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Abstract Ipomoea pes-caprae (Convolvulaceae), popularly known as “salsa-da-praia”, is used in folk medicine for the treatment of several diseases, including hypertension. The aim of this research was to evaluate hypotensive activity attributed to this species and identify the bioactive compounds responsible for this effect. Hydroalcoholic extract of aerial parts of Ipomoea pes-caprae (PIEA) was fractionated by column chromatography with Amberlite XAD-2, thus achieving a methanolic fraction (PIEA-M). The chemical profile investigation of PIEA-M was conducted by Ultra Performance Liquid Chromatography coupled to Mass Spectrometry (UPLC-MS) and compound isolation through High Performance Countercurrent Chromatography (HPCCC). Hemodynamic evaluations of PIEA, PIEA-M and isolated compounds were carried out on normotensive rats. The locomotor activity of PIEA and PIEA-M were performed by Rota Rod test using Swiss mice. UPLC-MS analysis of PIEA-M led to the identification of 11 compounds corresponding to seven phenolic acids and four flavonoids. By means of HPCCC, quercetin 6”-O-acetyl-3-O- glucoside (1), a mixture of quercetin-3-O-galactoside and quercetin-3-O- glucoside (2) and quercetin 3-O-glucoside (3) were isolated. PIEA, PIEA-M and the obtained compounds (1 and 2) significantly reduced blood pressure. Also, PIEA and PIEA-M caused significant impairment on mice locomotor activity. These results indicate the potential of Ipomoea pes-caprae as a source of hypotensive agents suggesting that phenolic compounds present in the species are responsible for its hypotensive activity.

We previously reported the different motor abilities of D1R knockout (KO), D2R KO and wild-type (WT) mice. To understand the interaction between the cerebellum and the striatal direct and indirect pathways, we examined the expression patterns of immediate early genes (IEG) in the cerebellum of these three genotypes of mice. In the WT naive mice, there was little IEG expression. However, we observed a robust expression of c-fos mRNA in the vermis and hemisphere after running rota-rod tasks. In the vermis, c-fos was expressed throughout the lobules except lobule 7, and also in crus 1 of the ansiform lobule (Crus1), copula of the pyramis (Cop) and most significantly in the flocculus in the hemisphere. jun-B was much less expressed but more preferentially expressed in Purkinje cells. In addition, we observed significant levels of c-fos and jun-B expressions after handling mice, and after the stationary rota-rod task in naive mice. Surprisingly, we observed significant expression of c-fos and jun-B even 30 min after single weighing. Nonetheless, certain additional c-fos and jun-B expressions were observed in three genotypes of the mice that experienced several sessions of motor tasks 24 h after stationary rota-rod task and on days 1 and 5 after rota-rod tasks, but no significant differences in expressions after the running rota-rod tasks were observed among the three genotypes. In addition, there may be some differences 24 h after the stationary rota-rod task between the naive mice and the mice that experienced several sessions of motor tasks.

ABSTRACT Indiscriminate use of pyrethroids has raised serious health related concerns, especially about their effects on children. The present study was designed to assess the developmental neurotoxicity of two pyrethroids; bifenthrin (BIF) and β-cyfluthrin (CYF) administered at 1/15 of LD50 in rats. Pregnant females were exposed to the test compounds orally throughout gestation and lactation periods. Neonates were weighed and sexed at birth and were observed for any gross abnormality. Growth, viability and weaning indices were calculated during the lactation period. Exposure to both the compounds did not alter the physical developmental parameters viz. eye opening, pinna detachment, and fur appearance. CYF significantly impaired growth and survivability of pups. Behavioral endpoints assessed in neonates (surface righting, pivoting, and negative geotaxis reflex) as well as adults (motor activity and motor coordination) exhibited marked effect of CYF treatment. Administration of BIF to pregnant dams impaired pivoting in neonates. Decreased locomotion in the open-field and impaired rota-rod performance were also witnessed in BIF-exposed animals. Enhanced oxidative stress was seen in corpus striatum, cerebellum, and hippocampus regions of the brain; reduced catalase, superoxide dismutase, and glutathione peroxidase activities were measured in BIF and CYF treated weanlings. Acetylcholinesterase activity was also found to be lowered following administration of both compounds at PND 21. The present results suggest that exposure to pyrethroids during critical periods of growth can induce long term effects on the behavior of animals. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1761-1770, 2016. [ABSTRACT FROM AUTHOR]

