessed an antioxidant effect, showed a reduction in the cerebral infarct volume after stroke. They also improved the cognitive function, learning process, and reduced memory impairment in many animal models. M. alba and its extracts ameliorated Parkinson''s disease-like behaviors, limited the complications of diabetes mellitus on the central nervous system, possessed anti-convulsant, anti-depressive, and anxiolytic effects.Conclusion Mulberry species proved beneficial to many neurological functions in animal models. The active ingredients of each species, especially M. alba, should be deeper studied for screening potential candidates for future treatments.     

缬草挥发油对中枢神经系统药理作用的研究

观察了缬草挥发油对中枢神经系统的影响，结果表明，缬草挥发油具有良好的镇静与抗惊厥作用。     

Diclofenac-induced biochemical and histopathological changes in white leghorn birds (Gallus domesticus)

Objective:

Objective: To evaluate diclofenac-induced biochemical and histopathological changes in White Leghorn birds.

Materials and Methods:

Six-week-old birds were equally divided into three groups of six birds each. Group I served as control and received vehicle orally. The birds of Group II and III were orally administered with a single low (2 mg/kg) and high dose (20 mg/kg) of diclofenac sodium, respectively, and were observed for 7 days. The acute toxicity was assessed by observing the clinical signs and symptoms, mortality, alterations in blood biochemistry, and necropsy findings.

Results:

The birds of Group II showed only mild symptoms of diarrhea. In Group III, 50% of birds died in between 24 and 36 h post-treatment showing the symptoms of segregatory behavior, lethargy, terminal anorexia, and severe bloody diarrhea. The birds of Group II and the surviving birds of Group III showed a significantly (P<0.05) increased plasma uric acid, creatinine and plasma glutamic pyruvic transaminase (PGPT), and decreased total protein and albumin at 12 and 24 h post-treatment which returned to the normal levels at 36 h post-treatment. The dead birds of the high-dose group also showed similar pattern of biochemical changes at 12 and 24 h post-treatment and revealed extensive visceral gout with characteristic histopathological lesions in liver, kidney, heart, spleen, and intestine on post-mortem.

Conclusion:

The results indicate that diclofenac sodium has hepatotoxic, nephrotoxic, and visceral gout inducing potentials in White Leghorn birds, especially at higher dose.     

Effects of 5-Fluorouracil Prodrugs on the Central Nervous System in Mice and Rats

The effects on the central nervous system (CNS) of mice and rats were determined for the 5-fluorouracil prodrugs, l-(2-tetrahydrofuranyl)-5-fluorouracil (FT), a combination of FT and uracil in a molar ratio of 1:4 (UFT), and l-hexylcarbamoyl-5-fluorouracil (HCFU). Both FT and UFT failed to produce a significant prolongation of hexobarital sleeping time in mice, while HCFU, at the same dose levels, caused a significant (P < 0.01) prolongation of hexo-barbital sleep. FT, UFT, and HCFU produced a slight suppression of coordinating ability in mice, but the effect of HCFU was more pronounced than that of FT and UFT. There were no significant changes in 5-hydroxytryptamine contents in the cerebral cortex and only small insignificant changes of dopamine contents in the corpus striatum by any of the drugs examined. Furthermore, HCFU was more potent than FT and UFT in potentiating the actions of ethanol. These results suggest that HCFU is more toxic to the CNS than are FT and UFT.     

奥硝唑对映体对小鼠中枢抑制作用的机制探究

目的:探讨右奥硝唑中枢抑制效应与脑内γ-氨基丁酸(gamma amino butyric acid,GABA)系统的关系。方法:经不同剂量右/左奥硝唑处理后使用N,N-二甲基二吖啶硝酸盐(1-(Ethoxycarbonylmethyl)-6-methoxyquinolinium bromide,MQAE)荧光探针检测原代培养小鼠皮层神经元氯离子浓度,并通过western blot方法检测GABAA受体亚基的表达。尾静脉注射给予右/左奥硝唑后测定小鼠高架十字迷宫行为。结果:右奥硝唑剂量依赖性激活小鼠皮层神经元的氯离子通道,经右奥硝唑处理后的皮层神经元能增加GABAA受体α1亚基的水平,且右奥硝唑有潜在的抗焦虑活性。结论:右/左奥硝唑中枢作用不同,右奥硝唑较强的中枢抑制作用可能与激活GABA系统有关。