Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In advanced Parkinson's disease, the combination of disease progression and levodopa therapy leads to the development of motor problems complicating the therapeutic response, known as motor response complications. The nonphysiological, pulsatile stimulation produced by most currently available dopaminergic therapies triggers a complicated series of responses resulting in the dysregulation of glutamate receptors and many other neurotransmitter systems on striatal neurons. Although a number of novel compounds that provide a more continuous dopaminergic stimulation are becoming available, no practical way to accomplish this in a truly physiological manner currently exists. Novel strategies for pharmacological intervention with the use of nondopaminergic treatments, with drugs targeting selected transmitter receptors expressed on striatal neurons appear more promising. These include NMDA or AMPA antagonists, or drugs acting on 5-hydroxytryptamine subtype 2A, alpha2-adrenergic, adenosine A2A and cannabinoid CB1 receptors. Future strategies may also target pre- and postsynaptic components that regulate firing pattern, like synaptic vesicle proteins, or nonsynaptic gap junction communication mechanisms, or drugs with actions at the signal transduction systems that modulate the phosphorylation state of NMDA receptors. These new therapeutic strategies, alone or in combination, hold the promise of providing effective control or reversal of motor response complications.
 ...
PMID:Novel pharmacological strategies for motor complications in Parkinson's disease. 1588 15

As befits the coming together of two major national societies, the Bristol meeting attracted a significant array of eminent pharmacologists and physiologists. This was reflected in the presentation of over 350 poster and oral communications stretching over the 3 days, with the host institution contributing substantially to the proceedings. A significant number of communications relating to glutamatergic transmission were presented, which will be the focus of this review. New information was disclosed relating to a novel class of metabotropic glutamate receptor modulators, recent advances in Glu(K5) compounds, AMPA/kainate and AMPA/NMDA receptor discriminators, and NMDA receptor subtype-selective compounds. Disclosures pertain to therapeutic areas including epilepsy, Parkinson's disease, cognitive enhancement, analgesia and psychosis.
 ...
PMID:British Pharmacological Society/The Physiological Society--joint meeting. Advances in glutamatergic pharmacology. 1595 78

It has become increasingly apparent that Parkinson's disease involves many transmitter systems other than dopamine. This nondopaminergic involvement impacts on the generation of symptoms, on the neurodegenerative process, but, most tellingly, in the generation of side effects of current treatments, in particular, levodopa-induced dyskinesia (LID). Such mechanisms contribute not only to the expression of LID once it has been established but also to the mechanisms responsible for the development, or priming, of the dyskinetic state and the subsequent maintenance of the brain in that primed state. Within the basal ganglia, abnormalities in different nondopaminergic components of the circuitry have been defined in LID. In particular, a role for enhanced inhibition of basal ganglia outputs by the GABAergic direct pathway has been suggested as a basic mechanism generating LID. We speculate that the external globus pallidus and subthalamic nucleus may play distinct roles in different forms of dyskinesia, e.g., chorea/dystonia; peak/diphasic/off. At the cellular level, an appreciation of abnormal signaling by, among others, glutamatergic (NMDA and AMPA receptors in particular), alpha2 adrenergic, serotonergic (5HT), cannabinoid and opioid mechanisms in both priming and expression of LID has begun to emerge over the last decade. This is being consolidated, though in many cases questions remain regarding the specific sites of such abnormality within the circuitry. Very recently, at the molecular level, mechanisms controlling neurotransmitter release and impacting on the ability of neurons to maintain particular forms of firing patterning and synchronization, e.g., SV2A, have been identified. This increased understanding has already delivered and will continue to define novel approaches to treatment that target both pre- and postsynaptic signaling molecules throughout the basal ganglia circuitry.
 ...
PMID:Nondopaminergic mechanisms in levodopa-induced dyskinesia. 1600 14

