Parasitoid wasp venom manipulates host innate behavior via subtype-specific dopamine receptor activation.

The subjugation strategy employed by the jewel wasp is unique in that it manipulates the behavior of its host, the American cockroach, rather than inducing outright paralysis. Upon envenomation directly into the central complex (CX), a command center in the brain for motor behavior, the stung cockroach initially engages in intense grooming behavior, then falls into a lethargic sleep-like state referred to as hypokinesia. Behavioral changes evoked by the sting are due at least in part to the presence of the neurotransmitter dopamine in the venom. In insects, dopamine receptors are classified as two families, the D1-like and the D2-like receptors. However, specific roles played by dopamine receptor subtypes in venom-induced behavioral manipulation by the jewel wasp remain largely unknown. In the present study, we used a pharmacological approach to investigate roles of D1-like and D2-like receptors in behaviors exhibited by stung cockroaches, focusing on grooming. Specifically, we assessed behavioral outcomes of focal CX injections of dopamine receptor agonists and antagonists. Both specific and non-specific compounds were used. Our results strongly implicate D1-like dopamine receptors in venom-induced grooming. Regarding induction of hypokinesia, our findings demonstrate that dopamine signaling is necessary for induction of long-lasting hypokinesia caused by brain envenomation.

Glycine-Binding Site Stimulants of NMDA Receptors Alleviate Extrapyramidal Motor Disorders by Activating the Nigrostriatal Dopaminergic Pathway.

Dysfunction of the N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathogenesis of schizophrenia. Although agonists for the glycine-binding sites of NMDA receptors have potential as new medication for schizophrenia, their modulation of antipsychotic-induced extrapyramidal side effects (EPS) has not yet been clarified. We herein evaluated the effects of glycine-binding site stimulants of NMDA receptors on antipsychotic-induced EPS in mice and rats. d-cycloserine (DCS) and d-serine significantly improved haloperidol (HAL)-induced bradykinesia in mice, whereas glycine showed no effects. Sodium benzoate, a d-amino acid oxidase inhibitor, also attenuated HAL-induced bradykinesia. Improvements in HAL-induced bradykinesia by DCS were antagonized by the NMDA antagonist dizocilpine or nitric oxide synthase inhibitor L-NG-Nitro-l-arginine methyl ester. In addition, DCS significantly reduced HAL-induced Fos expression in the dorsolateral striatum without affecting that in the nucleus accumbens. Furthermore, a microinjection of DCS into the substantia nigra pars compacta significantly inhibited HAL-induced EPS concomitant with elevations in dopamine release in the striatum. The present results demonstrated for the first time that stimulating the glycine-binding sites of NMDA receptors alleviates antipsychotic-induced EPS by activating the nigrostriatal dopaminergic pathway, suggesting that glycine-binding site stimulants are beneficial not only for efficacy, but also for side-effect management.

Effect of adenosine A2A receptor antagonists on motor disorders induced by 6-hydroxydopamine in rat.

PURPOSE: To investigate the role of adenosine A2A receptors on 6-OHDA-induced motor disorder in rat. METHODS: In order to induce experimental model of Parkinson's disease, 6-hydoxydopamine (8 µg/rat) was injected unilaterally into the SNc. After three weeks as a recovery period, 6-OHDA-induced bradykinesia and balance disturbances were assessed by using beam traversal test 10, 30 and 60 minutes after intraperitoneal injections of the drugs (caffeine, SCH58261). RESULTS: The results showed that 6-OHDA (8 µg/rat, Intra-SNc) induced motor disorders of Parkinson's disease and increased elapsed time in the beam test (p<0.001). Injection of caffeine (30 mg/kg, i.p.) and SCH58261 (2 mg/kg, i.p.) attenuated elapsed time on beam (p<0.01 and p<0.001). We showed that acute administration of caffeine and SCH 58261 can improve the 6-OHDA-induced bradykinesia and motor disturbance. CONCLUSION: Adenosine A2AR antagonists improve 6-OHDA-motor deficit and this effect seems to be mediated by the inhibition of A2A presynaptic receptors in substantia nigra pars compacta.

