Plasma amino acids in ecstasy users

Recreational use of the illegal drug "ecstasy" has increased dramatically in recent years. We have measured 33 different plasma amino acids in ecstasy users and controls. Significant differences were found for phosphoserine, glutamate, citrulline, methionine, tyrosine and histidine. Resembling changes in the plasma amino acids have been described in acute transient polymorphous psychosis. Thus, alterations in plasma - methionine and phosphoserine or other amino acids could be involved in the psychical symptoms produced by MDMA.     

Brain serotonin synthesis in MDMA (ecstasy) polydrug users: an alpha‐[11C]methyl‐l‐tryptophan study

3,4‐Methylenedioxymethamphetamine (MDMA, ecstasy) use may have long‐term neurotoxic effects. In this study, positron emission tomography with the tracer alpha‐[¹¹C]methyl‐l ‐tryptophan (¹¹C‐AMT) was used to compare human brain serotonin (5‐HT) synthesis capacity in 17 currently drug‐free MDMA polydrug users with that in 18 healthy matched controls. Gender differences and associations between regional ¹¹C‐AMT trapping and characteristics of MDMA use were also examined. MDMA polydrug users exhibited lower normalized ¹¹C‐AMT trapping in pre‐frontal, orbitofrontal, and parietal regions, relative to controls. These differences were more widespread in males than in females. Increased normalized ¹¹C‐AMT trapping in MDMA users was also observed, mainly in the brainstem and in frontal and temporal areas. Normalized ¹¹C‐AMT trapping in the brainstem and pre‐frontal regions correlated positively and negatively, respectively, with greater lifetime accumulated MDMA use, longer durations of MDMA use, and shorter time elapsed since the last MDMA use. Although the possibility of pre‐existing 5‐HT alterations pre‐disposing people to use MDMA cannot be ruled out, regionally decreased 5‐HT synthesis capacity in the forebrain could be interpreted as neurotoxicity of MDMA on distal (frontal) brain regions. On the other hand, increased 5‐HT synthesis capacity in the raphe and adjacent areas could be due to compensatory mechanisms.

     

Methamphetamine and MDMA (ecstasy) neurotoxicity: 'of mice and men'

Methamphetamine (METH) and 3,4-meythylenedioxymethamphetamine (MDMA; 'ecstasy') are currently major drugs of abuse. One of the major concerns of amphetamines abuse is their potential neurotoxic effect on dopaminergic and serotonergic neurons. Although data from human studies are somewhat limited, compelling evidence suggests that these drugs cause neurotoxicity in rodents and primates. Recent studies in transgenic and knockout mice identified the role of dopamine transporters, nitric oxide, apoptotic proteins, and inflammatory cytokines in amphetamines neurotoxicity. Further research into the mechanisms underlying the dopaminergic and serotonergic neurotoxicity and the behavioral corollaries of these neuronal insults could facilitate our understanding of the consequences of human abuse of METH and MDMA on cognition, drug-seeking behavior, extinction and relapse.     

Lead neurotoxicity: effects on brain nitric oxide synthase

Lead (Pb), a ubiquitous and potent neurotoxicant, induces several neurophysiological and behavioural changes, while Pb alters the function of multiple organs and systems, it primarily affects the central nervous system. In human adults, encephalopathy resulting from Pb intoxication is often characterized by sleeplessness, poor attention span, vomiting, convulsions and coma; in children, Pb-induced encephalopathy is associated with mental dullness, vomiting, irritability and anorexia; diminished cognitive function resulting in a mental deficit has been also observed during Prolonged exposure to Pb. Pb can produce oxidative stress, disrupt the blood–brain barrier and alter several Ca²⁺-dependent processes, including physiological processes that involve nitric oxide synthesis on central nervous system in development and adult animals. This review summarizes recent evidence showing that Pb can interfere with the production of nitric oxide and can disrupt the function of nitric oxide synthase. Lead interferes with nitric oxide-related physiological mechanisms, and Pb neurotoxicity may affect processes involved in learning and memory.     

Buspirone: correlation of its anxiolytic and electroencephalographic effects

The influence of diazepam (1 and 5 mg/kg, i. p.) and buspirone (5 and 10 mg/kg) on the Fourier's spectral EEG power of sensomotor cortex and a conflict behavior in freely moving rats were studied. Diazepam (1 mg/kg) and buspirone (5 mg/kg) produced slowing of EEG theta-activity. Large doses of diazepam and buspirone produced different and multiple EEG effects. To 15-1788 (10 mg/kg) completely antagonized all the effects of diazepam (5 mg/kg). The authors discuss possible mutual relations between the influence on EEG and anxiolytic effect of these tranquilizers.     

