Search Results (20)

L-DOPA-induced dyskinesia (LID) remains the most challenging complication of dopamine replacement therapy in Parkinson’s disease, correlated with maladaptive plasticity within corticostriatal circuits. Perineuronal nets (PNNs), extracellular matrix structures enwrapping mainly parvalbumin interneurons (PV-INs), are key regulators of neuronal stability and plasticity, yet their contribution to LID is unknown. Using a unilateral 6-hydroxydopamine rat model of Parkinsonism followed by chronic L-DOPA administration, we quantified PNN–PV associations by Wisteria floribunda agglutinin (WFA) and PV immunolabeling across striatal and motor cortical territories. Dopamine loss markedly reduced PNN density and intensity in the dorsolateral striatum (DLS), which only partially recovered after L-DOPA. In LID, canonical WFA⁺/PV⁺ cells remained low, whereas non-canonical WFA⁻/PV⁺ populations expanded in both DLS and M1 motor cortex (M1), indicating region-specific remodeling toward a high-plasticity state. To assess causality, we used Chondroitinase ABC (ChABC) for PNN degradation. DLS-targeted ChABC exacerbated abnormal involuntary movements and increased local PV density, while M1-ChABC had no behavioral effect but altered PV metrics within the DLS–M1 axis. These findings identify the DLS as a critical node where PNN fragility amplifies dyskinesia, highlight a functional coupling between striatal and cortical PNN–PV remodeling, and suggest that stabilizing extracellular matrix integrity could mitigate maladaptive plasticity underlying LID. Full article

Dopamine (DA) replacement by L-DOPA administration is the most common and effective treatment for Parkinson’s disease (PD). However, its chronic use leads to important side effects at advanced stages of the disease. Levodopa-induced dyskinesia (LID), characterized by involuntary, abnormal movements, is the main challenge of L-DOPA treatment. Although the causes underlying LID are not fully understood, abnormal plasticity in corticostriatal synapses and dysregulated DA release from serotonin terminals play a crucial role. In recent years, several studies have suggested the involvement of neuroinflammation and oxidative stress in the pathophysiology of LID. Interestingly, different evidence has shown that blocking these pathways reduces LID in experimental animal PD models, pointing to the use of antioxidant/anti-inflammatory agents as a potential therapy for LID. Numerous studies have shown the role of the brain renin–angiotensin system (RAS) and the ROCK pathway in neuroinflammation and oxidative stress. Compounds acting through these routes have strong neuroprotective properties in PD models. Additionally, the use of ROCK inhibitors, such as fasudil, and RAS blockers has shown potent anti-dyskinetic effects. Therefore, compounds acting on the RAS and ROCK pathways could have a dual role, slowing down the degeneration of dopaminergic neurons and reducing the development of LID. Full article

Parkinson’s disease is associated with the loss of more than 40% of dopaminergic neurons in the substantia nigra pars compacta. One of the therapeutic options for restoring striatal dopamine levels is the administration of L-3,4-dihydroxyphenylalanine (L-Dopa). However, Parkinson’s disease patients on long-term L-Dopa therapy often experience motor complications, such as dyskinesias. L-Dopa-induced dyskinesias (LIDs) manifest as abnormal involuntary movements and are produced by elevated striatal dopamine levels, which lead to increased activity of the basal ganglia direct striato-nigral pathway. Dopamine D₁ receptors are more than 95% confined to neurons of the direct pathway, where they colocalize with histamine H₃ receptors. There is evidence of functional interactions between D₁ and H₃ receptors, and here we review the consequences of these interactions on LIDs. Full article

Levodopa (L-DOPA) treatment represents the gold standard therapy for Parkinson’s disease (PD) patients. L-DOPA therapy shows many side effects, among them, L-DOPA-induced dyskinesias (LIDs) remain the most problematic. Several are the mechanisms underlying these processes: abnormal corticostriatal neurotransmission, pre- and post-synaptic neuronal events, changes in gene expression, and altered plasticity. In recent years, researchers have also suggested non-neuronal mechanisms as a possible cause for LIDs. We reviewed recent clinical and pre-clinical studies on neuroinflammation contribution to LIDs. Microglia and astrocytes seem to play a strategic role in LIDs phenomenon. In particular, their inflammatory response affects neuron-glia communication, synaptic activity and neuroplasticity, contributing to LIDs development. Finally, we describe possible new therapeutic interventions for dyskinesia prevention targeting glia cells. Full article