Effect of adenosine A2A receptor antagonists on motor disorders induced by 6-hydroxydopamine in rat

PURPOSE: To investigate the role of adenosine A2A receptors on 6-OHDA-induced motor disorder in rat. METHODS: In order to induce experimental model of Parkinson's disease, 6-hydoxydopamine (8 μg/rat) was injected unilaterally into the SNc. After three weeks as a recovery period, 6-OHDA-induced bradykinesia and balance disturbances were assessed by using beam traversal test 10, 30 and 60 minutes after intraperitoneal injections of the drugs (caffeine, SCH58261). RESULTS: The results showed that 6-OHDA (8 μg/rat, Intra-SNc) induced motor disorders of Parkinson's disease and increased elapsed time in the beam test (p<0.001). Injection of caffeine (30 mg/kg, i.p.) and SCH58261 (2 mg/kg, i.p.) attenuated elapsed time on beam (p<0.01 and p<0.001). We showed that acute administration of caffeine and SCH 58261 can improve the 6-OHDA-induced bradykinesia and motor disturbance. CONCLUSION: Adenosine A2AR antagonists improve 6-OHDA-motor deficit and this effect seems to be mediated by the inhibition of A2A presynaptic receptors in substantia nigra pars compacta.

Effects of the selective adenosine A2A receptor antagonist, SCH 412348, on the parkinsonian phenotype of MitoPark mice.

Adenosine A2A receptors are predominantly localized on striatopallidal gamma-aminobutyric acid (GABA) neurons, where they are colocalized with dopamine D2 receptors and are involved in the regulation of movement. Adenosine A2A receptor antagonists have been evaluated as a novel treatment for Parkinson's disease and have demonstrated efficacy in a broad spectrum of pharmacological and toxicological rodent and primate models. Fewer studies have been performed to evaluate the efficacy of adenosine A2A receptor antagonists in genetic models of hypodopaminergic states. SCH 412348 is a potent and selective adenosine A2A receptor antagonist that shows efficacy in rodent and primate models of movement disorders. Here we evaluated the effects of SCH 412348 in the MitoPark mouse, a genetic model that displays a progressive loss of dopamine neurons. The dopamine cell loss is associated with a profound akinetic phenotype that is sensitive to levodopa (l-dopa). SCH 412348 (0.3-10mg/kg administered orally) dose dependently increased locomotor activity in the mice. Moreover, SCH 412348 retained its efficacy in the mice as motor impairment progressed (12-22 weeks of age), demonstrating that the compound was efficacious in mild to severe Parkinson's disease-like impairment in the mice. Additionally, SCH 412348 fully restored lost functionality in a measure of hind limb bradykinesia and partially restored functionality in a rotarod test. These findings provide further evidence of the anti-Parkinsonian effects of selective adenosine A2A receptor antagonists and predict that they will retain their efficacy in both mild and severe forms of motor impairment.

Meta-analysis of the efficacy of sorafenib for hepatocellular carcinoma.

PURPOSE: By carrying out a meta-analysis of randomized controlled trials that compared sorafenib or combined chemotherapy with placebo or combined chemotherapy, the effectiveness of sorafenib in hepatocellular carcinoma was evaluated in the present study, which also provided clinical practice guidelines of evidence-based-medicine. METHODS: We reviewed PubMed citations concerning sorafenib treating hepatocellular carcinoma in randomized controlled trials from Jan 2000 to July 2012. All the literature was extracted by Cochrane systematic reviews and underwent meta-analysis with RewMan 5.0 software. RESULTS: Finally, four papers documenting randomized controlled studies were included. Compared with controls, sorafenib was shown to significantly increase overall survival (OS), time to progression (TTP), and disease control rates (DCR), but not the time to symptom progression (TTSP) in hepatocellular carcinoma patients. The incidence of grade-III/IV adverse reactions, including hand- foot-skin reactions, diarrhea, hypertension and skin rash or desquamation, in sorafenib treatment group was higher than that in controls. However, there was no significant difference in the incidence of hypodynamia between the two groups. CONCLUSIONS: Sorafenib exerts significant curative effects in hepatocellular carcinoma.