Platinum drugs and neurotoxicity: effects on intracellular calcium homeostasis

[Pt(O,O′-acac)(γ-acac)(DMS)] (PtAcacDMS) is a new platinum compound showing low reactivity with nucleobases and specific reactivity with sulfur ligands intracellularly. It induces apoptosis in breast cancer cells, but appears to be less neurotoxic to the developing cerebellum than cisplatin (cisPt). The aim of this study was to assess the neurotoxicity of platinum compounds on calcium homeostasis in the dentate gyrus and Cornu Ammonis regions of the hippocampal formation during rat postnatal development. Two intracellular calcium homeostasis systems were taken for measurement, calbindin, a calcium buffer protein, and a plasma membrane calcium ATPase (PMCA1). The platinum compounds showed different effects on these markers in the two areas. One day after injection (PD11), cisPt decreased calbindin immunoreactivity and PMCA1 labeling in both regions; at PD17, the downregulation of PMCA1 persisted. Instead, PtAcacDMS produced varying effects on calbindin immunoreactivity in the two regions at PD11 and PD17; but in all cases, the changes incurred in calbindin immunoreactivity were counterbalanced by changes produced in PMCA1 expression. In conclusion, PtAcacDMS seems to affect calcium homeostasis in the central nervous system differently than cisPt. Both the platinum compounds act early to alter the calbindin buffering system. However, the most important difference between cisPt and PtAcacDMS is that, in vivo, the latter acts early to stimulate calcium efflux from nerve cells as reflected by its effect on PMCA1. The rapid onset of an activated calcium pump appears to be essential to cope with the excessive intracellular calcium concentration stemming from the downregulation of calbindin which could damage neuron function and morphology.     

Arsenic-induced neurotoxicity in relation to toxicokinetics: effects on sciatic nerve proteins

In our previous study in rats acutely exposed to As, we observed an effect of As on neurofilaments in the sciatic nerve. This study deals with the effects of inorganic As in Wistar rats on the cytoskeletal protein composition of the sciatic nerve after subchronic intoxication. Sodium meta-arsenite (NaAsO2) dissolved in phosphate-buffered saline (PBS) was administered daily in doses of 0, 3 and 10 mg/kg body weight/day (n=9 rats/group) by intragastric route for 4, 8 and 12 week periods. Toxicokinetic measurements revealed a saturation of blood As in the 3- and 10-mg/kg dose groups at approximately 14 microg/ml, with an increase in renal clearance of As at increasing doses. After exsanguination, sciatic nerves were excised and the protein composition was analyzed. Analysis of the sciatic nerves showed compositional changes in their proteins. Protein expression of neurofilament Medium (NF-M) and High (NF-H) was unchanged. Neurofilament protein Low (NF-L) expression was reduced, while mu- and m-calpain protein expression was increased, both in a dose/time pattern. Furthermore, NF-H protein was hypophosphorylated, while NF-L and microtubule-associated protein tau (MAP-tau) proteins were (hyper)-phosphorylated. In conclusion, we show that expression of mu- and m-calpain protein is increased by exposure to As, possibly leading to increased NF-L degradation. In addition, hyperphosphorylation of NF-L and MAP-tau by As also contribute to destabilization and disruption of the cytoskeletal framework, which eventually may lead to axonal degeneration.     

Antioxidant activity of phenylethanoid glycosides on glutamate-induced neurotoxicity

ABSTRACT

Exposure of PC12 cells to 10 mM glutamate caused significant viability loss, cell apoptosis, decreased activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) as well as increased levels of malondialdehyde (MDA). In parallel, glutamate significantly increased the intracellular levels of ROS and intracellular calcium. However, pretreatment of the cells with acteoside and isoacteoside significantly suppressed glutamate-induced cellular events. Moreover, acteoside and isoacteoside reduced the glutamate-induced increase of caspase-3 activity and also ameliorated the glutamate-induced Bcl-2/Bax ratio reduction in PC12 cells. Furthermore, acteoside and isoacteoside significantly inhibited glutamate-induced DNA damage. In the mouse model, acteoside significantly attenuated cognitive deficits in the Y maze test and attenuated neuronal damage of the hippocampal CA1 regions induced by glutamate. These data indicated that acteoside and isoacteoside play neuroprotective effects through anti-oxidative stress, anti-apoptosis, and maintenance of steady intracellular calcium.     

