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The dopaminergic system has been the main focus for almost 70 years and dopaminergic-based strategies still remain the best symptomatic medication to improve quality of life of parkinsonian patients.

The early stage of Parkinson's disease (PD) (Hoehn-Yahr (HY) I-II stages) is characterized by a negative pull test, which clinically excludes postural instability. Previous studies with dynamic posturography detected balance disturbances even at the onset of the disease but the age dependency or prediction of dyskinesia with dynamic posturography are not known.We hypothesized that the postural instability evoked by dynamic posturography was part of the early stage of PD. Furthermore, we studied how we can provoke dyskinesia.Postural instability with static and dynamic posturography (passing balls with different weights around the body) was studied in 45 patients with PD in their HY I, II stages. They were compared with 35 age-matched healthy controls. Eighteen patients with dyskinesia were involved in the study. Fourteen patients were followed for two years.The pathway and velocity of the movement assessed by static and the dynamic posturography were significantly higher in the group65 years than that of age-matched healthy controls, while the group ≤65 years showed a significant increment only in the antero-posterior sway during dynamic posturography. The imbalance of patients with dyskinesia was significantly (p 0.05) provoked by dynamic posturography compared to patients with PD without dyskinesia. The results were independent of age.Postural instability is part of the early symptoms of PD. Non-dopaminergic pathways may be involved in the early stage of PD.

Currently all aspects of Parkinson's disease (PD) treatment are less than ideal and would benefit from new interventions. We focus on problems associated with brain neurotransmitters amenable to more specific subreceptor and temporal manipulation. In addition, we consider potentially treatable CNS non-PD co-pathologies or co-morbidities that may exacerbate progression of various aspects of PD.

L-DOPA accumulation in the extracellular medium was detected when the transfer of L-DOPA from the neurons containing tyrosine hydroxylase to the neurons containing aromatic L-amino acid decarboxylase was blocked, under conditions of inhibition of the L-DOPA degradation enzyme. Thus, the missing proof confirming the existence of cooperative synthesis of dopamine by neurons non-dopaminergic was obtained.

Parkinson's disease is characterized by a heterogeneous combination of motor and non motor symptoms. The nigrostriatal dopamine deficit is one of its essential pathophysiologic features. Areas covered: This invited narrative review provides an overlook over current available and future promising non dopaminergic therapeutics to modulate altered dopaminergic neurotransmission in Parkinson's disease. Current research strategies aim to proof clinical efficacy by amelioration of motor symptoms and preponderant levodopa related movement fluctuations. These so-called motor complications are characterized by involuntary movements as a result of an overstimulation of the nigrostriatal dopaminergic system or by temporary recurrence of motor symptoms, when beneficial effects of dopamine substituting drugs vane. Expert opinion: Non dopaminergic modulation of dopamine replacement is currently mostly investigated in well defined and selected patients with motor complications to get approval. However, the world of daily maintenance of patients with its individually adapted, so-called personalised, therapy will determine the real value of these therapeutics. Here the clinical experience of the treating neurologists and the courage to use unconventional drug combinations are essential preconditions for successful treatments of motor and associated non motor complications in cooperation with the patients and their care giving surroundings.

Author(s): Villasenor, Melina | Abstract: Parkinson’s disease is the second most common neurodegenerative disease in the world and yet has no effective treatments that treat all symptoms to date. The most common form of treatment is levodopa, a dopaminergic medication designed to compensate for the lack of dopamine in the brain. However, L-dopa has proven to cause more side-effects than it does provide solutions. These side effects are in the form of both motor and non-motor symptoms.L-dopa commonly causes dyskinesia, a symptom that increases difficulty for voluntary movement, and sleep problems in patients who suffer from Parkinson’s Disease. Moves to research in non-motor symptoms and treatment through non-dopaminergic means have begun due to the ineffectiveness of L-dopa. Unfortunately, no promising results have been brought to the forefront, suggesting the need for even more research in the field and in the non-dopaminergic route of treating patients.

Pomaglumetad methionil (LY2140023 monohydrate, hereafter referred to as LY2140023) is currently in clinical development as a potential new treatment for schizophrenia. If found to be effective, LY2140023 would represent a novel non-dopaminergic based therapy for this disorder that may restore balance to the glutamate dysregulation hypothesized to underlie schizophrenia. This article presents available clinical trial data that describe the safety, tolerability, and efficacy of LY2140023 in patients with schizophrenia. Data indicate that this compound appears to have an efficacy profile consistent with currently available antipsychotic drugs, although confirmation of its efficacy awaits further clinical testing. LY2140023 is generally well tolerated and appears to have a low association with adverse events related to dopamine D2 receptor antagonism and with weight gain, which are commonly seen with current antipsychotics. A potential association of LY2140023 treatment and seizure events has been identified, although an accurate and reliable understanding of the incidence of these events requires further clinical testing, which is underway. Evaluation of the safety, tolerability, and efficacy of LY2140023 is continuing. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Figure ​Figure11 of the article by Stayte and Vissel (2014) contained an error during editing, which we now rectify. In the original Figure ​Figure1,1, the blue arrows representing the GABAergic projections to the LGP originate from the cerebral cortex. However, the blue arrows should be originating from the striatum. We include the updated version of Figure ​Figure11 with this correction. Figure 1 Basal ganglia dysfunction in PD. Diagram representing the normal function of the basal ganglia (Left), the changes occurring in PD (Right), and the site of primary action of therapeutic targets discussed in this review (numbered). Arrows represent the ...