Involvement of the opioid system in the hypokinetic state induced in cockroaches by a parasitoid wasp.

The parasitoid wasp Ampulex compressa stings and injects venom into the cockroach brain to induce a long-lasting hypokinetic state. This state is characterized by decreased responsiveness to aversive stimuli, suggesting the manipulation of a neuromodulatory system in the cockroach's central nervous system. A likely candidate is the opioid system, which is known to affect responsiveness to stimuli in insects. To explore this possibility, we injected cockroaches with different opioid receptor agonists or antagonists before they were stung by a wasp and tested the escape behavior of these cockroaches to electric foot shocks. Antagonists significantly decreased the startle threshold in stung individuals, whereas agonists led to an increased startle threshold in controls. Yet, neither agonists nor antagonists had any effect on grooming. To further characterize the interaction between the venom and opioid receptors, we used an antenna-heart preparation. In un-stung individuals external application of crude venom completely inhibits antenna-heart contractions. In stung individuals the antenna-heart showed no contractions. Although acetylcholine restored contractions, the opioid receptor antagonist naloxone was unable to antagonize the venom inhibition. These results suggest that the venom of A. compressa might contribute to the manipulation of cockroach behavior by affecting the opioid system.

Chronic systemic treatment with a high-dose proteasome inhibitor in mice produces akinesia unrelated to nigrostriatal degeneration.

Supporting the hypothesis that proteasome dysfunction is involved in Parkinson's disease (PD), McNaught et al. (2004) reported that the systemic administration of the proteasome inhibitor Z-Ile-Glu(OtBu)-Ala-Leu-aldehyde (PSI) in rats led to the degeneration of the nigrostriatal pathway. However, several groups could not reproduce this finding. We herein attempted to improve the reliability of the PSI model by chronically delivering the inhibitor using osmotic minipumps in aged mice. We also tested whether PSI co-administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could act synergistically to induce toxicity. We found that PSI produced a significant reduction in locomotor activity that was mildly exacerbated by MPTP. However, PSI alone produced no sign of degeneration of the nigrostriatal dopaminergic pathway and did not exacerbate MPTP toxicity. To conclude, PSI administration does not provide a reliable phenotypic model of PD.

Fentanyl-induced bradykinesia and rigidity after deep brain stimulation in a patient with Parkinson disease.

A 58-year-old man with advanced Parkinson disease underwent battery replacement for a deep brain stimulator and experienced severe bradykinesia and rigidity postoperatively for 36 hours. The patient was administered fentanyl as an anesthetic during the procedure and as an analgesic periodically during the day after surgery. The severe bradykinesia and rigidity persisted despite reactivation of the deep brain stimulator and immediate reinstitution of Parkinson disease medications, but resolved completely several hours after discontinuation of fentanyl.

Nigral degeneration with inclusion body formation and behavioral changes in rats after proteasomal inhibition.

