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Dopamine (DA)-replacement therapy utilizing l-DOPA is the gold standard symptomatic treatment for Parkinson's disease (PD). A critical complication of this therapy is the development of l-DOPA-induced dyskinesia (LID). The endogenous opioid peptides, including enkephalins and dynorphin, are co-transmitters of dopaminergic, GABAergic, and glutamatergic transmission in the direct and indirect striatal output pathways disrupted in PD, and alterations in expression levels of these peptides and their precursors have been implicated in LID genesis and expression. We have previously shown that the opioid glycopeptide drug MMP-2200 (a.k.a. Lactomorphin), a glycosylated derivative of Leu-enkephalin mediates potent behavioral effects in two rodent models of striatal DA depletion. In this study, the mixed mu-delta agonist MMP-2200 was investigated in standard preclinical rodent models of PD and of LID to evaluate its effects on abnormal involuntary movements (AIMs). MMP-2200 showed antiparkinsonian activity, while increasing l-DOPA-induced limb, axial, and oral (LAO) AIMs by ∼10%, and had no effect on dopamine receptor 1 (D 1 R)-induced LAO AIMs. In contrast, it markedly reduced dopamine receptor 2 (D 2 R)-like-induced LAO AIMs. The locomotor AIMs were reduced by MMP-2200 in all three conditions. The N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801 has previously been shown to be anti-dyskinetic, but only at doses that induce parkinsonism. When MMP-2200 was co-administered with MK-801, MK-801-induced pro-parkinsonian activity was suppressed, while a robust anti-dyskinetic effect remained. In summary, the opioid glycopeptide MMP-2200 reduced AIMs induced by a D 2 R-like agonist, and MMP-2200 modified the effect of MK-801 to result in a potent reduction of l-DOPA-induced AIMs without induction of parkinsonism., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

L-3,4-Dihydroxyphenylalanine (l-DOPA), the gold standard therapy for Parkinson disease (PD), is associated with motor fluctuations and dyskinesias. This study sought to prevent the development of l-DOPA-induced dyskinesias (LID) with the metabotropic glutamate receptor type 5 (mGlu5 receptor) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in the de novo treatment of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a PD model. MPTP-lesioned monkeys were treated once daily for one month with either l-DOPA or l-DOPA + MPEP (10 mg/kg). MPEP (administered 15 min before l-DOPA) plasma concentrations were elevated during all the l-DOPA motor activation and did not accumulate during a month. The antiparkinsonian effect was maintained throughout the treatment period in MPTP-lesioned monkeys treated with l-DOPA + MPEP, while the duration of this effect decreased over time in MPTP-lesioned monkeys treated with l-DOPA alone, suggesting wearing-off. Over the month-long treatment, the mean dyskinesia score increased in l-DOPA-treated monkeys; interestingly, this increase was reduced by overall 72% in the l-DOPA + MPEP group. Mean dyskinesia scores of monkeys correlated inversely with plasma MPEP concentrations. Normal control and saline-treated MPTP-lesioned monkeys were also included for biochemical analyses. All MPTP-lesioned monkeys were extensively and similarly denervated. [(3)H]ABP688 specific binding to mGlu5 receptors increased in the putamen of l-DOPA-treated monkeys compared to control, saline or l-DOPA + MPEP-treated monkeys. Mean dyskinesia scores of MPTP-lesioned monkeys correlated positively with [(3)H]ABP688 specific binding in the putamen. This study showed a beneficial chronic antidyskinetic effect of MPEP in de novol-DOPA-treated MPTP-lesioned monkeys, supporting the therapeutic use of mGlu5 receptor antagonists in PD to prevent LID. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The effects of sesamin on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells were investigated. Sesamin at concentration ranges of 20-75 μM exhibited a significant increase in intracellular dopamine levels at 24 h: 50 μM sesamin increased dopamine levels to 133% and tyrosine hydroxylase (TH) activity to 128.2% of control levels. Sesamin at 20-100 μM rapidly increased the intracellular levels of cyclic AMP (cAMP) to 158.3%-270.3% of control levels at 30 min. At 50 μM, sesamin combined with L-DOPA (50, 100 and 200 μM) further increased the intracellular dopamine levels for 24 h compared to L-DOPA alone. In the absence or presence of L-DOPA (100 and 200 μM), sesamin (50 μM) increased the phosphorylation of TH, cAMP-dependent protein kinase (PKA), and cAMP-response element-binding protein (CREB), as well as the mRNA levels of TH and CREB for 24 h, an effect which was reduced by L-DOPA (100 and 200 μM). In addition, 50 μM sesamin exhibited a protective effect against L-DOPA (100 and 200 μM)-induced cytotoxicity via the inhibition of reactive oxygen species (ROS) production and superoxide dismutase reduction, induction of extracellular signal-regulated kinase (ERK)1/2 and BadSer112 phosphorylation and Bcl-2 expression, and inhibition of cleaved-caspase-3 formation. These results suggested that sesamin enhanced dopamine biosynthesis and L-DOPA-induced increase in dopamine levels by inducing TH activity and TH gene expression, which was mediated by cAMP-PKA-CREB systems. Sesamin also protected against L-DOPA (100-200 μM)-induced cytotoxicity through the suppression of ROS activity via the modulation of ERK1/2, BadSer112, Bcl-2, and caspase-3 pathways in PC12 cells. Therefore, sesamin might serve as an adjuvant phytonutrient for neurodegenerative diseases., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

