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PubMed2006

Control of dopamine-secretion by Tet-Off system in an in vivo model of parkinsonian rat.

We established a PC12 cell line (PC12TH Tet-Off) in which human tyrosine hydroxylase (TH) expression can be negatively controlled by Doxycycline (Dox). First, dopamine (DA)-secretion from PC12TH Tet-Off cells was controlled by Dox-administration in a dose-responsive manner ranging from 0 to 100 ng/ml for 70 days in vitro. Furthermore, Parkinson's disease model of rats receiving encapsulated PC12TH Tet-Off cells displayed a significant decrease of dopamine concentration in the cerebrospinal fluid (CSF) and increase of the number of apomorphine-induced rotations by Dox-administration, as compared to transplanted rats without Dox-administration, although the significant decrease of the reduction ratio of DA concentration in the CSF with Dox-administration was recognized over time. At 2 months post-implantation, concentration of dopamine in the implanted striatum and from the retrieved capsules demonstrated that the control of DA-secretion could be partially achieved for 2 months in vivo. Our results support both the value of cell therapy using Tet-Off system and the technique of encapsulation might be a feasible option for Parkinson's disease especially in resolving the problem of dopamine oversupply in the future, although a more efficient way to control DA-secretion with quicker regulation and much titration of dose should be explored before clinical application.

Animals↗
PubMed2006

Tandospirone, a 5-HT1A agonist, ameliorates movement disorder via non-dopaminergic systems in rats with unilateral 6-hydroxydopamine-generated lesions.

Serotonin 1A (5-HT1A) receptors are distributed throughout the brain with their highest concentrations in the frontal cortex, subthalamic nucleus and entopeduncular nucleus as well as the dorsal and median raphe nucleus. There is growing evidence that 5-HT1A receptor agonists have an antidepressant effect in individuals with major depressive disorders. Recent clinical studies suggest that tandospirone, a highly potent and selective 5-HT1A receptor agonist used clinically as an antidepressant in Japan and China, may act as an antiparkinsonian drug. In the present study, we investigated the effect of tandospirone on contralateral rotational behavior in a unilateral hemiparkinsonian rat model produced with 6-hydroxydopamine (6-OHDA). Tandospirone, as well as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), significantly increased contralateral turnings in a dose-dependent manner (0.5-10 mg/kg). Tandospirone also remarkably potentiated the contralateral turning induced by 0.025 mg/kg of apomorphine. Pretreatment with WAY-100635, a 5-HT1A receptor antagonist, almost completely blocked the contralateral turning behavior evoked by tandospirone and 8-OHDPAT, but not that by apomorphine. SCH-23390, a selective dopamine D1 receptor antagonist, did not affect on the tandospirone-induced rotational behavior. These results suggested that tandospirone could act on postsynaptic 5-HT1A receptors and modulate excitatory amino acid pathways in the basal ganglia. Thus, tandospirone could have therapeutic potential for the treatment of Parkinson's disease by modulating neuronal activities of non-dopaminergic pathways.

Analysis of Variance↗
PubMed2006

Abnormal involuntary movements (AIMs) following pulsatile dopaminergic stimulation: severe deterioration and morphological correlates following the loss of locus coeruleus neurons.

Parkinsonian patients are treated with dopamine replacement therapy (typically, intermittent administration of the dopamine precursor L-DOPA); however, this is associated with the onset of abnormal involuntary movements, which seriously impair the quality of life. The molecular mechanisms underlying abnormal involuntary movements represent an intense field of investigation in the area of neurobiology of disease, although their aetiology remains unclear. Apart from the fine cellular mechanisms, the pathways responsible for the generation of abnormal involuntary movements may involve changes in neurotransmitter systems. A potential candidate is noradrenaline, since a severe loss of this neurotransmitter characterizes Parkinson's disease, and noradrenergic drugs produce a symptomatic relief of L-DOPA-induced dyskinesia. In previous studies we found that pulsatile dopamine release, in the absence of the physiological noradrenaline innervation, produces motor alterations and ultrastructural changes within striatal neurons. In the present study we demonstrate that a unilateral damage to the noradrenaline system anticipates the onset and worsens the severity of L-DOPA-induced contralateral abnormal involuntary movements in hemi-parkinsonian rats. Similarly, ubiquitin-positive striatal ultrastructural changes occur in unilaterally dopamine-depleted, noradrenaline-deficient rats following chronic L-DOPA administration. This study confirms a significant impact of the noradrenergic system in the natural history of Parkinson's disease and extends its role to the behavioural and morphological effects taking place during pulsatile dopamine replacement therapy.