Few neurological diseases have received as much attention and investment in research as Parkinson's disease. Although great strides have been made in the development of agents to treat this neurodegenerative disease, none yet address the underlying problem associated with it, the progressive loss of dopaminergic neurons. Current therapeutic strategies for Parkinson's disease focus primarily on reducing the severity of its symptoms using dopaminergic medications. Although providing substantial benefit, these agents are burdened by adverse effects and long-term complications. This review highlights new and emerging therapies for Parkinson's disease, categorised as symptomatic, neuroprotective and neurorestorative, although at times, this distinction is not easily made. Novel symptomatic treatments target nondopaminergic areas in the hope of avoiding the motor complications seen with dopaminergic therapies. Two emerging treatment approaches under investigation are adenosine A(2A) receptor antagonists (such as istradefylline [KW-6002]) and glutamate AMPA receptor antagonists (such as talampanel [LY-300164]). In 2003, the results from two studies using istradefylline in patients with Parkinson's disease were published, with both showing a positive benefit of the study drug when used as adjunctive therapy to levodopa. In non-human primate models of Parkinson's disease, talampanel has been found to have antiparkinsonian effects when administered as high-dose monotherapy and antidyskinetic effects on levodopa-induced dyskinesias. NS-2330, another drug currently undergoing clinical trials, is a triple monoamine reuptake inhibitor that has therapeutic potential in both Parkinson's and Alzheimer's disease. A phase II proof-of-concept study is currently underway in early Parkinson's disease. However, a recently published study in advanced Parkinson's disease showed no therapeutic benefit of NS-2330 in this patient population. Even more exciting are agents that have a neuroprotective or neurorestorative role. These therapies aim to prevent disease progression by targeting the mechanisms involved in the pathogenesis of Parkinson's disease. Several lines of investigation for neuroprotective therapies have been taken, including the antioxidant coenzyme Q10 (ubidecarenone) and anti-apoptotic agents such as CEP-1347. Studies in patients with Parkinson's disease with coenzyme Q10 have suggested that it slows down functional decline. The PRECEPT study is currently in progress to assess the neuroprotective role of CEP-1347 in the early phase of the disease. Gene therapy is another exciting arena and includes both potentially neuroprotective and neurorestorative agents. Novel methods include subthalamic glutamic acid decarboxylase gene therapy and the use of glial cell line-derived neurotrophic factor (GDNF). Eleven of 12 patients have been enrolled in the first FDA-approved phase I subthalamic glutamic acid decarboxylase gene therapy trial for Parkinson's disease, with currently no evidence of adverse events. GDNF delivered intracerebroventricularly was studied in a small population of patients with Parkinson's disease, but unfortunately did not reveal positive results. Other methods of administering GDNF include direct delivery via infusions into the basal ganglia and the use of viral vectors; thus far, these approaches have shown promising results. This is an exciting and rewarding time for research into Parkinson's disease. With so many therapies currently under investigation, the time is ripe for the beginning of a new phase of treatment strategies.
 ...
PMID:Treatment of Parkinson's disease : what's on the horizon? 1614 89

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.
 ...
PMID:Combined blockade of AMPA and NMDA glutamate receptors reduces levodopa-induced motor complications in animal models of PD. 1620 1

Generation of dopaminergic (DA) neurons from multipotent embryonic progenitors represents a promising therapeutical strategy for Parkinson's disease (PD). Aim of the present study was the establishment of enhanced cell culture conditions, which optimize the use of midbrain progenitor cells in animal models of PD. In addition, the progenitor cells were characterized during expansion and differentiation according to morphological and electrophysiological criteria and compared to primary tissue. Here, we report that CNS precursors can be expanded in vitro up to 40-fold and afterwards be efficiently differentiated into DA neurons. After 4-5 days under differentiation conditions, more than 70% of the neurons were TH+, equivalent to 30% of the total cell population. Calcium imaging revealed the presence of calcium-permeable AMPA receptors in the differentiated precursors which are capable to contribute to many developmental processes. The overall survival rate, degree of reinnervation and the behavioral performance after transplantation of 4 days in-vitro-differentiated cells were similar to results after direct grafting of E14 ventral mesencephalic cells, whereas after shorter or longer differentiation periods, respectively, less effects were achieved. Compared to the amount of in-vitro-generated DA neurons, the survival rate was only 0.8%, indicating that these cells are very vulnerable. Our results suggest that expanded and differentiated DA precursors from attached cultures can survive microtransplantation and integrate within the striatum in terms of behavioral recovery. However, there is only a short time window during in vitro differentiation, in which enough cells are already differentiated towards a DA phenotype and simultaneously not too mature for implantation. However, additional factors and/or genetical manipulation of these expanded progenitors will be required to increase their in vivo survival in order to improve both the ethical and the technical outlook for the use of fetal tissue in clinical transplantation.
 ...
PMID:Dopaminergic properties and function after grafting of attached neural precursor cultures. 1625 57