Although alkyl nitrites are used as recreational drugs, there is only little research data regarding their effects on the central nervous system including their neurotoxicity. This study investigated the neurotoxicity of three representative alkyl nitrites (isobutyl nitrite, isoamyl nitrite, and butyl nitrite), and whether it affected learning/memory function and motor coordination in rodents. Morris water maze test was performed in mice after administrating the mice with varying doses of the substances in two different injection schedules of memory acquisition and memory retention. A rota-rod test was then performed in rats. All tested alkyl nitrites lowered the rodents’ capacity for learning and memory, as assessed by both the acquisition and retention tests. The results of the rota-rod test showed that isobutyl nitrite in particular impaired motor coordination in chronically treated rats. The mice chronically injected with isoamyl nitrite also showed impaired function, while butyl nitrite had no significant effect. The results of the water maze test suggest that alkyl nitrites may impair learning and memory. Additionally, isoamyl nitrite affected the rodents’ motor coordination ability. Collectively, our findings suggest that alkyl nitrites may induce neurotoxicity, especially on the aspect of learning and memory function. [ABSTRACT FROM AUTHOR]

Both D1R and D2R knock out (KO) mice of the major dopamine receptors show significant motor impairments. However, there are some discrepant reports, which may be due to the differences in genetic background and experimental procedures. In addition, only few studies directly compared the motor performance of D1R and D2R KO mice. In this paper, we examined the behavioral difference among N10 congenic D1R and D2R KO, and wild type (WT) mice. First, we examined spontaneous motor activity in the home cage environment for consecutive five days. Second, we examined motor performance using the rota-rod task, a standard motor task in rodents. Third, we examined motor ability with the Step-Wheel task in which mice were trained to run in a motor-driven turning wheel adjusting their steps on foothold pegs to drink water. The results showed clear differences among the mice of three genotypes in three different types of behavior. In monitoring spontaneous motor activities, D1R and D2R KO mice showed higher and lower 24 h activities, respectively, than WT mice. In the rota-rod tasks, at a low speed, D1R KO mice showed poor performance but later improved, whereas D2R KO mice showed a good performance at early days without further improvement. When first subjected to a high speed task, the D2R KO mice showed poorer rota-rod performance at a low speed than the D1R KO mice. In the Step-Wheel task, across daily sessions, D2R KO mice increased the duration that mice run sufficiently close to the spout to drink water, and decreased time to touch the floor due to missing the peg steps and number of times the wheel was stopped, which performance was much better than that of D1R KO mice. These incongruent results between the two tasks for D1R and D2R KO mice may be due to the differences in the motivation for the rota-rod and Step-Wheel tasks, aversion- and reward-driven, respectively. The Step-Wheel system may become a useful tool for assessing the motor ability of WT and mutant mice.

Previous studies have implicated the role of Purkinje cells in motor learning and the underlying mechanisms have also been identified in great detail during the last decades. Here we report that cyclin-dependent kinase 5 (Cdk5)/p35 in Purkinje cell also contributes to synaptic plasticity. We previously showed that p35−/− (p35 KO) mice exhibited a subtle abnormality in brain structure and impaired spatial learning and memory. Further behavioral analysis showed that p35 KO mice had a motor coordination defect, suggesting that p35, one of the activators of Cdk5, together with Cdk5 may play an important role in cerebellar motor learning. Therefore, we created Purkinje cell-specific conditional Cdk5/p35 knockout (L7-p35 cKO) mice, analyzed the cerebellar histology and Purkinje cell morphology of these mice, evaluated their performance with balance beam and rota-rod test, and performed electrophysiological recordings to assess long-term synaptic plasticity. Our analyses showed that Purkinje cell-specific deletion of Cdk5/p35 resulted in no changes in Purkinje cell morphology but severely impaired motor coordination. Furthermore, disrupted cerebellar long-term synaptic plasticity was observed at the parallel fiber-Purkinje cell synapse in L7-p35 cKO mice. These results indicate that Cdk5/p35 is required for motor learning and involved in long-term synaptic plasticity. [ABSTRACT FROM AUTHOR]