Adrenergic Uptake Inhibitors↗
PubMed2005

Added cognitive load through rotary auditory stimulation can improve the quality of postural control in the elderly.

This study examined the effect of rotary auditory stimulation on postural control in the elderly. Thirty-two subjects aged over sixty were submitted to two rotary auditory stimulations, with a meaningful and a non-meaningful message, during a postural task. Although the non-meaningful task did not lead to postural control modification, the meaningful task allowed a reduction in the postural parameter values and therefore, a better stabilisation of posture. The attention, paid to the geography of the sound in understanding the story being told, forced the subject into taking into consideration the regularity and rotation of the stimulation, which meant relying on an auditory anchorage and so facilitated posture regulation.

Acoustic Stimulation↗
PubMed2005

Increased fiber outgrowth from xeno-transplanted human embryonic dopaminergic neurons with co-implants of polymer-encapsulated genetically modified cells releasing glial cell line-derived neurotrophic factor.

We investigated whether a continuous supply of glial cell line-derived neurotrophic factor (GDNF) via encapsulated genetically modified cells can promote survival and fiber outgrowth from xenotransplanted human dopaminergic neurons. Cells genetically engineered to continuously secrete GDNF were confined in hollow fiber-based macrocapsules. Each hemiparkinsonian rat received either a single C2C12-hGDNF capsule (n=8) or a C2C12-control capsule (n=8) concomitantly with human embryonic ventral mesencephalic cell suspension transplants. Our results show that fiber outgrowth in the area between the capsule and the graft is more extensive in rats with GDNF-releasing capsules than in rats with control capsules. We suggest that continuous and safe delivery of GDNF to the brain could be a potential way to optimize neural transplantation as a therapy for Parkinson's disease.

Analysis of Variance↗
PubMed2006

Effects of group I metabotropic glutamate receptors blockade in experimental models of Parkinson's disease.

The present study was devoted to investigate the effects of the metabotropic glutamate receptor(mGluR)5 antagonist [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and the mGluR1 antagonist, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM), in animal studies indicative of antiparkinsonian-like activity such as haloperidol-induced catalepsy, hypoactivity in open field following haloperidol, and rotation in rats with unilateral 6-hydroxydopamine(OHDA)-induced lesions of the midbrain dopaminergic system (alone and in combination with L-DOPA). Moreover, antidyskinetic activity of different mGluR ligands was evaluated in the rat model of L-DOPA-induced dyskinesia. Both MTEP (5 mg/kg) and EMQMCM (4 mg/kg) slightly inhibited haloperidol (0.5 mg/kg)-induced catalepsy. However, neither substance reversed the hypoactivity produced by haloperidol (0.2 mg/kg). Although MTEP did not produce significant turning, it inhibited contralateral rotations after L-DOPA (at 5 mg/kg) and alleviated L-DOPA-induced dyskinesia (at 2.5 and 5 mg/kg) in 6-OHDA-lesioned rats. In contrast, mGluR1 antagonists EMQMCM and RS-1-aminoindan-1,5-dicarboxylic acid (AIDA) failed to modify L-DOPA-induced dyskinesia. The results of the present study suggest that either subtype of group I of mGluRs may be involved in the pathologically altered circuitry in the basal ganglia. However, the equivocal results do not strongly support the hypothesis that mGluR1 and mGluR5 antagonists may be beneficial in the symptomatic treatment of Parkinson's disease. However, mGluR5 antagonists may prove useful for the symptomatic treatment of L-DOPA-induced dyskinesia.

Analysis of Variance↗
PubMed2004

Sensory deficits in mice hypomorphic for a mammalian homologue of unc-53.

The migration of cells and the extension of cellular processes along pathways to their defined destinations are crucial in the development of higher organisms. Caenorhabditis elegans unc-53 plays an important role in cell migration and the outgrowth of cellular processes such as axons. To gain further insight into the biological function of unc53H2, a recently identified mammalian homologue of unc-53, we have generated mice carrying a mutation of unc53H2 and provide evidence that unc53H2 is involved in neuronal development and, more specifically, the development of different sensory systems. The unc53H2 hypomorphic mouse showed a general impaired acuity of several sensory systems (olfactory, auditory, visual and pain sensation) which in case of the visual system was corroborated by the morphological observation of hypoplasia of the optic nerve. We hypothesize that in analogy with its C. elegans homologue, unc53H2 may play a role in the processes of cellular outgrowth and migration.