Levodopa-induced dyskinesia represents an on-going challenge in the management of PD. Clinicians and scientists need to continue to work together in developing strategies to reduce and prevent LID. Here, we review and summarize the field to date as presented in the book and give an overview of future perspectives.

Dopaminergic replacement therapies are prescribed widely to improve motor problems in Parkinson’s disease (PD). However, as the disease progresses, the response to levodopa (l-dopa) doses becomes shorter and patients experience symptom recurrence at the end of the dose effect. These so-called OFF periods may become refractory to treatment, and may become associated with disabling motor fluctuations or dyskinesias. In addition to dopamine, glutamate excitotoxicity, resulting from disturbance of the homeostatic balance of neurotransmitters and elevated extracellular levels of glutamate, is potentially an important therapeutic target. Safinamide has been investigated in phase III clinical trials as adjunct therapy to l-dopa in mid- to late-stage fluctuating PD. Adding safinamide to l-dopa increases the time patients’ symptoms are controlled – so-called ON time, without increasing troublesome dyskinesia. Although safinamide has dopaminergic actions, recent data have suggested that the long-term effects of safinamide on dyskinesia are related to safinamide state- and use-dependent inhibition of sodium channels and stimulated glutamate release, rather than reduced dopaminergic stimulation. Safinamide’s unique dual mechanism of action makes it a valuable treatment option for fluctuating PD patients.

Parkinson's disease. Non-motor and non-dopaminergic features - Libros de Medicina - Neurologia general - 150,00

Corrigendum to “What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications” [Sleep Med Rev 18 (2014) 153e164] Magdolna Hornyak *, Hanna Scholz **, Ralf Kohnen , Juergen Bengel e, , Jan Kassubek , Claudia Trenkwalder f,g, j Oberer Eselsberg 45, 89081 Ulm, Germany Department of Psychiatry and Psychotherapy, University Medical Center, Hauptstrasse 6, 79095 Freiburg, Germany RPS Research Germany GmbH, 520 Virginia Drive, Fort Washington, PA 19034, USA Department of Psychology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany e Institute for Psychology, University of Freiburg, Engelberger Strasse 41, 79085 Freiburg, Germany f Paracelsus-Elena-Klinik, Center for Movements Disorders, Klinikstrasse 16, 34128 Kassel, Germany University of Goettingen, 37073 Gottingen, Germany

The substantia nigra pars lateralis (SN1) of the rat was found, by the anterograde and retrograde tracing methods, to send projection fibers to the peripheral shell region surrounding the central nucleus of the inferior colliculus (IC), bilaterally with a clear-cut ipsilateral dominance. SN1 neurons sending their axons to the IC were distributed throughout the entire rostrocaudal extent of the SN1. None of these SN1 neurons showed tyrosine hydroxylase-like immunoreactivity.

Following injection of fluorescent tracer into the rat temporal cortex, retrogradely labeled cells were found in the subparafascicular area. In the thalamus, numerous cell labeling was seen in the medial geniculate complex. Labeled cells in the subparafascicular area were small (10–20 μm), and did not display tyrosine hydroxylase immunoreactivity. From these findings, the subparafascicular area has, at least, two distinct projection systems towards the cerebral cortex; the previously described large dopaminergic cells innervating the frontal cortex and small non-dopaminergic cells innervating the temporal cortex.

International audience; Ideally, animal models of neurodegenerative diseases should reproduce the clinical manifestation of the disease and a selective neuronal loss. In this review we will take as an example Parkinson's disease because its pathophysiology is well known and the neuronal loss well characterized. Indeed, Parkinson's disease is characterized by a loss of some but not all dopaminergic neurons, a loss of some non dopaminergic neurons and alpha-synuclein positive inclusions resembling Lewy bodies. There are at least two ways to develop animal models of PD based on the etiology of the disease and consist in 1) reproducing in animals the mutations seen in inherited forms of PD; 2) intoxicating animals with putative environmental toxins causing PD. In this review we discuss the advantages and the drawbacks in term of neuroproction of the currently used models.

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The dorsolateral part of the substantia nigra (SN) of the rat was observed to send projection fibers to the reticular formation (RF) around the trigeminal motor nucleus (Vm), bilaterally with a clear-cut ipsilateral dominance, by the anterograde and retrograde tracing techniques with PHA-L and WGA-HRP. A combination of retrograde tracing and immunohistochemistry for tyrosine hydroxylase (TH) revealed that no SN neurons sending their axons to the RF around the Vm showed TH-like immunoreactivity.