Simulation of human sleep: ultradian dynamics of electroencephalographic slow-wave activity

The typical declining trend of electroencephalographic (EEG) slow-wave activity (SWA) within a sleep period is represented in the two-process model of sleep regulation by an exponentially decaying process (Process S). The model has been further elaborated to simulate not only the global changes of SWA, but also the dynamics within non-rapid-eye-movement (non-REM) sleep episodes. In this new model, the initial intraepisodic buildup of SWA is determined by the combined action of an exponentially increasing process and a saturation process, whereas its fall at the end of an episode is due to an exponentially decreasing process. The global declining trend of SWA over consecutive episodes results from the monotonic decay of the intraepisodic saturation level. In contrast to Process S in the two-process model, this decay is not represented by an exponential function, but is proportional to the momentary level of SWA. REM sleep episodes are triggered by an external function. The model allows one to simulate the ultradian pattern of SWA for baseline nights as well as changes induced by a prolonged waking period, a daytime nap, a partial slow-wave sleep deprivation, or an antidepressant drug.     

Influence of lithium hydroxybutyrate on the electroencephalographic effects of fenamin

Lithium hydroxybutyrate (10 mg/kg) prevents the amphetamine-induced EEG arousal and amplitude frequency alterations in the motor and visual cortex, posterior hypothalamus, midbrain reticular formation, and caudate nucleus but potentiates the action of the psychostimulant on the EEG of the hippocamp and amygdala. The response to the light flickering rhythm in the visual cortex remains within initial upon concurrent administration of both the drugs.     

Plasma concentrations of 5-HT, 5-HIAA,norepinephrine, epinephrine and dopamine in ecstasy users

Recreational use of the synthetic methamphetamine derivative MDMA (3,4-methylenedioxymethamphetamine), the main constituent of the illegal drug "ecstasy", has increased dramatically in recent years. The reasons for ecstasy-associated cardiovascular complications like tachycardia, arrhythmias and hypertensive crises and psychiatric symptoms like psychotic episodes are not well understood. We have measured the plasma concentrations of 5-HIAA, 5-HT, norepinephrine, epinephrine and dopamine in 159 ecstasy users and controls. Ecstasy users showed elevated resting sympathetic activity, reflected in increased norepinephrine, epinephrine and dopamine levels. The levels of these catecholamines correlated positively with the cumulative dose and also with consumption during the last 30 days and 12 months. Although it is known that significant changes in 5-HT and 5-HIAA appear in the cerebrospinal fluid in ecstasy users, we could not detect alterations in serotonergic neurotransmitters in plasma in this large sample of subjects. Thus, in the drug-free interval, ecstasy users show lowered central serotonergic activity (lowered 5-HT and 5-HIAA concentrations in CSF) along with unchanged central noradrenergic and dopaminergic activity (HVA and MHPG unchanged in CSF) and elevated peripheral noradrenergic, dopaminergic and adrenergic activity along with unchanged peripheral serotonergic activity (plasma levels). We conclude, that the data presented here could argue for a noradrenergic hyperreactivity in the drug-free interval in ecstasy users resulting from previous ecstasy consumption. Also for an association with psychotic episodes and cardiovascular complications like tachycardia, arrhythmias.     

Differential effects of carboxyfullerene on MPP+/MPTP-induced neurotoxicity

The effects of carboxyfullerene on a well-known neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenyl-pyridinium (MPP+) were investigated. In chloral hydrate-anesthetized rats, cytosolic cytochrome c was elevated in the infused substantia nigra 4 h after an intranigral infusion of MPP+. Five days after local application of MPP+, lipid peroxidation (LP) was elevated in the infused substantia nigra. Furthermore, dopamine content and tyrosine hydroxylase (TH)-positive axons were reduced in the ipsilateral striatum. Concomitant intranigral infusion of carboxyfullerene abolished the elevation in cytochrome c and oxidative injuries induced by MPP+. In contrast, systemic application of carboxyfullerene did not prevent neurotoxicity induced by intraperitoneal injection of MPTP. In mice, systemic administration of MPTP induced a dose-dependent depletion in striatal dopamine content. Simultaneous injection of carboxyfullerene (10 mg/kg) actually potentiated MPTP-induced reduction in striatal dopamine content. Furthermore, systemic administration of carboxyfullerene (30 mg/kg) caused death in the MPTP-treated mice. An increase in the striatal MPP+ level and reduction in hepatic P450 level were observed in the carboxyfullerene co-treated mice. These data showed that systemic application of carboxyfullerene appears to potentiate MPTP-induced neurotoxicity while local carboxyfullerene has been suggested as a neuroprotective agent. Furthermore, an increase in striatal MPP+ level may contribute to the potentiation by carboxyfullerene of MPTP-induced neurotoxicity.     

