Відкриття української книгарні “Смолоскип”

The present medication in Parkinson’s disease (PD) is unable to stop or slow down the progression of the disease. Therefore pharmacological intervention at crucial steps in the neuronal cell death processes would be a better strategy. Cannabinoids are potent neuroprotective compounds in models of oxidative stress and excitotoxicity and offer potential protection in models of PD. Therefore the present study determines the neuroprotective effects of 9- tetrahydrocannabinol ( 9-THC) in the marmoset 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model on behavior and pathology. Twelve marmoset monkeys were treated with a total cumulative dose of 6 mg/kg MPTP in 9 days. Seven of these animals received simultaneously a daily oral dose of 9-THC (4 mg/kg) and five animals received simultaneously vehicle for 27 days. The parkinsonian symptoms were observed daily and locomotor activity and hand-eye coordination were tested once a week during the experimental period. Postmortem, dopamine levels in the striatum were analyzed and tyrosine hydroxylase immunohistochemistry was applied to determine viable dopaminergic neurons in the substantia nigra. 9-THC has no protective effects on any parameter. These negative results might be related to the severity of the cell death induction by MPTP in relation to the low dose of 9-THC used in this Parkinson model

Automated TV based system for open field studies: Effects of methamphetamine

A method is described whereby open field behaviour of rats can be automatically registered using a TV camera, a video converter, an X-Y recorder and a papertape puncher. Use is made of the scanning properties of the TV camera to obtain the X and Y coordinates of the rat's position and to print this position on an X-Y recorder to obtain the running pattern. In addition, the X and Y coordinates at 1 sec intervals are punched on papertape. With computer processing of the tape, one can obtain, for any given period, the distance run, a frequency distribution of speeds, the number of entries into an inner field, the time spent in an inner field as well as the number of changes in corner positions. As an example the effects of 1 and 2 mg/kg methamphetamine are shown. This drug enhances all parameters measured in a dose dependent fashion except the changes in corner positions which were not altered significantly. Chemicals/CAS: methamphetamine, 28297-73-6, 51-57-0, 537-46-2, 7632-10-2; Methamphetamine, 537-46-

Efficacy of prophylaxis and treatment against soman intoxication

The efficacy against lethality and post-intoxication incapacitation after 2x LD50 soman of different subacute pretreatment scenarios of 12 days was tested with or without post-intoxication therapy in guinea pigs. These pretreatment regimes were 1) the currently used pretreatment with pyridostigmine (PYR, 0.04 mg/kg/hr), 2) the combination of physostigmine (PHY, 0.025 mg/kg/hr) with the muscarinic receptor antagonist scopolamine (SCO, 0.018 mg/kg/hr), and 3) the combination of PHY with the anti-Parkinson drug procyclidine (PC, 3 mg/kg, sc). The post-intoxication therapy consisted of HI-6 (21.4 mg/kg, im), atropine sulphate (AS, 0.085 mg/kg, im), and diazepam (DZP, 0.21 mg/kg, im). Different behavioral and observational read-out systems were used to elucidate objectively the severity of soman induced incapacitation. There were no big differences in the symptomatology between the animals pretreated with PHY+SCO or with PYR. On the other hand, animals pretreated with PHY+PC did not show worse symptoms as was found in the other groups. In some cases the post-intoxication therapy was even not necessary. Although the symptomatology between the animals treated with PHY+SCO and PYR were comparable the effects on incapacitation and survival were not comparable: all animals pretreated with PYR and the post- intoxication therapy did not perform in the behavioral test systems and died within 24 hours. This was the same result as what was found in unpretreated animals which were treated only with the post-intoxication therapy. The mortality in animals pretreated with PHY+SCO was 25%. The addition of a post intoxication therapy in PHY+SCO pretreated animals did not improve the efficacy. On the other hand, animals pretreated with PHY+PC all survived even without post-intoxication therapy. The performance in the behavioral test systems was similar for animals retreated with PHY+SCO or PHY+PC. Animals without any treatment, besides soman, all died within one hour. Prophylaxis with the combination of PHY and SCO seems to be a good alternative for the current PYR pretreatment, in particular since this pretreatment showed no side effects in previous studies with guinea pigs and marmoset monkeys and protects efficiently against 2x LD50 soman. The addition of PC to PHY, instead of SCO, augments the efficacy of the pretreatment against soman poisoning. In that case an additional post-intoxication therapy is not necessary. The combination of PHY + PC seems to be very promising and should be further investigated