Animals↗
PubMed2003

Rotarod studies in the rat of the GABAA receptor agonist gaboxadol: lack of ethanol potentiation and benzodiazepine cross-tolerance.

All benzodiazepines and benzodiazepine site agonists impair motor performance dose-dependently and potentiate the effects of ethanol. In order to evaluate the risk of benzodiazepine and ethanol interaction with the direct acting GABA(A) receptor agonist 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridin-3-ol (gaboxadol), we studied impairment of motor coordination for combinations of gaboxadol, ethanol and a series of benzodiazepines (flunitrazepam, zolpidem and indiplon) in a rat rotarod model. All compounds produced a dose-dependent motor impairment and, in agreement with earlier data, a supra-additive effect of the benzodiazepine ligands and ethanol 1 g/kg was seen. In contrast, no significant potentiation of the effects of gaboxadol by ethanol was detected, and furthermore, no synergistic interaction between gaboxadol and any of the benzodiazepines was seen. A 30-day tolerance study was conducted with daily injections of gaboxadol (7.9 mg/kg) and zolpidem (1.25 mg/kg), respectively. A time-dependent tolerance developed to the motor impairment produced by both compounds. On day 31, cross-tolerance studies between zolpidem/gaboxadol and gaboxadol/zolpidem were conducted. No cross-tolerance was observed, indicating that the motor coordination effects observed with gaboxadol and zolpidem may arise from interaction with different receptor populations.

Animals↗
PubMed2005

Does contraversive circling in the 6-OHDA-lesioned rat indicate an ability to induce motor complications as well as therapeutic effects in Parkinson's disease?

Circling behaviour in unilateral 6-OHDA-lesioned rats is interpreted as being opposite in direction to the side of the brain with highest striatal dopaminergic activation. Ipsiversive rotation indicates an action on the intact striatum, while contraversive rotation demonstrates an effect on dopamine receptors in the denervated striatum and is taken as predictive of symptomatic benefit in Parkinson's disease. But does an equivalent behavioural outcome result from stimulating the intact and denervated striatum to the same degree? We report on the behavioural responses produced by administration of L-dopa and the monoamine uptake inhibitor BTS 74,398. These were given alone, or in combination, at doses equivalent to their ED(25), ED(50) and ED(75) for inducing circling in unilateral 6-OHDA-lesioned rats. L-dopa administered alone induced dose-dependent contraversive circling while BTS 74,398 produced ipsiversive rotation. However, L-dopa and BTS 74,398 in combination, produced the same contraversive circling response as when L-dopa was administered alone. Little or no ipsiversive rotation occurred, irrespective of the combination of doses employed. This surprising finding suggests that there are major differences in the outcome of stimulating the intact and denervated striatum with the latter dominating the behavioural response. Since repeated administration of L-dopa but not BTS 74,398, sensitises rotational responses and induces abnormal movements, it may be that contraversive rotation is predictive of both clinical response in PD and the ability to induce motor complications.

Adrenergic Agents↗
PubMed2005

Combined blockade of AMPA and NMDA glutamate receptors reduces levodopa-induced motor complications in animal models of PD.

AMPA and NMDA receptors, abundantly expressed on striatal medium spiny neurons, have been implicated in the regulation of corticostriatal synaptic efficacy. To evaluate the contribution of both glutamate receptor types to the pathogenesis of motor response alterations associated with dopaminergic treatment, we studied the ability of the selective AMPA receptor antagonist GYKI-47261 and the selective NMDA receptor antagonists, MK-801 and amantadine, to mitigate these syndromes in rodent and primate models of Parkinson's disease. The effects of GYKI-47261 and amantadine (or MK-801), alone and in combination, were compared for their ability to modify dyskinesias induced by levodopa. In rats, simultaneous administration of subthreshold doses of AMPA and NMDA receptor antagonists completely normalized the wearing-off response to acute levodopa challenge produced by chronic levodopa treatment (P < 0.05). In primates, the glutamate antagonists GYKI-47261 and amantadine, co-administered at low doses (failing to alter dyskinesia scores), reduced levodopa-induced dyskinesias by 51% (P < 0.05). The simultaneous AMPA and NMDA receptor blockade acts to provide a substantially greater reduction in the response alterations induced by levodopa than inhibition of either of these receptors alone. The results suggest that mechanisms mediated by both ionotropic glutamate receptors make an independent contribution to the pathogenesis of these motor response changes and further that a combination of both drug types may provide relief from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone.

Amantadine↗
PubMed2004

Treatment with a catalytic antioxidant corrects the neurobehavioral defect in ataxia-telangiectasia mice.