Many of the motoric features that define Parkinson's disease (PD) result primarily from the loss of dopaminergic neurons of the substantia nigra. l-dopa remains at present the most powerful symptomatic drug for the treatment of this condition. However, motor complications of chronic l-dopa treatment have emerged as a major limitation of this therapy. Slowing or delaying the progression of the disease with neuroprotective therapies may delay the need for l-dopa. In the past few years, novel insight into the pathogenetic mechanisms of neurodegeneration in PD has been provided. Mitochondrial function deficiency, increased oxidative stress, apoptosis, excitotoxicity, and inflammation are part of the processes that ultimately result in neurodegeneration. Drugs that are now under clinical scrutiny as neuroprotectant include molecules that combine one or more of the following properties: (1) monoamine oxidase inhibition (rasagiline, safinamide); (2) mitochondrial enhancement (coenzyme Q10, creatine); (3) antiapoptotic activity; (4) anti-inflammatory activity; (5) protein aggregation inhibition; (6) neurotrophic activity. In advanced Parkinson's disease, the combination of disease progression and l-dopa therapy leads to the development of motor response complications, particularly wearing off, on off, dyskinesias and dystonias. The nonphysiologic pulsatile stimulation of striatal dopamine receptors, produced by the currently available dopaminergic drugs, may trigger a dysregulation of many neurotransmitter systems within the basal ganglia, mainly localized on medium spiny striatal neurons. These include alterations of glutamatergic, serotonergic, adrenergic and adenosine A(2A) receptors. Novel strategies for pharmacological intervention with nondopaminergic treatments hold the promise of providing effective control or reversal of motor response complications. Of particular interest are NMDA and AMPA antagonists or drugs acting on 5-HT subtype 2A, alpha2-adrenergic, and adenosine A(2) receptors. Future strategies may also target pre- and postsynaptic components that regulate firing pattern of basal ganglia neurons, such as synaptic vesicle proteins, nonsynaptic gap junction communication mechanisms, or signal transduction systems that modulate the phosphorylation state of glutamatergic receptors.
 ...
PMID:New pharmacologic horizons in the treatment of Parkinson disease. 1703 Jul 38

The neurobiological mechanisms by which high-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates the motor symptoms of Parkinson's disease (PD) remain unclear. In this study, we analyzed the effects of STN-HFS on motor behavior in intact or hemiparkinsonian rats (6-hydroxydopamine lesion of the substantia nigra pars compacta) and investigated the correlation between these effects and extracellular glutamate (Glu) and GABA levels, assessed by intracerebral microdialysis in the substantia nigra pars reticulata (SNr). STN-HFS at an intensity corresponding to the threshold inducing contralateral forelimb dyskinesia, increased Glu levels in the SNr of both intact and hemiparkinsonian rats. In contrast, STN-HFS at half this intensity did not affect Glu levels in the SNr in intact or hemiparkinsonian rats but increased GABA levels in hemiparkinsonian rats only. STN-HFS-induced forelimb dyskinesia was blocked by microinjection of the Glu receptor antagonist kynurenate into the SNr and facilitated by microinjection of a mixture of the Glu receptor agonists AMPA and NMDA into the SNr. These new neurochemical data suggest that STN-HFS-induced forelimb dyskinesia is mediated by glutamate, probably via the direct activation of STN axons, shedding light on the mechanisms of STN-HFS in PD.
 ...
PMID:Subthalamic stimulation-induced forelimb dyskinesias are linked to an increase in glutamate levels in the substantia nigra pars reticulata. 1731 40