The efficacy of some bis-pyridinium oximes as antidotes to soman in isolated muscles of several species including man

Previous results had shown that bis-pyridinium oximes, particularly HI-6 are quite effective therapeutically in soman-poisoned rats and mice in vivo and in the rat diaphragm preparation in vitro. The aim of the present study was to investigate the efficacy of bis-pyridinium oximes on soman-inhibited neuromuscular transmission in muscle preparations from several species including man. The muscles tested were preparations of rat diaphragm and intercostal muscle, guinea-pig diaphragm, dog external intercostal muscle and human external intercostal muscle. These muscles were stimulated indirectly with field stimulation. With a few exceptions the preparations were exposed to soman for 2.5 or 15 min. In some cases different exposure times were employed or the organophosphate sarin was administered instead of its analogue soman. After the degree of inhibition of neuromuscular transmission had been established, oximes were added to the bath fluid. After washout 15 min later, recovery of neuromuscular transmission was tested. Subsequently, a second dose of soman was administered to investigate whether the recovery observed had been caused by cholinesterase reactivation. The results of these experiments indicate that the oximes tested, mostly HI-6, were quite effective as soman antidotes in muscle preparations of rats, guinea-pigs and dogs. In the human preparation while these oximes were quite effective after sarin intoxication they were essentially without effect against soman. Chemicals/CAS: 1 (3 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl ether, 22625-23-6; 1 (4 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl ether, 34433-31-3; sarin, 107-44-8; soman, 96-64-0; tubocurarine chloride, 57-94-3, 57-95-4, 8006-51-7; Antidotes; Chorionic Gonadotropin; HGG 52, 77704-19-9; HI 6, 34433-31-3; HS 6, 22625-23-6; Organophosphorus Compounds; Pralidoxime Compounds; Pyridinium Compounds; Sarin, 107-44-8; Soman, 96-64-

Two new test methods to quantify motor deficits in a marmoset model for Parkinson's disease

The validity of the common marmoset (Callithrix jacchus) as a model for human disease depends on the development of parameters with clinical relevance. We tested the effect of treatment with MPTP in two newly developed non-invasive motor behavioral paradigms in the context of Parkinson's disease. The "Tower" was designed to quantify the marmoset's natural jumping behavior as a measure for akinesia, the "Hourglass" to test the marmoset's natural righting reflex as measure for rigidity, analogous to axial motor behavior in humans. MPTP treatment affected marmoset behavior in both testing paradigms. The marmoset's righting reflex in the Hourglass remained significantly impaired during the full 3-week period after the MPTP intoxication. In the Tower, the marmosets were not able to jump the largest distances one week after MPTP and showed a persistent reduction in activity during the 3-week period after the MPTP intoxication. Because not all aspects of motor behavior are similarly affected by MPTP, a complete behavioral sketch of parkinsonian marmosets should preferably include a range of motor behavior functions to create an overview of the full range of motor impairments. Both the Hourglass and Tower test provide important behavioral parameters in a clinically relevant multiple testing approach in motor disorder models

Therapeutic effects of Delta9-THC and modafinil in a marmoset Parkinson model

Current therapies for Parkinson's disease (PD) like l-dopa and dopamine (DA) agonists have declined efficacy after long term use. Therefore, research towards supplementary or alternative medication is needed. The implementation in PD can be expedited by application of compounds already used in the clinic. In this study the therapeutic effects of the psychoactive compounds Δ9-tetrahydrocannabinol (Δ9-THC) and modafinil were tested in the 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)–marmoset model for PD. The anti-parkinson effects of Δ9-THC (4 mg/kg) and modafinil (100 mg/kg) in parkinsonian marmosets were assessed with two behavioral rating scales covering parkinsonian symptoms and involuntary movements and two test systems assessing the locomotor activity and hand–eye coordination. Δ9-THC improved activity and hand–eye coordination, but induced compound-related side-effects. Modafinil improved activity and observed parkinsonian symptoms but not hand–eye coordination. It can be concluded that both compounds have therapeutic values and could supplement existing therapies for PD