Both D1R and D2R knock out (KO) mice of the major dopamine receptors show significant motor impairments. However, there are some discrepant reports, which may be due to the differences in genetic background and experimental procedures. In addition, only few studies directly compared the motor performance of D1R and D2R KO mice. In this paper, we examined the behavioral difference among N10 congenic D1R and D2R KO, and wild type (WT) mice. First, we examined spontaneous motor activity in the home cage environment for consecutive 5 days. Second, we examined motor performance using the rota-rod task, a standard motor task in rodents. Third, we examined motor ability with the Step-Wheel task in which mice were trained to run in a motor-driven turning wheel adjusting their steps on foothold pegs to drink water. The results showed clear differences among the mice of three genotypes in three different types of behavior. In monitoring spontaneous motor activities, D1R and D2R KO mice showed higher and lower 24 h activities, respectively, than WT mice. In the rota-rod tasks, at a low speed, D1R KO mice showed poor performance but later improved, whereas D2R KO mice showed a good performance at early days without further improvement. When first subjected to a high speed task, the D2R KO mice showed poorer rota-rod performance at a low speed than the D1R KO mice. In the Step-Wheel task, across daily sessions, D2R KO mice increased the duration that mice run sufficiently close to the spout to drink water, and decreased time to touch the floor due to missing the peg steps and number of times the wheel was stopped, which performance was much better than that of D1R KO mice. These incongruent results between the two tasks for D1R and D2R KO mice may be due to the differences in the motivation for the rota-rod and Step-Wheel tasks, aversion- and reward-driven, respectively. The Step-Wheel system may become a useful tool for assessing the motor ability of WT and mutant mice. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's Disease (AD) is a chronic neurological disorder characterized by memory impairment, cognitive dysfunction, behavioral disturbances, and deficits in activities of daily living. AD has been found to be associated with a cholinergic deficit in the post-mortem brain characterized by a significant decrease in acetylcholine amount and loss of cholinergic neurons of the nucleus basalis of Meynert (NBM). This study investigated the effect of Zizyphus jujuba (ZJ) extract on motor activity in NBM-lesioned rat model of AD and intact rats. Methods: In this study, 49 wistar rats were divided into 7 groups. Rats received bilateral electrolytic lesions of the NBM. The control and sham group received distilled water while NBM-lesioned groups received ZJ extract via gastric gavage for 20 days. Intact rats received ZJ extract for 20 days without any surgery. The motor activity assessed with rota-rod apparatus. Data were compared using one way ANOVA followed by LSD post test. Results: ZJ extract for 20 days improved motor activity in NBM-lesioned rats and intact rats that received extract at the dose of 1000 mg/kg. Conclusion: Results suggest that ZJ extract can improve the motor coordination both in NBM-lesioned rats and in intact rats. [ABSTRACT FROM AUTHOR]

ABSTRACT Epidemiology studies have clearly documented that the central nervous system is highly susceptible to methylmercury toxicity, and exposure to this neurotoxicant in humans primarily results from consumption of contaminated fish. While the effects of methylmercury exposure have been studied in great detail, comparatively little is known about the effects of moderate to low dose methylmercury toxicity in the aging central nervous system. We examined the toxic effects of a moderate dose of methylmercury on the aging mouse cerebellum. Male and female C57BL/6 mice at 16-20 months of age were exposed to methylmercury by feeding a total dose of 5.0 mg kg−1 body weight and assessed using four behavioral tests. Methylmercury-treated aged mice performed significantly worse in open field, footprint analysis and the vertical pole test compared with age-matched control mice. Isolated cerebellar granule cells from methylmercury-treated aged mice exhibited higher levels of reactive oxygen species and reduced mitochondrial membrane potentials, but no differences in basal intracellular calcium ion levels compared with age-matched control mice. When aged mice were exposed to a moderate dose of methylmercury, they exhibited a similar degree of impairment when compared with young adult mice exposed to the same moderate dose of methylmercury, as reported in earlier studies from this laboratory. Thus, at least in mice, exposure of the aged brain to moderate concentrations methylmercury does not pose greater risk compared with the young adult brain exposed to similar concentrations of methylmercury. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Drug-resistance and adverse effects of current drugs are the most obstacles in the treatment of epilepsy. In a plan for finding new natural anticonvulsant agents, we studied the anticonvulsant effects of essential oil (ZMEO) and methanolic extract (ZMME) of Zhumeria majdae in pentylene tetrazol (PTZ) and maximal electro-shock (MES) models in mice. Mice received different doses of ZMEO and ZMME, 30 min before induction of chemical and electrical convulsions. Neurotoxicity (movement toxicity and sedation) was evaluated using rota-rod test. The mortality was determined after 24 h following injection of different doses of the ZMEO and ZMME. The obtained results show that ZMEO dose-dependently protected mice from tonic convulsions induced by PTZ and MES with effective doses (ED) of 0.26 (0.13-0.39) and 0.27 (0.17-0.37) ml/kg respectively. Toxic doses (TD) in rota-rod test for ZMEO was 0.55 (0.42-0.70) ml/kg. ZMME at dose of 2 g/kg decreased tonic convulsions as much as 40 %. For ZMEO, TD of 0.55 (0.45-0.69) ml/kg was obtained. ZMME significantly decreased the walking time in rota-rod test at dose of 2 g/kg. Lethal dose (LD) of ZMEO was determined as 2.35 (1.98-2.65) ml/kg. ZMME showed about 34 % death of the animals at dose 5 g/kg. The essential oil of Z. majdae could be a good candidate for further anticonvulsive studies. [ABSTRACT FROM AUTHOR]

