Using artificial intelligence to identify drugs for repurposing to treat l-DOPA-induced dyskinesia.

Repurposing regulatory agency-approved molecules, with proven safety in humans, is an attractive option for developing new treatments for disease. We identified and assessed the efficacy of 3 drugs predicted by an in silico screen as having the potential to treat l-DOPA-induced dyskinesia (LID) in Parkinson's disease. We analysed ∼1.

Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson's Disease.

Disease modification in Parkinson's disease (PD) is an unmet medical need. In the current study, we evaluated trehalose, a safe and well-tolerated disaccharide that has previously demonstrated efficacy in rodent models of neurodegenerative diseases, including PD. In a rat model of PD, based on delivery of adeno-associated virus serotype 1/2 containing the mutated human A53T -synuclein gene (AAV1/2-hourA53T-aSyn) to the substantia nigra (SN), we showed that rats administered trehalose (2.

Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques.

Background: Pridopidine, in development for Huntington's disease, may modulate aberrant l-dopa-induced effects including l-dopa-induced dyskinesia (LID).

Objective: This study investigated whether pridopidine could reduce LID in the MPTP macaque model of Parkinson's disease and characterized the observed behavioral effects in terms of receptor occupancy.

Methods: The pharmacokinetic profile and effects of pridopidine (15-30 mg/kg) on parkinsonism, dyskinesia, and quality of on-time, in combination with l-dopa, were assessed in MPTP macaques with LID.

DPI-289, a novel mixed delta opioid agonist / mu opioid antagonist (DAMA), has L-DOPA-sparing potential in Parkinson's disease.

L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (K: 0.

RGS4 is involved in the generation of abnormal involuntary movements in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease.

Regulators of G-protein signalling (RGS) proteins are implicated in striatal G-protein coupled receptor (GPCR) sensitisation in the pathophysiology of l-DOPA-induced abnormal involuntary movements (AIMs), also known as dyskinesia (LID), in Parkinson's disease (PD). In this study, we investigated RGS protein subtype 4 in the expression of AIMs in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of LID. The effects of RGS4 antisense brain infusion on the behavioural and molecular correlates of l-DOPA priming in 6-OHDA-lesioned rats were assessed.

Rotigotine polyoxazoline conjugate SER-214 provides robust and sustained antiparkinsonian benefit.

Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including "wearing-off" and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects.

Alternative splicing of AMPA receptor subunits in the 6-OHDA-lesioned rat model of Parkinson's disease and L-DOPA-induced dyskinesia.

Abnormal corticostriatal plasticity is a key mechanism of L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). Antagonists at glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, such as IEM 1460, reduce induction and expression of dyskinesia in rat and non-human primate models of PD. AMPA receptor function is regulated by post-transcriptional splicing of subunit mRNA to produce flip and flop isoforms, which may therefore influence corticostriatal plasticity.

Synergistic antidyskinetic effects of topiramate and amantadine in animal models of Parkinson's disease.

L-Dopa-induced dyskinesia in patients with Parkinson's disease can be alleviated by amantadine, an antagonist at N-methyl-D-aspartate glutamate receptors. The antiepileptic drug topiramate, which blocks α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, has also been shown to reduce dyskinesia. The purpose of this study was to examine the behavioral pharmacology of topiramate alone and in combination with amantadine in animal models of PD and L-dopa-induced dyskinesia.

Dopamine transporter binding is unaffected by L-DOPA administration in normal and MPTP-treated monkeys.

Background: Radiotracer imaging of the presynaptic nigrostriatal dopaminergic system is used to assess disease progression in Parkinson's disease (PD) and may provide a useful adjunct to clinical assessment during therapeutic trials of potential neuroprotective agents. Several clinical trials comparing dopamine agonists to L-DOPA or early vs. late L-DOPA have revealed differences between clinical assessment and imaging of the presynaptic dopaminergic system, hence questioning the comparability of these measures as neuroprotection outcome variables.

Neuroanatomical study of the A11 diencephalospinal pathway in the non-human primate.

Background: The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain control at the spinal cord level. When disrupted, it is thought to be involved in numerous painful conditions such as restless legs syndrome and migraine. Its anatomical organization, however, remains largely unknown in the non-human primate (NHP).

Migration and differentiation of human mesenchymal stem cells in the normal rat brain.

Objectives: Transplanted mesenchymal stem cells migrate toward brain lesions and differentiate into neurons, glial cells, and neural stem cells in diseased or injured animal models. The migratory routes and differentiation patterns of mesenchymal stem cells in normal rats are, however, unknown. Here, labelled human mesenchymal stem cells (or saline) were transplanted into the striatum of adult rats to observe their migration and differentiation.

Calcium-permeable AMPA receptors are involved in the induction and expression of l-DOPA-induced dyskinesia in Parkinson's disease.

Overactivity of striatal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors is implicated in the pathophysiology of L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). In this study, we evaluated the behavioural and molecular effects of acute and chronic blockade of Ca(2+)-permeable AMPA receptors in animal models of PD and LID. The acute effects of the Ca(2+)-permeable AMPA receptor antagonist 1-trimethylammonio-5-(1-adamantane-methylammoniopentane) dibromide hydrobromide (IEM 1460) on abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat and LID in the MPTP-lesioned non-human primate were assessed.

Striatal histone modifications in models of levodopa-induced dyskinesia.

Despite recent advances in the treatment of Parkinson disease (PD), levodopa remains the most effective and widely used therapy. A major limitation to the use of levodopa is the development of abnormal involuntary movements, termed levodopa-induced dyskinesia (LDID), following chronic levodopa treatment. Since recent studies have suggested that modifications of chromatin structure may be responsible for many long-lasting changes in brain function, we have examined post-translational modifications of striatal histones in two models of LDID: an acute murine model and a chronic macaque monkey model, both exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Neuroprotective effects of rotigotine in the acute MPTP-lesioned mouse model of Parkinson's disease.