A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications of long-term L-DOPA therapy in Parkinson’s disease (PD). Yet, LIDs remain a clinical challenge for the management of patients with advanced disease. Glutamatergic dysregulation of striatal projection neurons (SPNs) appears to be a key contributor to altered motor responses to L-DOPA. Targeting striatal hyperactivity at the glutamatergic neurotransmission level led to significant preclinical and clinical trials of a variety of antiglutamatergic agents. In fact, the only FDA-approved treatment for LIDs is amantadine, a drug with NMDAR antagonistic actions. Still, novel agents with improved pharmacological profiles are needed for LID therapy. Recently other therapeutic targets to reduce dysregulated SPN activity at the signal transduction level have emerged. In particular, mechanisms regulating the levels of cyclic nucleotides play a major role in the transduction of dopamine signals in SPNs. The phosphodiesterases (PDEs), a large family of enzymes that degrade cyclic nucleotides in a specific manner, are of special interest. We will review the research for antiglutamatergic and PDE inhibition strategies in view of the future development of novel LID therapies. Full article

L-DOPA is the mainstay of treatment for Parkinson’s disease (PD). However, over time this drug can produce dyskinesia. A useful acute PD model for screening novel compounds for anti-parkinsonian and L-DOPA-induced dyskinesia (LID) are dopamine-depleted dopamine-transporter KO (DDD) mice. Treatment with α-methyl-para-tyrosine rapidly depletes their brain stores of DA and renders them akinetic. During sensitization in the open field (OF), their locomotion declines as vertical activities increase and upon encountering a wall they stand on one leg or tail and engage in climbing behavior termed “three-paw dyskinesia”. We have hypothesized that L-DOPA induces a stereotypic activation of locomotion in DDD mice, where they are unable to alter the course of their locomotion, and upon encountering walls engage in “three-paw dyskinesia” as reflected in vertical counts or beam-breaks. The purpose of our studies was to identify a valid index of LID in DDD mice that met three criteria: (a) sensitization with repeated L-DOPA administration, (b) insensitivity to a change in the test context, and (c) stimulatory or inhibitory responses to dopamine D1 receptor agonists (5 mg/kg SKF81297; 5 and 10 mg/kg MLM55-38, a novel compound) and amantadine (45 mg/kg), respectively. Responses were compared between the OF and a circular maze (CM) that did not hinder locomotion. We found vertical counts and climbing were specific for testing in the OF, while oral stereotypies were sensitized to L-DOPA in both the OF and CM and responded to D1R agonists and amantadine. Hence, in DDD mice oral stereotypies should be used as an index of LID in screening compounds for PD. Full article

Statins have been proposed for L-DOPA-induced dyskinesia (LID) treatment. Statin anti-dyskinetic effects were related to the inhibition of the Ras-ERK pathway. However, the mechanisms responsible for the anti-LID effect are unclear. Changes in cholesterol homeostasis and oxidative stress- and inflammation-related mechanisms such as angiotensin II and Rho-kinase (ROCK) inhibition may be involved. The nigra and striatum of dyskinetic rats showed increased levels of cholesterol, ROCK, and the inflammatory marker IL-1β, which were reduced by the angiotensin type-1 receptor (AT1) antagonist candesartan, simvastatin, and the ROCK inhibitor fasudil. As observed for LID, angiotensin II-induced, via AT1, increased levels of cholesterol and ROCK in the rat nigra and striatum. In cultured dopaminergic neurons, angiotensin II increased cholesterol biosynthesis and cholesterol efflux without changes in cholesterol uptake. In astrocytes, angiotensin induced an increase in cholesterol uptake, decrease in biosynthesis, and no change in cholesterol efflux, suggesting a neuronal accumulation of cholesterol that is reduced via transfer to astrocytes. Our data suggest mutual interactions between angiotensin/AT1, cholesterol, and ROCK pathways in LID, which are attenuated by the corresponding inhibitors. Interestingly, these three drugs have also been suggested as neuroprotective treatments against Parkinson’s disease. Therefore, they may reduce dyskinesia and the progression of the disease using common mechanisms. Full article