Ataxia-telangiectasia is caused by mutations in the ATM gene, the protein product of which is essential for effective response to double-stranded DNA breaks. Loss of ATM function explains most aspects of the disease, but not the cerebellar neurodegeneration characteristic of the disease. Mice lacking ATM provide an excellent model of the human disorder. In addition to deficient response to DNA damage, these mice exhibit oxidative stress, which we hypothesized is the cause of cerebellar dysfunction. We show that treatment with a catalytic antioxidant corrects the neurobehavioral deficit in these mice.

Animals↗
PubMed2005

A cell encapsulation device for studying soluble factor release from cells transplanted in the rat brain.

The transplantation of a variety of naturally occurring and genetically modified cell types has been shown to be an effective experimental method to achieve sustained delivery of therapeutic molecules to specific target areas in the brain. To acquire a better understanding of dosing, implant mechanism of action, and how certain cell types affect remodeling of central nervous system (CNS) tissue, a refillable cell encapsulation device was developed for introducing cells into the brain while keeping them physically isolated from contact with brain tissue with a semipermeable membrane. The stereotactically placed device consists of a hollow fiber membrane (HFM), a polyurethane grommet with watertight cap that snaps into a precisely drilled hole in the rat skull, and a removable cell-containing insert. The cell-containing insert can be introduced or removed in a time-dependent manner to study the influence of soluble factors released from transplanted cells. The study describes the device design and validates its utility using a well-established cell transplantation model of Parkinson's disease.

Animals↗
PubMed2006

Spinal gene transfer using ultrasound and microbubbles.

Spinal gene therapy is a promising option for treating various spinal-related disorders. Several previous studies using viral vectors reported successful transfer of therapeutic genes into the spinal nerve system. However, because of the considerable immunogenicity related to the use of viruses, non-viral gene transfer still needs to be developed. One possible approach is the combined use of ultrasound and echo-contrast microbubbles. The present study shows that this method can be applied for targeted intrathecal gene delivery. We intrathecally injected a mixture of plasmid-DNA encoded with luciferase and commercially available albumin microbubbles by needle puncture at the lower lumbar intervertebral space in mice. Subsequent percutaneous ultrasonication on the lumbar vertebrae significantly enhanced the luciferase expression, analyzed by imaging luciferin bioluminescence, in the dorsal meningeal cells at the insonated region. No apparent neurological damages were induced by the present spinal interventions. In addition to the general benefits of the combined use of ultrasound and microbubbles, our approach can offer some advantages specific to spinal gene transfection including minimal invasiveness of simple percutaneous dural puncture, targetability due to the limited access of ultrasound waves through anatomical apertures of the vertebrae, and possible paracrine delivery of therapeutic molecules to the spinal nerve system.

Animals↗
PubMed2006

Systematic, standardized and comprehensive neurological phenotyping of inbred mice strains in the German Mouse Clinic.

Neurological and psychiatric disorders are among the most common and most serious health problems in developed countries. Transgenic mouse models mimicking human neurological diseases have provided new insights into development and function of the nervous system. One of the prominent goals of the German National Genome Research Network is the understanding of the in vivo function of single genes and the pathophysiological and clinical consequences of respective mutations. The German Mouse Clinic (GMC) offers a high-throughput primary screen of genetically modified mouse models as well as an in-depth analysis in secondary and tertiary screens covering various fields of mouse physiology. Here we describe the phenotyping methods of the Neurological Screen in the GMC, exemplified in the four inbred mouse lines C57BL/6J, C3HeB/FeJ, BALB/cByJ, and 129S2/SvPas. For our primary screen, we generated "standard operating procedures" that were validated between different laboratories. The phenotyping of inbred strains already showed significant differences in various parameters, thus being a prerequisite for the examination of mutant mouse lines.

Analysis of Variance↗
PubMed2006

Antinociceptive, antiedematogenic and antiangiogenic effects of benzaldehyde semicarbazone.