OBJECTIVE: We were interested in studying nigral degeneration with inclusion body formation and behavioral changes in rats after proteasomal inhibition. METHODS: Observation of progressive behavioral and pathological changes in rats following a unilateral nigral injection of lactacystin, a selective proteasome inhibitor. RESULTS: After administration at a concentration of 10 microg (2 microl) of lactacystin, when tyrosine hydroxylase (TH) immunostaining decreased gradually in the substantia nigra pars compacta (SNc) and corpus striatum, alpha-synuclein-immunopositive inclusion appeared extensively in the surviving neurons. We also observed the degeneration of diverse cellular organelles by transmission electron microscopy. The effect of cellular organelle degeneration on behavior, a clinical index, was striking and was statistically significant. Over the 3 weeks following the administration of lactacystin, a highly significant decrease in TH immunostaining was observed and alpha-synuclein-immunopositive inclusions gradually appeared. Interestingly, there was a strong correlation in behavioral changes and the increase in alpha-synuclein-immunopositive inclusions whereas the decrease in TH immunostaining did not seem to induce any behavioral changes. CONCLUSIONS: Our results reveal that unilateral nigral proteasome inhibition induces degeneration in the SNc and corpus striatum as well as behavioral changes demonstrating strong time dependence. Behavioral changes were driven by the formation of alpha-synuclein inclusions, but not by decreased TH neurons.

Nicotine induces conditioned place preferences over a large range of doses in rats.

RATIONALE: Conditioned place preference (CPP) procedures provide one measure of potential rewarding effects of abused drugs. Many attempts to induce CPP with nicotine have been unsuccessful. OBJECTIVES: To assess the influence of nicotine dose and stimulus assignment procedure on development of nicotine-induced CPP. METHODS: Initial preferences for one side of a two-compartment apparatus were first determined in Sprague-Dawley rats. In subsequent conditioning trials, the compartment paired with nicotine was the initially preferred side for half of the rats, and the initially non-preferred side for the other half. Rats received either an injection of nicotine (0.01-2 mg/kg SC) before being placed in one compartment (three trials) or saline before being placed in the other compartment (three trials). Control rats had saline injections associated with both compartments. A final test trial with no injection assessed final place preference. RESULTS: Significant CPP were induced by 0.1-1.4 mg/kg doses of nicotine. Nicotine-induced CPP were only apparent when nicotine was paired with the initially non-preferred side. Moreover, a very high dose of nicotine (2 mg/kg) induced conditioned place aversion when paired with the initially preferred side of the apparatus. CONCLUSIONS: Nicotine induced significant CPP across a wide range of doses, in accordance with its role as the primary addictive component of tobacco. Small preferences for one side of the apparatus played a major role in the development of nicotine-induced CPP. These findings suggest that biased procedures may be more suitable than unbiased procedures for evaluation of rewarding effects of nicotine using CPP paradigms.

Lysophosphatidylcholine decreases locomotor activities and dopamine turnover rate in rats.

Lysophosphatidylcholine (lyso-PTC), a secondary product of S-adenosylmethionine (SAM)-dependent phosphatidylethanolamine (PTE) methylation, is a potent cytotoxin and might be involved in the pathogenesis of Parkinson's disease (PD). Our previous studies showed that the injection of SAM into the brain caused PD-like changes in rodents. Moreover, 1-methyl-4-phenylpyridinium (MPP+), a Parkinsonism-inducing agent, increased lyso-PTC formation via the stimulation of PTE methylation pathway. These results indicate a possible role of lyso-PTC in the PD-like changes seen following the injection of SAM or MPP+. In the present study, lyso-PTC was injected into the lateral ventricle of rats and locomotor activities and the biogenic amine levels were measured to evaluate the effects of lyso-PTC on the dopaminergic system. Quinacrine, a phospholipase A2 (PLA2) inhibitor, was employed to determine its protective effect on SAM-induced PD-like changes by the inhibition of lyso-PTC formation. The results showed that 1 h after the injection, 0.4 and 0.8 micromol of lyso-PTC increased striatal dopamine (DA) by 20 and 24%, decreased 3,4-dihydroxyphenylacetic acid (DOPAC) by 37 and 45% and decreased homovanilic acid (HVA) by 24 and 13%, respectively. Consequently, dopamine turnover rate, (DOPAC + HVA)/DA, was significantly reduced by 44 and 48% in the rat striatum. Meanwhile, the administration of 0.4 or 0.8 micromol of lyso-PTC decreased movement time by 52 and 63%, total distance by 44 and 48% and the number of movements by 43 and 64%, respectively. Quinacrine attenuated SAM-induced hypokinesia without affecting SAM metabolism prior to its action on rat brain. The results obtained indicate that the hypokinesia observed following the administration of lyso-PTC might be related to the decline in DA turnover in the striatum in response to lyso-PTC exposure. The present study suggests that inhibitory effects of lyso-PTC on dopaminergic neurotransmission is one of the contributing factors in SAM and MPP+-induced PD-like changes.