This study was designed to investigate possible antidepressant-like effects of the extract prepared from the flowers of Hypericum montbretti Spach. (Guttiferae, Clusiaceae). Phytochemical constituents of the methanolic extract were analysed by HPLC method. The main flavonoid component was detected as rutin, and another highly concentrated phenolic compound was quercitrin. Antidepressant activity of the extract was examined by tail suspension and modified forced swimming tests, whereas the motor coordination of the animals was tested by the Rota-Rod apparatus. Reboxetine at a dose of 20  mg kg−1 was used as a reference drug. Dose-dependent antidepressant activity was observed in both tests following the administration of extract at 100 and 250 mg kg−1 doses. To the best of our knowledge, this is the first study reporting the antidepressant activity of H. montbretti extract. Additionally, the results of this work support previous papers reporting the antidepressant activity of rutin. [ABSTRACT FROM PUBLISHER]

Background: Achyranthes aspera Linn., an indigenous herb, has been reported to have antifertility, antihyperlipidemic, antidiabetic, immunomodulatory, anticarcinogenic, diuretic, cardiotonic, analgesic anti-inflammatory, hypnotic, antifungal, antibacterial, and central antinociceptive activities. Aims: This study was designed to evaluate depressant effects on central nervous system (CNS) and behavioral effects of ethanol extract of A. aspera (EEAA) and to find the phytochemical responsible for these activities. Materials and Methods: The pharmacological assays used to study CNS depressant effect in albino mice were rota rod and actophotometer performance test. Effects on behavioral activity were studied using open field test. The extract was given intraperitoneally (i.p.) at a dose of 400 mg/kg. Diazepam (2 mg/kg body weight i.p.) was used as standard. Statistical Analysis Used: Data were analyzed by using analysis of variance followed by Dunnett's test. P < 0.05 was considered significant. Results: Phytochemical screening revealed presence of triterpenoids, saponins, alkaloids (betaine, achyranthine), and steroids as major constituents. The result of this study reflected that EEAA (400 mg/kg i.p.) decreased locomotor activity, produced muscle relaxation, and showed anxiolytic activity. Conclusions: EEAA exhibit CNS depressant and significant anxiolytic activity comparable to diazepam. [ABSTRACT FROM AUTHOR]

Achyranthes Aspera Linn., known as Chirchira (Hindi), Agadha (Marathi) is an indigenous herb found in India. The herb has been reported to have variety of activities like antifertility, antihyperlipidemic, antidiabetic, immunomodulatory, anticarcinogenic, diuretic and cardiotonic, analgesic, anti-inflammatory, hypnotic, antifungal and antibacterial activity. It has been also reported to have central anti-nociceptive activity in thermal induced pain methods in our earlier studies. We wanted to study its neuropharmacological effects, which may throw light on understanding the underlying mechanism for its central activity. Purpose: The present study was designed to evaluate CNS depressant and behavioral effects of A. Aspera extract and to study the phytochemical responsible for these activities with possible mode of action. Methods: The effects on behavioral activity was studied using open field test (OFT). The extract was given intraperitoneally at a dose of 400 mg/kg. Diazepam (2mg/kg body weight i.p.) was used as standard. Data was analyzed by ANOVA test followed by Dunnett's test. All the results were expressed as Mean (±). P <0.05 was considered significant. Results: Phytochemical screening revealed presence of triterpenoids, saponins, alkaloids (betaine, achyranthine) and steroids as major constituents. The result of the study demonstrated that ethanol extract of A. Aspera (400 mg/kg i.p.) decreased locomotor activity, produced muscle relaxation and showed antianxiety activity. Conclusions: Ethanols extract of A. Aspera exhibit CNS depressant action and significant anxiolytic activity comparable to diazepam. [ABSTRACT FROM AUTHOR]

Abstract: Some triazolo-pyrazoline derivatives were synthesized to investigate their potential antidepressant activities. The chemical structures of the compounds were elucidated by IR, NMR and FAB+-MS spectral data and elemental analyses. Antidepressant-like activities of the test compounds (100mg/kg) were screened using both modified forced swimming and tail suspension tests. Rota-Rod test was performed for the examination of probable neurological deficits due to the test compounds, which may interfere with the test results. The test compounds in the series exhibited different levels of antidepressant activities when compared to reference drug fluoxetine. None of the test compounds changed motor coordination of animals when assessed in the Rota-Rod test. Therefore, experimental results in this study were not interfered with motor abnormalities. [ABSTRACT FROM AUTHOR]