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by motor symptoms that result from loss of nigrostriatal dopamine (DA) cells. While L-DOPA provides symptom alleviation, its chronic use often results in the development of L-DOPA-induced dyskinesia (LID). Evidence suggests that neuroplasticity within the serotonin (5-HT) system contributes to LID onset, persistence, and severity. This has been supported by research showing 5-HT compounds targeting 5-HT_1A/1B receptors and/or the 5-HT transporter (SERT) can reduce LID. Recently, vortioxetine, a multimodal 5-HT compound developed for depression, demonstrated acute anti-dyskinetic effects. However, the durability and underlying pharmacology of vortioxetine’s anti-dyskinetic actions have yet to be delineated. To address these gaps, we used hemiparkinsonian rats in Experiment 1, examining the effects of sub-chronic vortioxetine on established LID and motor performance. In Experiment 2, we applied the 5-HT_1A antagonist WAY-100635 or 5-HT_1B antagonist SB-224289 in conjunction with L-DOPA and vortioxetine to determine the contributions of each receptor to vortioxetine’s effects. The results revealed that vortioxetine consistently and dose-dependently attenuated LID while independently, 5-HT_1A and 5-HT_1B receptors each partially reversed vortioxetine’s effects. Such findings further support the promise of pharmacological strategies, such as vortioxetine, and indicate that broad 5-HT actions may provide durable responses without significant side effects. Full article

The heteromer composed of dopamine D1 and D3 receptors (D1R–D3R) has been defined as a structure able to trigger Erk1/2 and Akt signaling in a G protein-independent, beta-arrestin 1-dependent way that is physiologically expressed in the ventral striatum and is likely involved in the control of locomotor activity. Indeed, abnormal levels of D1R-D3R heteromer in the dorsal striatum have been correlated with the development of L-DOPA-induced dyskinesia (LID) in Parkinson’s disease patients, a motor complication associated with striatal D1R signaling, thus requiring Gs protein and PKA activity to activate Erk1/2. Therefore, to clarify the role of the D1R/D3R heteromer in LID, we investigated the signaling pathway induced by the heteromer using transfected cells and primary mouse striatal neurons. Collectively, we found that in both the cell models, D1R/D3R heteromer-induced activation of Erk1/2 exclusively required the D1R molecular effectors, such as Gs protein and PKA, with the contribution of the phosphatase Shp-2 and beta-arrestins, indicating that heterodimerization with the D3R abolishes the specific D3R-mediated signaling but strongly allows D1R signals. Therefore, while in physiological conditions the D1R/D3R heteromer could represent a mechanism that strengthens the D1R activity, its pathological expression may contribute to the abnormal PKA-Shp-2-Erk1/2 pathway connected with LID. Full article

N-methyl-D-aspartate (NMDA) receptors have been implicated in L-Dopa-induced dyskinesias (LID) in Parkinson’s disease patients, but the use of antagonists that directly inhibit this receptor is associated with severe side effects. L-4-chlorokynurenine (4-Cl-KYN or AV-101) is a pro-drug of 7-chlorokynurenic acid (7-Cl-KYNA), a potent and specific antagonist of the glycine (GlyB) co-agonist site of NMDA receptors. The 7-Cl-KYNA has limited ability to cross the blood–brain barrier, whereas AV-101 readily accesses the brain. We investigated if AV-101 reduces LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys while maintaining the antiparkinsonian activity of L-Dopa. A first pilot study using three dyskinetic MPTP monkeys showed that acute AV-101 treatment (250 and 450 mg/kg) reduced LID and maintained the antiparkinsonian activity of L-Dopa. The main study using six additional dyskinetic MPTP monkeys showed that repeated AV-101 treatment (250 mg/kg, b.i.d. for 4 consecutive days) maintained their L-Dopa antiparkinsonian response. We measured significantly less LID when AV-101 was combined with L-Dopa treatment. AV-101 alone or with L-Dopa had no non-motor adverse effects in MPTP monkeys. Our study showed antidyskinetic activity of AV-101 in MPTP monkeys was comparable to amantadine tested previously in our laboratory in this model. We observed no adverse effects with AV-101, which is an improvement over amantadine, with its known side effects. Full article