[Primary assessment of treatment effect of thymosin alpha1 on chemotherapy-induced neurotoxicity].

BACKGROUND & OBJECTIVE: Clinical trails showed that thymosin alpha1 offers protection from toxicities (nausea, vomiting, fatigue) of chemotherapy. This study was designed to investigate the protection of thymosin alpha1 to nervous system. METHODS: Twenty-two patients with advanced lung cancer, or advanced breast cancer were treated with vinorelbine (25 mg/m(2), d(1), d(8)) combined with cisplatin (80 mg/m(2), d(1)), or gemcitabine (1.25 g/m(2), d(1), d(8)) combined with cisplatin (80 mg/m(2), d(1)),or paclitaxel (80 mg/m(2), d(1), d(8), d(15)) combined with carboplatin (AUC=6 d(1)),or paclitaxel (80 mg/m(2), d(1), d(8), d(15)) combined with epirubicin (80 mg/m(2), d(1)). They all experienced grade 2 to 4 of neurotoxicities according to common toxicity criteria of National Cancer Institute after chemotherapy. The same chemotherapy regimens were combined with thymosin alpha1 (1.6 mg/d for 4 days before chemotherapy, and 1.6 mg twice weekly for 1-3 weeks after chemotherapy began) in the next cycle. Clinical neurologic evaluation was performed at baseline every week. RESULTS: In 10 patients (45.4%), neurotoxicities reduced from grade 2-4 before chemotherapy to less than grade 2 after chemotherapy. CONCLUSION: Thymosin alpha1 may prevent patients from chemotherapy-induced neurotoxicities.

Study on quantitative structure-toxicity relationships of benzene derivatives acting by narcosis.

Hydrophobicity (logP) as well as quantiative structure-toxicity relationships (QSTRs) of some benzene derivatives acting by narcosis have been established based on narcotic mechanisms of action and toxicity data to the fathead minnow, Daphnia magna and Vibrio fischeri using information-theoretic topological index (Id). Excellent results are obtained in multiparametric regression upon introduction of dummy parameters (indicator variables). Consistent increase in R(2)(A) values indicated that inspite of collinarity between Id and one of the indicator variables (I(3-6)) the proposed models are statistically significant.

Maze learning and motor activity deficits in adult mice induced by iron exposure during a critical postnatal period.

Newborn mice were administered Fe(2+) (iron succinate: 7.5 mg/kg, b. wt) on either Days 3-5, 10-12 or 19-21, or vehicle (saline) at the same times, postnatally. Spontaneous motor behaviour and radial arm maze learning were tested at the age of 3 months. It was found that mice treated with Fe(2+) during postnatal Days 10-12 were markedly hypokinetic during the 1st 20-min test period and hyperkinetic during the 3rd and final 20-min test period. These mice showed an almost complete lack of habituation of spontaneous motor activity parameters to the test chambers. In the radial arm maze, the Days 10-12 treatment group evidenced significantly both more errors in arm choices and longer latencies to acquire all eight pellets; these mice showed also a severe trial-to-trial retention deficit as indexed by retention quotients. These behavioural deficits were observed also in animals treated with Fe(2+) during postnatal Days 3-5, but the effects were less pronounced, indicating the higher susceptibility of the brain for Fe(2+)-induced damage during Days 10-12 postpartum. Treatment with Fe(2+) on Days 19-21 did not induce behavioural alterations in comparison with its respective control (vehicle) group. Analysis of total brain iron content indicated significantly more iron (microg/g) accumulation in the basal ganglia, but not frontal cortex, of mice from the Days 3-5 and 10-12 Fe(2+) (7.5 mg/kg) treatment groups. The contribution of iron overload during the immediate postnatal to later functional deficits seems to implicate symptoms of Parkinsonism but the kinetics of iron uptake to the brain and its regional distribution at this critical period of development awaits elucidation.

Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP.

RATIONALE: Current treatment of Parkinson's disease (PD) is based on dopamine replacement therapy, but this leads to long term complications, including dyskinesia. Adenosine A2A receptors are particularly abundant in the striatum and would be a target for an alternative approach to the treatment of PD. OBJECTIVES: The purpose of this study is to examine the efficacy and potency of the novel selective adenosine A2A receptor antagonist (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dhydro- 1H-purine-2,6- dione (KW-6002) in ameliorating the motor deficits in various mouse models of Parkinson's disease. METHODS: We evaluated the efficacy and potency of KW-6002 and other reference compounds in the selective adenosine A2A receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680)-, haloperidol- or reserpine-induced catalepsy models. The effect of KW-6002 on reserpine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride(MPTP)-induced hypolocomotion was also examined. RESULTS: The ED50s of KW-6002 in the reversal of CGS21680-induced and reserpine-induced catalepsy were 0.05 mg/kg, PO and 0.26 mg/kg, PO, respectively. Compared to the ED50 of other adenosine antagonists and dopamine agonist drugs, KW-6002 is over 10 times as potent in these models. KW-6002 also ameliorated the hypolocomotion (minimum effective dose; 0.16 mg/kg) induced by nigral dopaminergic dysfunction with MPTP or reserpine treatment. Combined administrations of subthreshold doses of KW-6002 and L-dopa (50 mg/kg, PO) exerted prominent effects on haloperidol-induced and reserpine-induced catalepsy, suggesting that there may be a synergism between the adenosine A2A receptor antagonist KW-6002 and dopaminergic agents. CONCLUSIONS: To our knowledge, KW-6002 is the most potent and orally active adenosine A2A receptor antagonist in experimental models of Parkinson's disease, and may offer a new therapeutic approach to the treatment of Parkinson's disease.

H1-antagonism improves intestinal mucosal pH and heart function in porcine hypodynamic endotoxic shock.

Porcine hypodynamic shock was induced by continuous infusion of 5 micrograms lipopolysaccharide/kg per hour. This resulted in a decrease of cardiac output from baseline values of 3.5 +/- .9 L/min to 1.5 +/- .8 L/min and a reduced left ventricular stroke work index in the endotoxin-group (n = 6 animals). Pretreatment with the H1-antagonist dimethindene (2 mg/kg) in a second group (n = 6) significantly prevented these effects. Furthermore animals pretreated with the H1-antagonist showed a stable mean arterial blood pressure, whereas the control endotoxin-treated group revealed a drastic reduction in mean arterial blood pressure (99 +/- 4.7 mmHg versus 65.8 +/- 10 mmHg after 240 min, respectively). Pulmonary function and systemic vascular resistance were not ameliorated by the H1-antagonist in hypodynamic shock. Gastrointestinal mucosal pH (pHi), which indicates oxygenation of the mucosa, was decreased by endotoxin-infusion (7.45 +/- .32 baseline value to 6.92 +/- .24 after 120 min). This parameter as well as base excess values and lactate levels were significantly improved by dimethindene-pretreatment (p < .05). These results may indicate a beneficial effect of H1-antagonist-pretreatment on endotoxin-induced deterioration of the microcirculation. Furthermore our results clearly demonstrated that only pretreatment before endotoxemia with H1-antagonism is effective, since infusion of H1-antagonist in hypodynamic shock 45 min after addition of endotoxin (n = 6 animals) did not improve the cardiovascular system or the microcirculation.