Abstract: In the present study, some pyrazoline derivatives were synthesized to investigate their potential antinociceptive activities. 1-[(Benzoxazole/benzimidazole-2-yl)thioacetyl]pyrazoline derivatives were obtained by reacting 3,5-diaryl-1-(2-chloroacetyl)pyrazolines with 2-marcaptobenzoxazole/benzimidazole. The chemical structures of the compounds were elucidated by IR, 1H NMR and FAB+-MS spectral data and Elemental Analyses. All of the compounds (100mg/kg) exhibited significant antinociceptive activities in both hot plate and acetic acid-induced writhing tests. Naloxone (5mg/kg) pre-treatment reversed the antinociceptive activities suggesting the involvement of opioid system in the analgesic actions. None of the compounds impaired motor coordination of animals when assessed in the Rota-Rod model. These results support the previous papers reporting the opioid sensitive antinociceptive activities of various benzoxazole/benzimidazole–pyrazoline derivative compounds. [Copyright &y& Elsevier]

Abstract: Wfs1-deficient mice were generated by disrupting the 8th exon of Wfs1 gene. Reproduction rates of homozygous Wfs1-deficient mice were slightly below the expected values, they displayed intolerance to glucose and overall lower body weight. The present behavioural study was performed in female Wfs1-deficient mice due to their milder metabolic disturbances. Non-fasting blood glucose levels did not differ between homozygous Wfs1-deficient mice and wild-type littermates. While there was no difference in baseline plasma corticosterone, exposure to stress induced a nearly three-fold elevation of corticosterone in Wfs1-deficient mice in relation to wild-type littermates. Wfs1-deficient mice did not display obvious shortcomings in sensory and motor functioning as exemplified by intact responses in conditioned learning paradigms and rota-rod test. Locomotor activity of Wfs1-deficient mice was significantly lower only in brightly lit environment. Short-term isolation had a significant anxiogenic-like effect on the behaviour of Wfs1-deficient mice in dark/light exploration test. Lower exploratory activity of Wfs1-deficient mice in the plus-maze was antagonised by pre-treatment with diazepam (1mg/kg), a GABAA receptor agonist. Wfs1-deficient mice displayed increased anxiety-like behaviour in hyponeophagia test. The locomotor stimulatory effects of amphetamine (2.5–7.5mg/kg) and apomorphine (3mg/kg) were significantly attenuated and facilitated, respectively, in Wfs1-deficient mice. There were no differences between Wfs1-deficient mice and wild-types in forced swimming behaviour and conditioned fear responses. Subtle impairments in reversal learning were apparent in Wfs1-deficient mice in the Morris water maze. Altogether, the present study demonstrates impaired behavioural adaptation of Wfs1-deficient mice in stress-inducing situations. It is likely that Wfs1 protein plays a major role in the behavioural adaptation mechanisms to novel and stressful environments. [Copyright &y& Elsevier]

Abstract: Pyruvate markedly reduces neuronal death following transient global ischemia. In the present study, we investigated the possible neuroprotective effect of pyruvate in focal ischemia. Pyruvate (62.5–250 mg/kg) treatment, regardless of whether given intraperitoneally (ip) or intravenously (iv), decreased infarct volume by more than 50% in both transient (1 h) and permanent occlusion models. The infarct-reducing effects of pyruvate were maintained 14 days (d) after MCAO. Interestingly, higher doses failed to reduce the infarct size. Pyruvate administration also reduced motor deficits. Magnetic resonance (MR) spectroscopy revealed that protective doses of pyruvate, but not the non-protective doses, were associated with a reduction in the level of lactate compared with saline controls. Diffusion-weighted MR images further confirmed infarct reduction in pyruvate-treated rats. Pyruvate is an endogenous metabolite of glycolysis, and hence is unlikely to have serious side effects. Considering its substantial neuroprotective capacity in focal cerebral ischemia, a clinical trial is warranted. [Copyright &y& Elsevier]

Abstract: The requirement for de novo protein synthesis during multiple forms of learning, memory and behavior is well-established; however, we are only beginning to uncover the regulatory mechanisms that govern this process. In order to determine how translation initiation is regulated during neuroplasticity we engineered mutant C57Bl/6J mice that lack the translation repressor eukaryotic initiation factor 4E-binding protein 2 (4E-BP2) and have previously demonstrated that 4E-BP2 plays a critical role in hippocampus-dependent synaptic plasticity and memory. Herein, we examined the 4E-BP2 knockout mice in a battery of paradigms to address motor activity and motor skill learning, anxiety and social dominance behaviors, working memory and conditioned taste aversion. We found that the 4E-BP2 knockout mice demonstrated altered activity in the rotating rod test, light/dark exploration test, spontaneous alternation T-maze and conditioned taste aversion test. The information gained from these studies builds a solid foundation for future studies on the specific role of 4E-BP2 in various types of behavior, and for a broader, more detailed examination of the mechanisms of translational control in the brain. [Copyright &y& Elsevier]

