Milacemide therapy for Parkinson's disease (original) (raw)
Related papers
Journal of Clinical Neuroscience, 2021
Glutamate is the major excitatory neurotransmitter in the central nervous system and, as such, many brain regions, including the basal ganglia, are rich in glutamatergic neurons. The importance of the basal ganglia in the control of voluntary movement has long been recognised, with the effect of dysfunction of the region exemplified by the motor symptoms seen in Parkinson's disease (PD). However, the basal ganglia and the associated glutamatergic system also play a role in the modulation of emotion, nociception and cognition, dysregulation of which result in some of the non-motor symptoms of PD (depression/anxiety, pain and cognitive deficits). Thus, while the treatment of PD has traditionally been approached from the perspective of dopaminergic replacement, using agents such as levodopa and dopamine receptor agonists, the glutamatergic system offers a novel treatment target for the disease. Safinamide has been approved in over 20 countries globally for fluctuating PD as add-on therapy to levodopa regimens for the management of 'off' episodes. The drug has both dopaminergic and non-dopaminergic pharmacological effects, the latter including inhibition of abnormal glutamate release. The effect of safinamide on the glutamatergic system might present some advantages over dopamine-based therapies for PD by providing efficacy for motor (levodopa-induced dyskinesia) as well as non-motor (anxiety, mood disorders, pain) symptoms. In this article, we discuss the potential role of glutamatergic inhibition on these symptoms, using illustrative real-world examples of patients we have treated with safinamide.
Neuropharmacology, 1999
Antiparkinsonian-like activity of glutamate receptor antagonists (mostly of N-methyl-D-aspartate (NMDA) receptors) has been demonstrated in animals and for uncompetitive agents, also in humans. In the present study we investigated the potential antiparkinsonian-like activity of compounds acting at the glycine site of the NMDA receptor complex in three animal models of Parkinson's disease and compared them with the new uncompetitive NMDA receptor antagonist MRZ 2/579. Haloperidol-induced catalepsy was inhibited by the Merz glycine B site antagonists MRZ 2/570, MRZ 2/571 and MRZ 2/576 but not by another antagonist L-701,324 or the glycine site partial agonists ACPC and D-CS. None of the tested glycine site antagonists or partial agonists increased locomotor activity or potentiated L-DOPA responses in reserpine and h-MT treated rats. In rats with a unilateral 6-OHDA medial forebrain bundle lesion neither glycine site antagonists nor partial agonists affected rotations on their own or enhanced the contralateral rotations induced by L-DOPA. In contrast, the uncompetitive NMDA receptor antagonist MRZ 2/579 was active in all antiparkinsonian tests used in this study. Based on the present data the therapeutic potential of the glycine site antagonists and partial agonists tested for the treatment of Parkinson's disease is rather doubtful. Uncompetitive NMDA receptor antagonists seem to possess a better profile as antiparkinsonian agents.
Effects of a NR2B selective NMDA glutamate antagonist, CP-101,606, on dyskinesia and parkinsonism
Movement Disorders, 2008
Glutamate antagonists decrease dyskinesia and augment the antiparkinsonian effects of levodopa in animal models of Parkinson's disease (PD). In a randomized, double-blind, placebo-controlled clinical trial we investigated the acute effects of placebo and two doses of a NR2B subunit selective NMDA glutamate antagonist, CP-101,606, on the response to two-hour levodopa infusions in 12 PD subjects with motor fluctuations and dyskinesia. Both doses of CP-101,606 reduced the maximum severity of levodopa-induced dyskinesia approximately 30% but neither dose improved parkinsonism. CP-101,606 was associated with a dose-related dissociation and amnesia. These results support the hypothesis that glutamate antagonists may be useful antidyskinetic agents. However, future studies will have to determine if the benefits of dyskinesia suppression can be achieved without adverse cognitive effects.
Therapeutic potential of targeting glutamate receptors in Parkinson’s disease
Journal of Neural Transmission, 2014
Glutamate plays a complex role in many aspects of Parkinson's disease including the loss of dopaminergic neurons, the classical motor symptoms as well as associated non-motor symptoms and the treatment-related side effect, L-DOPA-induced dyskinesia. This widespread involvement opens up possibilities for glutamate-based therapies to provide a more rounded approach to treatment than is afforded by current dopamine replacement therapies. Beneficial effects of blocking postsynaptic glutamate transmission have already been noted in a range of preclinical studies using antagonists of NMDA receptors or negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5), while positive allosteric modulators of mGlu4 in particular, although at an earlier stage of investigation, also look promising. This review addresses each of the key features of Parkinson's disease in turn, summarising the contribution glutamate makes to that feature and presenting an up-to-date account of the potential for drugs acting at ionotropic or metabotropic glutamate receptors to provide relief. Whilst only a handful of these have progressed to clinical trials to date, notably NMDA and NR2B antagonists against motor symptoms and L-DOPA-induced dyskinesia, with mGlu5 negative allosteric modulators also against L-DOPA-induced dyskinesia, the mainly positive outcomes of these trials, coupled with supportive preclinical data for other strategies in animal models of Parkinson's disease and L-DOPA-induced dyskinesia, raise cautious optimism that a glutamate-based therapeutic approach will have significant impact on the treatment of Parkinson's disease.
NMDA antagonists as Parkinson’s disease therapy: disseminating the evidence
Neurodegenerative Disease Management, 2014
SUMMARY Oral levodopa is the current baseline therapy in the management of Parkinson’s disease, but nonmotor complications and therapy-related dyskinesias pose an important challenge for clinicians. Glutamate receptors have been implicated in the neurodegenerative process of Parkinson’s disease and also in the development of levodopa-induced dyskinesias. This article discusses the role of NMDA receptors in Parkinson’s disease and their modulation as a possible therapeutic approach.