Semicarbazones induce an anticonvulsant effect in different experimental models. As some anticonvulsant drugs also have anti-inflammatory activity, the effects of benzaldehyde semicarbazone (BS) on models of nociception, edema and angiogenesis were investigated. BS (10, 25 or 50 mg/kg, i.p.) markedly inhibited the second phase of nociceptive response induced by formaldehyde (0.34%, 20 microl) in mice, but only the highest dose inhibited the first phase of this response. The thermal hyperalgesia and mechanical allodynia induced by carrageenan (1%, 50 microl, i.pl.) in rats were also inhibited by BS (50 mg/kg, i.p.). However, treatment of mice with BS did not induce an antinociceptive effect in the hot-plate model. The paw edema induced by carrageenan (1%, 50 microl, i.pl.) in rats was inhibited by BS (25 or 50 mg/kg, i.p.). Treatment of mice with BS (0.25, 0.5 or 2.5 mg/kg/day, i.p., 7 days) also inhibited angiogenesis induced by subcutaneous implantation of a sponge disc. It is unlikely that the antinociceptive effect induced by BS results from motor incoordination or a muscle relaxing effect, as the mice treated with this drug displayed no behavioral impairment in the rotarod apparatus. In conclusion, we demonstrated that BS presents antinociceptive, antiedematogenic and antiangiogenic activities. An extensive investigation of the pharmacological actions of BS and its derivatives is justified and may lead to the development of new clinically useful drugs.

Animals↗
PubMed2006

Effects of second generation tetracyclines on penicillin-epilepsy-induced hippocampal neuronal loss and motor incoordination in rats.

Epileptic seizures cause pathological changes such as sclerosis and pyramidal neuronal loss in the hippocampus. Experimentally, epilepsy can be induced by application of various chemicals directly to the cerebral cortex. In this study, epilepsy was induced in rats by intracortical application of 500 IU penicillin G, and the effect of minocycline and doxycycline on the resulting motor incoordination (rotarod) and hippocampal neuronal loss in CA1, CA2 and CA3 fields (optical fractionator method) were investigated. The rotarod performance was reduced in the epilepsy group to 285.1+/-6.9 s (P<0.05 vs. sham-300 s). Minocycline and doxycycline increased this performance to 297.4+/-1.0 s and 296.9+/-1.2 s respectively. No significant difference was detected between minocycline and doxycycline. The present results also showed that the number of neurons (x10(3)) in the sham group was 150+/-9. In the penicillin-epileptic rats, the number was decreased to 105+/-7 (P<0.01). Minocycline, but not doxycycline (125+/-8), significantly increased the number to 131+/-3 (P<0.05). In conclusion, the second generation tetracycline minocycline decreased the loss of hippocampal neurons and motor incoordination in penicillin-epileptic rats. Minocycline could protect against a variety of neurological insults including epilepsy.

Animals↗
PubMed2005

Altered dopaminergic innervation and amphetamine response in adult Otx2 conditional mutant mice.

Here, we have investigated the neurological consequences of restricted inactivation of Otx2 in adult En1(cre/+); Otx2(flox/flox) mice. In agreement with the crucial role of Otx2 in midbrain patterning, the mutants had a substantial reduction in tyrosine hydroxylase containing neurons. Although the reduction in the number of DAergic neurons was comparable between the SNc and the VTA, we found an unexpected selectivity in the deinnervation of the terminal fields affecting preferentially the ventral striatum and the olfactory tubercle. Interestingly, the mutants showed no abnormalities in exploratory activity or motor coordination. However, the absence of normal DA tone generated significant alterations in DA D1-receptor signalling as indicated by increased mutant striatal levels of phosphorylated DARPP-32 and by an altered motor response to amphetamine. Therefore, we suggest that the En1(cre/+); Otx2(flox/flox) mutant mouse model represents a genetic tool for investigating molecular and behavioural consequences of developmental neuronal dysfunction in the DAergic system.

Amphetamines↗
PubMed2004

Mice with a fra-1 knock-in into the c-fos locus show impaired spatial but regular contextual learning and normal LTP.

The immediate early gene c-fos is part of the AP-1 transcription factor complex, which is involved in molecular mechanisms underlying learning and memory. Mice that lack c-Fos in the brain show impairments in spatial reference and contextual learning, and also exhibit a reduced long-term potentiation of synaptic transmission (LTP) at CA3-to-CA1 synapses. In the present study, we investigated mice in which c-fos was deleted and replaced by fra-1 (c-fos(fra-1) mice) to determine whether other members of the c-fos gene family can substitute for the functions of the c-fos gene. In c-fos(fra-1) mice, both CA3-to-CA1 LTP and contextual learning in a Pavlovian fear conditioning task were similar to wild-type littermates, indicating that Fra-1 expression restored the impairments caused by brain-specific c-Fos depletion. However, c-Fos-mediated learning deficits in a reference memory task of the Morris watermaze were also present in c-fos(fra-1) mice. These findings suggest that different c-Fos target genes are involved in LTP, contextual learning, and spatial reference memory formation.

Animals↗