Rationale: Several reports have suggested the involvement of brain adenosine and dopamine receptors in different actions produced by ethanol such as motor incoordination or anxiolytic, hypnotic and reinforcing effects. The co-localization and interaction between adenosine and dopamine receptors in different brain regions has also been well documented. However, few studies have demonstrated the involvement of these mechanisms in the tolerance induced by ethanol. Objectives: The aim of the present study was to evaluate the role of adenosine and dopamine receptors in the development of rapid tolerance to ethanol-induced motor incoordination in mice. Methods: In connection with the rota-rod apparatus, the effects of acute administration of the adenosine receptor antagonists caffeine (non-selective), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, adenosine A1 receptor antagonist) and 4-(2-[7- amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino] ethyl) phenol (ZM241385, adenosine A2A receptor antagonist), together with R(+)-7-cloro-8-hidroxi-3-metil-1-fenil-2,3,4,5-tetrahidro-1H-3-benzazepine (SCH23390, dopamine D1 receptor antagonist) and sulpiride (dopamine D2 receptor antagonist), alone or in combination with ethanol (2.25 g/kg, i.p.), were studied. Twenty-four hours after, all animals were re-tested on the rota-rod after receiving the same dose of ethanol. Results: The repeated administration of ethanol promoted a significant reduction of motor impairment on day 2 (i.e. rapid tolerance). This effect was blocked by caffeine (3.0--30.0 mg/kg, i.p.), DPCPX (3.0--6.0 mg/kg, i.p.) or SCH23390 (0.01--0.03 mg/kg, s.c.), but not with ZM241385 (0.5--1.0 mg/kg, i.p.) or sulpiride (1.0--3.0mg/kg, i.p.). Conclusions: Our results suggest that the rapid tolerance to ethanol-induced motor impairment in mice may be modulated by adenosine A1 receptors and dopamine D1 receptors. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Centrally muscle relaxants (CMRs) are used mainly for treating muscle spasticities of neurological origin, and painful muscle spasms due to rheumatologic conditions. Their use is frequently associated with dose-limiting adverse effects. New drugs with improved side-effect characteristics are badly needed. However, there is no general agreement in the pharmacological literature on what methods are adequate to assess CMR effect and side effects in behaving rodents, which may hinder the development of new drugs. Here we report on the establishment of a simple pharmacological test battery, which was used to compare efficacies and side effect profiles of 11 compounds with central muscle relaxant action, in mice (intraperitoneal application). Methods: For measuring muscle relaxant activity, (1) a new tremor model (GYKI 20039-induced tremor) and (2) the morphine-induced Straub-tail assay were used. The former, newly developed method has advantages over harmaline- or LON-954-induced tremor. For detecting side effect liability (ataxia, sedation, impairment of voluntary motor functions), (1) the rota-rod test, (2) measurement of spontaneous motility, (3) the weight-lifting test and (4) the thiopental sleep test were used. Results: Among the 11 muscle relaxant compounds tested (tolperisone, eperisone, silperisone, diazepam, baclofen, tizanidine, afloqualon, mephenesin, zoxazolamine, memantine and carisoprodol), the calculated safety ratios (i.e. ID50 for side effect/ID50 for muscle relaxant effect) varied in a wide range. Silperisone seems to have the most advantageous profile (safety ratios range between 1.7 and 3.3 in the different pairs of assays) compared to the other tested drugs with lower (one or more ratios below 1.5, and often far below 1) and more varying ratios. Discussion: Therapeutic indices calculated from the results of these in vivo experiments for the clinically used muscle relaxants are in agreement with their adverse effect profiles in humans. Thus the present test battery seems to be suitable for predicting the possible clinical utility of newly synthesized compounds. [Copyright &y& Elsevier]

Abstract: Patients with Alzheimer''s disease suffer from progressive cognitive impairments and show distinct post-mortem neuropathology, including β-amyloid plaques. Transgenic (Tg) CRND8 mice carry a mutated human amyloid precursor protein gene and show age-related increases in β-amyloid production and plaque deposition. It was previously reported that during the early stages of plaque deposition, Tg CRND8 mice demonstrated Morris maze impairments. However, it is unknown if Tg mice would be impaired at an earlier age prior to plaque deposition or more impaired at a later age with more extensive plaque deposition. In the current study, we describe Tg CRND8 age-progressing β-amyloid neuropathology and cognitive abilities in greater detail. At all ages, Tg mice showed normal short-term memory in the Y-maze. Pre-plaque Tg and age-matched Non-Tg mice did not differ in learning the spatial Morris water maze. However, both early and late plaque Tg mice showed impairments during acquisition. In addition, although early plaque Tg mice performed well in the probe trial, late plaque Tg mice demonstrated impaired probe trial performance. Therefore compared to their Non-Tg littermates, Tg CRND8 mice demonstrate cognitive impairments that progressed with age and seemed to coincide with the onset of β-amyloid plaque deposition. [Copyright &y& Elsevier]