Dopamine agonists used to manage Parkinsonian motor symptoms have been suggested to be neuroprotective. The study was designed to assess the neuroprotective potential of the D(3)/D(2)/D(1) dopamine receptor agonist rotigotine in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned (MPTP) mouse model of Parkinson's disease by measuring mesencephalic degenerating neurons using FluoroJade staining and the remaining dopaminergic nerve endings in the striatum using dopamine transporter binding. Continuous administration of rotigotine at a dose of 3mg/kg significantly attenuated MPTP-induced acute cell degeneration in the FluoroJade-staining paradigm.

Rotigotine treatment partially protects from MPTP toxicity in a progressive macaque model of Parkinson's disease.

Clinical DA agonist monotherapy trials, which used in vivo imaging of the DA transporter (DAT) to assess the rate of progression of nigrostriatal degeneration, have failed to demonstrate consistent evidence for neuroprotection. The present study aims at reconciling these experimental and clinical data by testing the protective property of the continuously delivered D3/D2/D1 dopamine receptor agonist rotigotine. Using a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned (MPTP) macaque model that mimics the progression of Parkinson's disease in vivo ([99mTc]-TRODAT-1 single photon emission computed tomography (SPECT)) and ex vivo ([125I]-nortropane DAT labelling) endpoints were evaluated.

Antiparkinsonian effects of the novel D3/D2 dopamine receptor agonist, S32504, in MPTP-lesioned marmosets: Mediation by D2, not D3, dopamine receptors.

L-dopa remains the most common treatment for Parkinson's disease. However, there is considerable interest in D3/D2 receptor agonists such as the novel agent S32504, since they exert antiparkinsonian properties in the absence of dyskinesia. An important question concerns the roles of D2 vs.

Phenotype of striatofugal medium spiny neurons in parkinsonian and dyskinetic nonhuman primates: a call for a reappraisal of the functional organization of the basal ganglia.

The classic view of anatomofunctional organization of the basal ganglia is that striatopallidal neurons of the "indirect" pathway express D2 dopamine receptors and corelease enkephalin with GABA, whereas striatopallidal neurons of the "direct" pathway bear D1 dopamine receptors and corelease dynorphin and substance P with GABA. Although many studies have investigated the pathophysiology of the basal ganglia after dopamine denervation and subsequent chronic levodopa (L-dopa) treatment, none has ever considered the possibility of plastic changes leading to profound reorganization and/or biochemical phenotype modifications of medium spiny neurons. Therefore, we studied the phenotype of striatal neurons in four groups of nonhuman primates, including the following: normal, parkinsonian, parkinsonian chronically treated with L-dopa without exhibiting dyskinesia, and parkinsonian chronically treated with L-dopa exhibiting overt dyskinesia.

Increased slow oscillatory activity in substantia nigra pars reticulata triggers abnormal involuntary movements in the 6-OHDA-lesioned rat in the presence of excessive extracellular striatal dopamine.

Since electrophysiological correlates of L-dopa-induced dyskinesia (LID) are almost unknown, changes of striatal dopamine (DA) transmission and electrophysiological activity of the substantia nigra pars reticulata (SNr) were recorded before and after acute L-dopa administration in sham-operated and 6-hydroxydopamine (6-OHDA)-lesioned rats that were previously treated with vehicle or L-dopa for 10 days. Abnormal involuntary movements occurred only in the L-dopa-primed 6-OHDA-lesioned rats that showed after acute l-dopa administration a decrease in firing rate, the highest local field potential power in the theta/alpha band, a consequent oscillatory activity in the same frequency band at the single neuron level and an excessive increase in striatal DA release associated with the lowest level of DA metabolism. These results suggest that increased synchronised afferent activity may drive SNr oscillations in the same frequency band and is associated with abnormal involuntary movements, further suggesting the potential use of desynchronising drugs for managing LID in Parkinson's disease.

Levetiracetam potentiates the antidyskinetic action of amantadine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate model of Parkinson's disease.

Levetiracetam (LEV) (Keppra; UCB Pharma, Brussels, Belgium) has recently been reported to have antidyskinetic activity against levodopa (L-DOPA)-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset and macaque models of Parkinson's disease. Amantadine is frequently used as adjunctive therapy for L-DOPA-induced dyskinesia, but adverse effects limit its clinical utility. The current study was designed to investigate whether LEV can potentiate the antidyskinetic action of amantadine.

Ropinirole versus L-DOPA effects on striatal opioid peptide precursors in a rodent model of Parkinson's disease: implications for dyskinesia.

The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), remains the most common treatment for Parkinson's disease. However, following long-term treatment, disabling side effects, particularly L-DOPA-induced dyskinesias, are encountered. Conversely, D2/D3 dopamine receptor agonists, such as ropinirole, exert an anti-parkinsonian effect while eliciting less dyskinesia when administered de novo in Parkinson's disease patients.

Pattern of levodopa-induced striatal changes is different in normal and MPTP-lesioned mice.

While levodopa-induced neurochemical changes have been studied in animal models of Parkinson's disease, very little is known regarding the effects of levodopa administration in normal animals. The present study investigates the effects normal and MPTP-lesioned mice chronically treated with two different doses of levodopa. We assess changes in striatal dopamine (DA) receptor binding, striatal DA receptor mRNA levels and striatal neuropeptide precursor levels (preproenkephalin-A [PPE-A]; preprotachykinin [PPT]; preproenkephalin-B [PPE-B]).