褐黑素对大鼠海马神经元谷氨酸所致毒性的拮抗作用

在大鼠海马脑片上电刺激Ｓｃｈａｆｆｅｒ侧支纤维,胞外记录ＣＡ１区锥体细胞层诱发群体锋电位,观察灌流谷氨酸和褪黑素对ＰＳ的影响。结果显示：５．０ｍｍｏｌ／Ｌ浓度的Ｇｌｕ可使ＰＳ值下降至对照值的４．１％;ＭＥ（０．４、０．５和０．６μｍｏｌ／Ｌ）一５．０ｍｍｏｌ／Ｌ浓度的Ｇｌｕ可使ＰＳ值下降至对照值的１４．７％、１０５．２％、２４．３％;ＭＥＬ、Ｇｌｕ,与赛庚啶混合给药,ＰＳ值下降至０。上述结果提示。     

Analysis of the electroencephalographic activity associated with thalamic tumors

A physiologically based model of corticothalamic dynamics is used to investigate the electroencephalographic (EEG) activity associated with tumors of the thalamus. Tumor activity is modeled by introducing localized two-dimensional spatial non-uniformities into the model parameters, and calculating the resulting activity via the coupling of spatial eigenmodes. The model is able to reproduce various qualitative features typical of waking eyes-closed EEGs in the presence of a thalamic tumor, such as the appearance of abnormal peaks at theta ( approximately 3Hz) and spindle ( approximately 12Hz) frequencies, the attenuation of normal eyes-closed background rhythms, and the onset of epileptic activity, as well as the relatively normal EEGs often observed. The results indicate that the abnormal activity at theta and spindle frequencies arises when a small portion of the brain is forced into an over-inhibited state due to the tumor, in which there is an increase in the firing of (inhibitory) thalamic reticular neurons. The effect is heightened when there is a concurrent decrease in the firing of (excitatory) thalamic relay neurons, which are in any case inhibited by the reticular ones. This is likely due to a decrease in the responsiveness of the peritumoral region to cholinergic inputs from the brainstem, and a corresponding depolarization of thalamic reticular neurons, and hyperpolarization of thalamic relay neurons, similar to the mechanism active during slow-wave sleep. The results indicate that disruption of normal thalamic activity is essential to generate these spectral peaks. Furthermore, the present work indicates that high-voltage and epileptiform EEGs are caused by a tumor-induced local over-excitation of the thalamus, which propagates to the cortex. Experimental findings relating to local over-inhibition and over-excitation are discussed. It is also confirmed that increasing the size of the tumor leads to greater abnormalities in the observable EEG. The usefulness of EEG for localizing the tumor is investigated.     

Protective effects of isoquercitrin on streptozotocin‐induced neurotoxicity

Alzheimer's disease (AD) is characterized by irreversible and progressive memory loss and has no effective treatment. Recently, many small molecule nature products have been identified with neuroprotective functions and shown beneficial effects to AD patients. In the current study, we thus performed a small scale screening to determine the protective effects of natural compounds on streptozotocin (STZ)‐induced neurotoxicity and Alzheimer's disease (AD). We found that a lead flavonoid compound, isoquercitrin (ISO) display the most effective anti‐cytotoxic activities via inhibiting STZ‐induced apoptosis, mitochondria dysfunction and oxidative stress. Treatment with ISO largely rescues STZ‐induced differentiation inhibition and enhances neurite outgrowth of Neuro2a (N2a) cells in vitro. Moreover, oral administration of ISO protects hippocampal neurons from STZ‐induced neurotoxicity and significantly improves the cognitive and behavioural impairment in STZ‐induced AD rats. In general, our screening identifies ISO as an effective therapeutic candidate against STZ‐induced neurotoxicity and AD‐like changes.