Abstract: The present study investigated whether the differential sensitivity of selectively bred γ-hydroxybutyric acid (GHB)-sensitive (GHB-S) and GHB-resistant (GHB-R) rats to GHB- and baclofen-induced sedation/hypnosis generalized to the motor incoordinating effect of the two drugs. To this aim, GHB-S and GHB-R rats were tested on a Rota-Rod after the acute administration of GHB (100–500 mg/kg, i.p.) and baclofen (1.25–5 mg/kg, i.p.). Significant line differences were observed in the dose–response curves for both GHB and baclofen, with GHB-S rats displaying a greater sensitivity to the motor incoordinating effects of both drugs than GHB-R rats. No line difference was observed in diazepam (1.25–5 mg/kg, i.p.), pentobarbital (5–15 mg/kg, i.p.), and ethanol (1–1.5 g/kg, i.p.) dose–response curves. These results suggest that the differential sensitivity of GHB-S and GHB-R rats to GHB and baclofen extends to the effects produced by doses of the two drugs which are 5–10 times lower than those for which rats have been selectively bred. These results are discussed in terms of the GABAB receptor being the likely neural substrate on which the differential sensitivity of GHB-S and GHB-R rats resides. [Copyright &y& Elsevier]

Age-associated cognitive impairment and related neurodegenerative disorders are an increasing major public health problem. Nicotinamide adenine dinucleotide (NADH), a co-substrate for energy transfer in the mitochondrial respiratory chain, is speculated to induce positive effects in some of these diseases. Studies showed diminished mitochondrial function in patients with M. Alzheimer. In a preliminary clinical trial NADH given peripherally improved cognitive function in Alzheimer disease.Previous own experiments revealed an increased NADH level in the rat brain following peripheral application of NADH (10–100 mg/kg, i.p.+ i.v.). Therefore, we wanted to know, whether or not NADH has an effect on cognitive function in animals. We analysed the effect of repeated i.p. injection of NADH on the performance of 3-month-old and 22-month-old Wistar rats in the Morris water maze and in the rota-rod test of motor coordination. The rats were injected for 10 days once daily with the doses of NADH used in the bioavailability study (10–100 mg/kg) or vehicle 20 min before the behavioural tests. The repeated administration of NADH improved the performance of old rats in the acquisition phase (place version) and the spatial probe of the Morris water maze compared to vehicle-treated controls. The effect of NADH on learning-related processes is supported by the lack of effects on motor performance on the rota-rod. In summary, our results suggest cognitive enhancing properties of NADH in learning impaired old rats. [Copyright &y& Elsevier]

The goal of this study was to determine if relatively complex motor training on Rota-rod involving balance and coordination plays an essential role in improving motor function in ischemic rats, as compared with simple locomotor exercise on treadmill.Adult male Sprague–Dawley rats with (n=40) or without (n=40) ischemia were trained under each of three conditions: (1) motor balance and coordination training on Rota-rod; (2) simple exercise on treadmill; and (3) non-trained controls. Motor function was evaluated by a series of tests (foot fault placing, parallel bar crossing, rope and ladder climbing) before and at 14 or 28 days after training procedures in both ischemic and normal animals. Infarct volume in ischemic animals was determined with Nissl staining.Compared with both treadmill exercised and non-trained animals, Rota-rod-trained animals with or without ischemia significantly (P<0.01) improved motor performance of all tasks except for foot fault placing after 14 days of training, with normal rats having better performance. Animals trained for up to 28 days on the treadmill did not show significantly improved function. With regard to foot fault placing task, performance on foot placing was improved in ischemic rats across the three measurements at 0, 14 and 28 days regardless of training condition, while the normal group reached their best performance at the beginning of measurement.No significant differences in infarct volume were found in rats trained either with Rota-rod (47±4%; mean±S.E.), treadmill (45±5%) or non-exercised control (45±3%). In addition, no obvious difference could be detected in the location of the damage which included the dorso-lateral portion of the neostriatum and the frontoparietal cortex, the main regions supplied by the middle cerebral artery.The data suggest that complex motor training rather than simple exercise effectively improves functional outcome. [Copyright &y& Elsevier]