Midbrain dopaminergic neurons are involved in the symptomotology of motor disorders such as Parkinsonism as well as psychiatric disorders such as schizophrenia. The normal functioning of substantia nigra (SN) dopaminergic neurons is greatly influenced by their afferent inputs as evidenced by significant differences in the physiological characteristics of in vivo vs. in vitro preparations. Although the sources and neurotransmitters of many afferents to the SN are known, because dopaminergic and non-dopaminergic dendrites co-mingle in pars reticulata, the precise postsynaptic targets, particularly those of the presumed excitatory inputs, remain to be determined. In the present study inputs from the subthalamic (STN) and the pedunculopontine (PPN) nuclei (both presumed excitatory) to the SN were investigated by combined anterograde tracing and tyrosine hydroxylase (TH) immunocytochemistry at the light and electron microscopic levels.The anterograde tracers biocytin or PHA-L were iontophoretically injected into either the STN or the PPN. Following appropriate survival times the animals were perfused transcardially with a mixture of 4% paraformaldehyde and 0.2% glutaraldehyde.

The neurons located in the ventromedial tegmentum (VMT) and projecting either to the frontal cortex, to the septum or to the nucleus accumbens were identified by the antidromic activation method in normal rats and in animals whose dopaminergic (DA) system had been previously lesioned by microinjections of 6-hydroxydopamine (6-OHDA). Two groups of VMT neurons innervating each structure could be distinguished. The first group (group S) are slow conducting neurons whose number is reduced in 6-OHDA lesioned rats and which may correspond to A10 DA neurons. The second group (group F) are fast conducting neurons which are resistant to 6-OHDA treatment and therefore probably non-DA VMT cells.

Male ICR albino mice kept in a closed space tend to rotate and have a preferred direction of rotation, which is more often to the left (65%) than to the right (35%). This circling asymmetry was measured with a rotometer in a group of animals following administration of various drugs. Morphine, amphetamine, apomorphine, atropine and pentylenetetrazol caused hyperactivity which was maximal for morphine and decreased in that order. All the drugs also increased the rate of rotation and the percentage of turning in the preferred direction, the latter again being maximal for morphine and decreasing in the order morphine, atropine, amphetamine, apomorphine, pentylenetetrazol. The dopaminergic agonists amphetamine and apomorphine also increased several-fold the rate of turning in the non-preferred direction, but this effect was much less obvious for the other drugs. Our results do not support a previous suggestion that rotational asymmetry is related to dopaminergic asymmetry in the brain. While the rotational asymmetry is influenced by the degree of activity of the animals, other unidentified factors are operating.

Apomorphine-induced pecking in pigeons was first reported by Amsler (1923), who also reported that removal of corpora striata could prevent it. Detailed observations on apomorphine-induced pecking were published independently and simultaneously by Burkmann (1960) and Dhawan and Saxena (1960).

Publisher Summary The Substantia Nigra (SN) is classically divided into two parts on the basis of cellular density: (1) pars compacta and (2) pars reticulata. The nigral neurons are characterized by extensive dendritic fields and there is an overlap between those from cells localized in both parts. The pars compacta appears as a narrow area with numerous cells that are pigmented in primates. The pars reticulata, localized between the pars compacta and the cerebral peduncle, is broader and contains scattered cells. The homogenous nature of nigro-thalamic and nigro-collicular neurons is reinforced by studies of their neurochemical and pharmacological characteristics. The nigrally induced inhibition of thalamic neurons is antagonized by the systemic injection of picrotoxin and is unaffected by strychnine. Neurochemical data and this complementary pharmacological observation suggest strongly that the inhibitory effect of nigrothalamic neurons is mediated by gamma-aminobutyric acid (GABA).

Sixteen per cent of the substantia nigra cell bodies normally labeled from the injection of a fluorescent retrograde tracer in the caudate-putamen complex could still be labeled by the same procedure after multiple intracisternal 6-hydroxydopamine treatments that depleted dopamine levels in the caudate-putamen complex to 1.0% of control. However, the demonstration of glyoxylic-acid-induced catecholamine histofluorescence in tissue from these lesioned rats revealed that many of the surviving retrogradely-labeled substantia nigra cell bodies still contained dopamine. The persistence of some dopamine in the substantia nigra of the lesioned animals was confirmed biochemically. Therefore, retrograde tracing in 6-hydroxydopamine lesioned rats overestimated the extent of the non-dopaminergic nigrostriatal tract. The simultaneous combination of retrograde fluorescent tracing and catecholamine histofluorescence in unlesioned animals revealed that only 5% or less of the substantia nigra cell bodies retrogradelylabeled from the caudate-putamen complex were without catecholamine fluorescence. These apparently non-dopaminergic nigrostriatal cells were located primarily in the ventral tegmental area, substantia nigra pars reticulata and extreme medial edge of the substantia nigra pars compacta.