Glutamate NMDA receptor dysregulation in Parkinson's disease with dyskinesias
Brain, 2011
Levodopa-induced dyskinesias are a common complication of long-term therapy in Parkinson's disease. Although both pre-and post-synaptic mechanisms seem to be implicated in their development, the precise physiopathology of these disabling involuntary movements remains to be fully elucidated. Abnormalities in glutamate transmission (over expression and phosphorylation of N-methyl-D-aspartate receptors) have been associated with the development of levodopa-induced dyskinesias in animal models of Parkinsonism. The role of glutamate function in dyskinetic patients with Parkinson's disease, however, is unclear. We used 11 C-CNS 5161 [N-methyl-3(thyomethylphenyl)cyanamide] positron emission tomography, a marker of activated N-methyl-D-aspartate receptor ion channels, to compare in vivo glutamate function in parkinsonian patients with and without levodopa-induced dyskinesias. Each patient was assessed with positron emission tomography twice, after taking and withdrawal from levodopa. Striatal and cortical tracer uptake was calculated using a region of interest approach. In the 'OFF' state withdrawn from levodopa, dyskinetic and non-dyskinetic patients had similar levels of tracer uptake in basal ganglia and motor cortex. However, when positron emission tomography was performed in the 'ON' condition, dyskinetic patients had higher 11 C-CNS 5161 uptake in caudate, putamen and precentral gyrus compared to the patients without dyskinesias, suggesting that dyskinetic patients may have abnormal glutamatergic transmission in motor areas following levodopa administration. These findings are consistent with the results of animal model studies indicating that increased glutamatergic activity is implicated in the development and maintenance of levodopa-induced dyskinesias. They support the hypothesis that blockade of glutamate transmission may have a place in the management of disabling dyskinesias in Parkinson's disease.
In Parkinson's Disease / Book 4. Pages 165-174. ISBN: 978-953-307-463-4. Edited by Prof. David Finkelstein. Intech Open Access Publisher., 2011
"It has been widely accepted that the degeneration of the dopaminergic neurons within the nigrostriatal pathway following treatment with the neurotoxin 6-hydroxy dopamine (6-OH-DA) to be used as a good model of Parkinson’s Disease. This model was used here to investigate the effect of pre-treatment with a glutamate metabotropic receptor agonist Sub-type III, L-2-amino-4-phosphonobutyrate (LAP4) and a glutamate metabotropic receptor antagonist, (RS)-a-methyl-4-phosphono-phenylglycine (MPPG) injected into the nigrostriatal bundle or to the striatum, in-vivo on rats with motor disorders induced by intra-cerebral microinjection of 6-OH-DA using the following coordinates: AP= -1.8 mm, L= ± 1.8 mm and V = - 6.1 mm. This caused the animals to become Parkinsonian with decreases in locomotion and in body weight, and significant increases in rotational movement and rearing. The volume of 2 µL buffer phosphate solution or the same volume of the drugs solution, were slowly micro-injected in a speed of 2 µL per 2 min. to avoid brain damage The glutamate presynaptic agonist LAP4 was micro-injected unilaterally into the nigrostriatal bundle (the above coordinates), 15 min before injection of 6-OH-DA. LAP4 significantly reduced the motor disorders. Locomotion was increased to normal values from (8.22 ± 1.03 (36) to 16.17 ± 1.46 (18) (P<0.005), the percentage increase in body weight was reversed from 2% to 37%, (P<0.01), while rotation movements were reduced by 35% (P<0.05) after one week and by 61% (P<0.0005) after 4 weeks, while rearing was reduced significantly by 83% (P<0.0005) after one week and 93 % after four weeks (P<0.0005). Pre-treatment with MPPG which was focally micro-injected into the same area, has produced no significant decrease in locomotion produced by 6-OH-DA, and similar effect with rotation and rearing. The only significant activity was observed in body weight which was reduced from 2% to 22%. Similar changes in locomotion, rotation and rearing were observed when LAP4 was injected to the striatum where using a second cannula which was implanted in the striatum, using the following coordinates: AP= -2.4 mm, L= ± 1.3 mm and V = - 7.8 mm. These results suggest that agonists of glutamate metabotropic receptors sub-type III, which decrease glutamate release by decreasing Ca++ uptake into presynaptic membranes in glutamatergic neurons in basal ganglia circuits, might prevent development of clinical features of Parkinson's disease."
Metabotropic Glutamate Receptors for Parkinson's Disease Therapy
Parkinson's Disease, 2013
Excessive glutamatergic signalling within the basal ganglia is implicated in the progression of Parkinson's disease (PD) and in the emergence of dyskinesia associated with long-term treatment with L-DOPA. There is considerable research focus on the discovery and development of compounds that modulate glutamatergic signalling via glutamate receptors, as treatments for PD and L-DOPA-induced dyskinesia (LID). Although initial preclinical studies with ionotropic glutamate receptor antagonists showed antiparkinsonian and antidyskinetic activity, their clinical use was limited due to psychiatric adverse effects, with the exception of amantadine, a weak N-methyl-d-aspartate (NMDA) antagonist, currently used to reduce dyskinesia in PD patients. Metabotropic receptor (mGlu receptor) modulators were considered to have a more favourable side-effect profile, and several agents have been studied in preclinical models of PD. The most promising results have been seen clinically with selective antagonists of mGlu5 receptor and preclinically with selective positive allosteric modulators of mGlu4 receptor. The growing understanding of glutamate receptor crosstalk also raises the possibility of more precise modulation of glutamatergic transmission, which may lead to the development of more effective agents for PD.