The present study evaluated the central activity of the essential oil and the ethanolic extract from Artemisia annua L. in animals as a part of a psychopharmacological screening of this plant. The extract was prepared with fresh leaves in ethanol (AEE) and the essential oil (AEO) was obtained by hidrodestilation. The ED50 and the LD50 obtained for the essential oil were 470 mg/kg (correlation coefficient r=0.97333 and linear regression y=−26.52x+0.158) and 790 mg/kg, and for the extract, 450 mg/kg (correlation coefficient r=0.99266 and linear regression y=−27.34+0.156) and more than 2 g/kg, respectively. The doses increased the latency time to convulsions induced by picrotoxin and pilocarpine but prevented the onset of pentylenotetrazol and strychnine induced seizures. In addition to, the products have caused marked inhibition in the Rota-rod assay. According to the results, the AEO has a high acute toxicity and a possible cholinergic action, and the AEE showed a possible central activity as dopaminergic and cholinergic agents, and did not present a significant acute toxicity. These differences should be due to chemical substances present in each product. These products had no significant effect as an anticonvulsant, while exhibited a strong depressant activity on the CNS. [Copyright &y& Elsevier]

Targeted deletion of the neuronal basic helix–loop–helix transcription factor Nhlh2 results in adult-onset obesity in mice. Measurement of body weight and body composition in animals aged 3–25 weeks indicates that while male and female Nhlh2 knockout (N2KO) animals both show adult-onset obesity, the time frame for development of obesity is different, with females becoming obese by 7 weeks of age and males becoming obese by 10 weeks of age. Heterozygous (HET) animals also become obese but with a slower onset, indicating a dosage effect for the activity of the Nhlh2 transcription factor. Food intake, body temperature, and voluntary activity were measured in both preobese and obese N2KO, HET, and wild-type (WT) animals to determine which factors contributed to weight gain. While increased food intake and decreased body temperature were found in older obese N2KO animals, only reduced physical activity preceded the onset of obesity in N2KO mice. N2KO animals had no deficit in either circadian rhythm or balance and motor control, indicating that reduced voluntary activity is the result of a behavioral change. These data demonstrate a role for the Nhlh2 transcription factor in controlling genes important to energy expenditure, and more specifically voluntary physical activity of animals. [Copyright &y& Elsevier]

Objective: In neurons, trans-acting RNA-binding proteins regulate splicing, polyadenylation, stability and transport at axons and dendrites. Their misregulation or functional disruption due to mutations or sequestration into nuclear or cytoplasmic inclusions have been linked to pathogenesis of several neuropsychiatric and neurodegenerative disorders. In this study, we aimed to create an animal model by using virus-mediated gene transfer to induce proteinopathic changes in neurons. Methods: Adeno-Associated Virus (AAV) serotype-9 is used to design construction of a casette encoding TarDNA binding protein- 43 (TDP43) expression. The control plasmid is comprised sequences for replication and structural proteins, green fluorescent protein (GFP), polyadenylation signal driven by cytomegalovirus (CMV) promoter between two inverted terminal repeats, while the transgene plasmid is additionally included wild-type TDP43 sequences. Systemic delivery of viruses to rats (n=3 for each age) were done throughout diverse injection sites at different ages. Facial and tail veins were used in neonatal (postnatal day 3) and adult (postnatal day 80) animals, respectively. Phenotypic changes were followed by walking pattern and rota-rod tests. Results: In neonatal animals, motor deficits observed two weeks after injections. Hindpaw withdrawal reflex was disturbed in all CMV-TDP43-GFP-injected animals. Due to the excessive weight loss, muscle weakness and respiratory problems animals were perfused on postnatal day '5. Adult animals survived without a major motor deficit. Their motor performances were examined with regular intervals by rota-rod test between P80- P350. No significant difference was found between CMVTDP43- GFP and CMV-GFP-injected animals. Conclusion: Discoveries of new AAV vectors crossing bloodbrain barrier have made gene transfer possible to adult animals by intravascular injections. However, timing of injection significantly influences the biodistribution of AAV. Neonatal injections result in widespread expression in the central nervous system, but transduction is quite limited in adult animals. Therefore, manufacturing improvements are still necessary for translational gene therapy paradigms. [ABSTRACT FROM AUTHOR]

This paper reports the development of a three-channel automatic speed-matching climbing training system that could train three rats at the same time for rehabilitation after an ischemic stroke. An infrared (IR) remote sensor was installed at the end of each channel to monitor the real-time position of a climbing rat. This research was carried out in five stages: i) system design; ii) hardware circuit; iii) running speed control; iv) functional testing; and v) verification using an animal model of cerebral stroke. The rehabilitated group significantly outperformed the middle cerebral artery occlusion (MCAo) sedentary group in the rota-rod and inclined plate tests 21 days after a stroke. The rehabilitated group also had a cerebral infarction volume of 28.34±19.4%, far below 56.81±18.12% of the MCAo group 28 days after the stroke, validating the effectiveness of this training platform for stroke rehabilitation. The running speed of the climbing rehabilitation training platform was designed to adapt to the physical conditions of subjects, and overtraining injuries can be completely prevented accordingly.