Neurodegenerative diseases are now generally considered as a group of disorders that seriously and progressively impair the functions of the nervous system through selective neuronal vulnerability of specific brain regions. Alzheimer's disease is the most common neurodegenerative disease, followed in incidence by Parkinson's disease; much less common are frontotemporal dementia, Huntington's disease, amyothrophic lateral sclerosis (Lou Gehrig's disease), progressive supranuclear palsy, spinocerebellar ataxia, Pick's disease and, lastly, prion disease. In this review, the authors intend to survey new drugs in different clinical phases but not in the preclinical or discovery stages nor already in the market, with new molecules aimed at interrupting or at attenuating different pathogenic pathways of neurodegeneration and/or at ameliorating symptoms. Drugs in different pharmacological phases are under study or are ready to be introduced into therapy for Alzheimer's disease, which display anti-beta-amyloid activity or nerve growth factor-like activity or anti-inflammatory properties. Other drugs possess mixed mechanisms of action, such as acetylcholinesterase inhibition and impairment of beta-amyloid formation through inhibition of beta-amyloid precursor protein synthesis and/or modulation of secretase activity. Other therapeutic approaches are based on immunotherapy, control of metal ions interactions with beta-amyloid and ensuing oxidative reactions as well as metabolic or hormonal regulation. The symptomatic therapy of motor behaviour in Parkinson's disease, based on l-DOPA, is registering adenosine A(2A) receptor antagonists, monoamine oxidase B inhibitors and ion channel modulators, as well as dopamine uptake inhibitors and glutamate AMPA receptor antagonists. There are also many other drugs involved, including astrocyte-modulating agents, 5-HT(1A) agonists and alpha(2)-adrenergic receptor antagonists, which are targeted at preventing or ameliorating Parkinson's disease-related or l-DOPA-induced dyskinesias. Huntington's disease therapy envisages a Phase III drug, LAX-101, which displays antiapoptotic properties by promoting membrane stabilisation and mitochondrial integrity. Other drugs with antioxidant and antiapoptotic steroid-like and neuroprotective activity are under investigation for the therapy of the less common neurodegenerative diseases.
 ...
PMID:An update on pharmacological approaches to neurodegenerative diseases. 1715 54

An extracellular nonsynaptic taurine pool of glial origin was recently reported in the substantia nigra (SN). There is previous evidence showing taurine as an inhibitory neurotransmitter in the SN, but the physiological role of this nonsynaptic pool of taurine has not been explored. By using microdialysis methods, we studied the action of local osmolarity on the nonsynaptic taurine pool in the SN of the rat. Hypoosmolar pulses (285-80 mosM) administered in the SN by the microdialysis probe increased extrasynaptic taurine in a dose-dependent way, a response that was counteracted by compensating osmolarity with choline. The opposite effect (taurine decrease) was observed when osmolarity was increased. Under basal conditions, the blockade of either the AMPA-kainate glutamate receptors with 6-cyano-7-nitroquinoxaline-2,3-dionine disodium or the purinergic receptors with pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid modified the taurine concentration, suggesting that both receptors modulate the extrasynaptic pool of taurine. In addition, these drugs decreased the taurine response to hypoosmolar pulses, suggesting roles for glutamatergic and purinergic receptors in the taurine response to osmolarity. The participation of purinergic receptors was also supported by the fact that ATP (which, under basal conditions, increased the extrasynaptic taurine in a dose-dependent way) administered in doses saturating purinergic receptors also decreased the taurine response to hypoosmolarity. Taken together, present data suggest osmoregulation as a role of the nonsynaptic taurine pool of the SN, a function that also involves glutamate and ATP and that could influence the nigral cell vulnerability in Parkinson's disease.
 ...
PMID:Substantia nigra osmoregulation: taurine and ATP involvement. 1721 20


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>