Low levels of sarin affect the EEG in marmoset monkeys: A pilot study

The main purpose of this pilot study was to estimate the lowest observable adverse effect level (LOAEL) for the electroencephalogram (EEG) upon long-term, low-level exposure of vehicle-pretreated and pyridostigmine-pretreated marmoset monkeys to sarin vapour. This is the C·t value (t = 5 h) of exposure at which the EEG becomes significantly different from that resulting from air exposure of the same animals. The LOAELs for effects on the EEG in vehicle- and pyridostigmine-pretreated marmosets appeared to be 0.2 and 0.1 mg min m -3, respectively. Comparatively, the latter LOAEL values are at least an order of magnitude lower than the previously established LOAEL for miosis and only 2-5 times higher than the lowest observable effect level (LOEL) of bound sarin in blood. The second aim of the study was to analyse the EEG of the same marmosets again during a 5-h exposure to air 1 year after exposure to sarin vapour. All the marmosets still demonstrated significant (P < 0.05) EEG differences. In most vehicle-pretreated marmosets the energy (μV2) per EEG band was higher than that observed 1 year earlier, which might indicate that neurons had become more sensitive to excitation. This phenomenon was less pronounced in pyridostigmine-pretreated animals. Visual examination of the EEG records revealed clear bursts of alpha frequencies (ca. 9 Hz), resembling sleep-spindles, that were present more frequently in both groups of exposed marmosets than in naive animals. These late changes in spindle oscillation might be the result of changes in the cholinergic system due to exposure to sarin vapour 1 year previously. In conclusion, EEG abnormalities persisting for more than 1 year may occur in humans during long-term (5 h) exposure to subclinical levels of sarin that are not detectable by the currently fielded alarm systems. Copyright © 2004 John Wiley & Sons, Ltd

Whole body exposure of marmoset monkeys to low levels of sarin: Lowest observable effect level in blood, and early effects on pupil size and EEG

Realistic scenarios for low-level exposure to nerve agents will often involve exposures over several hours to extremely low doses of agent. The purpose of this pilot study was to indicate for sarin: (i) the lowest observable effect level (LOEL), i.e., the C.t-value (t = 5 h) of exposure at which an internal dose (fluoride-regenerated sarin from blood BuChE) becomes measurable; (ii) The lowest observable adverse effect level (LOAEL) for miosis and EEG-abnormalities in marmosets. For that purpose a validated system was developed for exposing conscious animals to the lowest controllable concentrations of sarin (8-80 ppt: 0.05-0.5μg.m-3), and to increase concentrations (7-150 μg.m-3) and exposure times (t ≤ 5 h) until observable adverse effect levels become measurable. The ratio of pupil and iris diameters, measured on digital photographs taken on-line during exposure, was calculated as a measure for miosis. EEG-signals were recorded telemetrically; the averaged amounts of energy (μV2) per EEG-band of air-exposed animals were compared to the amounts of energy of the corresponding bands of sarin-exposed animals. The LOEL was observed at Ct = 0.04 ± 0.01 mg.min.m-3. This level is several orders of magnitude lower than that based on classical measurement of depressed ChE activity. Pupil size was significantly (p < 0.05) decreased at a dose of 2.5 ± 0.8 mg.min.m-3. The earliest significant (p < 0.05) changes on the EEG-bands were observed at a dose of 0.2 mg.min.m-3. The latter LOAEL-value is an order of magnitude lower than that for miosis, and only 2-5 times higher than the LOEL. One year after the exposure to sarin vapor all marmosets still demonstrated significant (p < 0.05) EEG differences. In most marmosets the energy (μV2) per EEG-band was higher than that observed one year earlier, which might indicate that neurons had become more sensitive to excitation. Visual examination of the EEG-records revealed clear bursts of alpha frequencies (around 9 Hz), resembling sleep-spindles, which were more frequently present in exposed than in naive animals. These late changes in spindle oscillation might be the result of persistent changes in the cholinergic system due to exposure to sarin vapor one year before. In conclusion, LOEL levels, miosis, and EEG-abnormalities, may occur in humans during long term (5 h) exposure to levels of sarin which are not detectable by the currently fielded alarm systems