L-dopa therapy for Parkinson's disease leads to dyskinesias or abnormal involuntary movement (AIMs) for which there are few treatment options. Our previous data showed that nicotine administration reduced L-dopa-induced AIMs in parkinsonian monkeys and rats. To further understand how nicotine mediates its antidyskinetic action, we investigated the effect of nicotinic receptor (nAChR) agonists in unilateral 6-OHDA-lesioned rats with varying striatal damage. We first tested the drugs in L-dopa-treated rats with a near-complete striatal dopamine lesion (>99%), the standard rodent dyskinesia model. Varenicline, an agonist that interacts with multiple nAChRs, did not significantly reduce L-dopa-induced AIMs, while 5-iodo-A-85380 (A-85380), which acts selectively at α4β2* and α6β2* subtypes, reduced AIMs by 20%. By contrast, both varenicline and A-85380 reduced L-dopa-induced AIMs by 40-50% in rats with a partial striatal dopamine lesion. Neither drug worsened the antiparkinsonian action of L-dopa. The results show that selective nicotinic agonists reduce dyskinesias, and that they are optimally effective in animals with partial striatal dopamine damage. These findings suggest that presynaptic dopamine terminal α4β2* and α6β2* nAChRs are critical for nicotine's antidyskinetic action. The current data have important implications for the use of nicotinic receptor-directed drugs for L-dopa-induced dyskinesias, a debilitating motor complication of dopamine replacement therapy for Parkinson's disease., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Sensitization of NMDA receptors containing the NR2B subunit has been increasingly associated with various forms of synaptic plasticity, including those implicated in the pathogenesis of extrapyramidal motor dysfunction. To determine whether activation of NR2B containing receptors contributes to the development and maintenance of levodopa-induced response changes in parkinsonian animals, we evaluated the effects of the selective NR2B antagonist CP-101,606 on these response alterations in unilateral 6-hydroxydopamine (6-OHDA) lesioned rats. Three weeks of twice-daily levodopa treatment decreased the duration of the rotational response to acute levodopa challenge. The response alteration was associated with an increase in GluR1 (S831) phosphorylation in medium spiny neurons of the dorsolateral striatum. Both the attenuated rotational response and augmented GluR1 phosphorylation were decreased by CP-101,606 treatment. These CP-101,606 effects were observed when the compound was administered either at the end of chronic levodopa treatment (ameliorative effect) or together with the twice-daily levodopa treatment for 3 weeks (preventive effect). Furthermore, concurrent administration of CP-101,606 with levodopa potentiated the ability of levodopa challenge to reverse the 6-OHDA lesion-induced contralateral forelimb movement deficit as measured in a drag test. These results suggest that activation of NR2B subunit containing NMDA receptors contributes to both the development and maintenance of levodopa-induced motor response alterations, through a mechanism that involves an increase in GluR1 phosphorylation in striatal spiny neurons.

Rats preselected as "low responders" to the hyperactivity-inducing action of (-)N-n-propylnorapomorphine [(-)NPA] responded to an infusion of dopamine into the nucleus accumbens (25 micrograms/24 hr for 13 days) with hyperactivity during the infusion and long-term increased sensitivity to (-)NPA administered after the infusion. Both effects were antagonised by ketotifen (intraperitoneal infusion, 1 mg/kg/day), administered during the period of infusion of dopamine. Animals subject to infusion of dopamine also showed enhanced hyperactivity to L-DOPA (plus benserazide): this enhanced response was also antagonised by ketotifen, given acutely as a single dose (1 mg/kg i.p.). When haloperidol was given concurrently with the infusion of dopamine, spontaneous locomotor activity was markedly increased after the infusion for a period of at least 7 weeks: this long-term change was antagonised by ketotifen (1 mg/kg/24 hr), given during the period of treatment with dopamine/haloperidol or by a single acute injection of ketotifen (0.1-1.0 mg/kg i.p.) on an established response. Ketotifen, in doses up to 20 mg/kg (i.p.) did not reduce spontaneous locomotor activity, cause catalepsy or antagonise amphetamine-induced stereotypy in normal rats. In the marmoset, an enhanced sensitivity to the locomotor-stimulant effects of L-DOPA was induced 5 to 8 weeks after a treatment for 4 days with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which led to the development of akinesia and severe depletion of dopamine in the striatum. Treatment with a single dose of ketotifen (1 mg/kg i.p.) 60 min before L-DOPA antagonised the enhanced locomotor responsiveness to the L-DOPA/benserazide regimen.(ABSTRACT TRUNCATED AT 250 WORDS)