The facilitation of corticostriatal transmission is modulated by the pharmacological inhibition of striatal phosphodiesterase 10A (PDE10A). Since L-DOPA-induced dyskinesia is associated with abnormal corticostriatal transmission, we hypothesized that inhibition of PDE10A would modulate L-DOPA-induced dyskinesia (LID) by regulating corticostriatal activity. 6-OHDA-lesioned rats were chronically treated with L-DOPA for one week. After that, for two additional weeks, animals were treated with the PDE10A inhibitor PDM-042 (1 and 3 mg/kg) one hour before L-DOPA. Behavioral analyses were performed to quantify abnormal involuntary movements (AIMs) and to assess the antiparkinsonian effects of L-DOPA. Single-unit extracellular electrophysiological recordings were performed in vivo to characterize the responsiveness of MSNs to cortical stimulation. The low dose of PDM-042 had an antidyskinetic effect (i.e., attenuated peak-dose dyskinesia) and did not interfere with cortically evoked spike activity. Conversely, the high dose of PDM-042 did not affect peak-dose dyskinesia, prolonged AIMs, and increased cortically evoked spike activity. These data suggest that the facilitation of corticostriatal transmission is likely to contribute to the expression of AIMs. Therefore, cyclic nucleotide manipulation is an essential target in controlling LID. Full article

Treatment with levodopa (L-dopa) in Parkinson’s disease (PD) leads to involuntary movements termed L-dopa-induced dyskinesia (LID). There are contradictory data about the influence of hormone therapy in female PD patients with LID and of 17-β-estradiol (E2) on animal correlates of LID-abnormal involuntary movements (AIMs). Our aim was to characterize the influence of E2 on motor impairment and AIMs in ovariectomized 6-hydroxydopamine (6-OHDA) rat model of PD. Half of the rats received empty and the other half implants filled with E2. Following the 6-OHDA surgery, the rats received daily treatment with either L-dopa or saline for 16 days. They were assessed for AIMs, contralateral rotations, and FAS. In the L-dopa-treated rats, E2 intensified and prolonged AIMs and contralateral rotations. On the other hand, it had no effect on motor impairment. Postmortem tyrosine hydroxylase immunostaining revealed an almost complete unilateral lesion of nigrostriatal dopaminergic neurons. E2 partially prevented the upregulation of striatal ΔFosB caused by dopamine depletion. L-dopa potentiated the upregulation of ΔFosB within the dopamine-depleted striatum and this effect was further enhanced by E2. We speculate that the potentiating effects of E2 on AIMs and on contralateral rotations could be explained by the molecular adaptations within the striatal medium spiny neurons of the direct and indirect striatofugal pathways. Full article

Proinflammatory markers were found in brains of Parkinson’s disease (PD) patients. After years of L-Dopa symptomatic treatment, most PD patients develop dyskinesias. The relationship between inflammation and L-Dopa-induced dyskinesias (LID) is still unclear. We previously reported that MPEP (a metabotropic glutamate receptor 5 antagonist) reduced the development of LID in de novo MPTP-lesioned monkeys. We thus investigated if MPEP reduced the brain inflammatory response in these MPTP-lesioned monkeys and the relationship to LID. The panmacrophage/microglia marker Iba1, the phagocytosis-related receptor CD68, and the astroglial protein GFAP were measured by Western blots. The L-Dopa-treated dyskinetic MPTP monkeys had increased Iba1 content in the putamen, substantia nigra, and globus pallidus, which was prevented by MPEP cotreatment; similar findings were observed for CD68 contents in the putamen and globus pallidus. There was a strong positive correlation between dyskinesia scores and microglial markers in these regions. GFAP contents were elevated in MPTP + L-Dopa-treated monkeys among these brain regions and prevented by MPEP in the putamen and subthalamic nucleus. In conclusion, these results showed increased inflammatory markers in the basal ganglia associated with LID and revealed that MPEP inhibition of glutamate activity reduced LID and levels of inflammatory markers. Full article

N-phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compounds was found to be consistent with their ability to bind at the D3 dopamine receptor subtype in a bitopic manner. In this study, a series of the 3-thiophenephenyl and 4-thiazolylphenyl fluoride substituted N-phenylpiperazine analogs were evaluated. Compound 6a was found to bind at the human D3 receptor with nanomolar affinity with substantial D3 vs. D2 binding selectivity (approximately 500-fold). Compound 6a was also tested for activity in two in-vivo assays: (1) a hallucinogenic-dependent head twitch response inhibition assay using DBA/2J mice and (2) an L-dopa-dependent abnormal involuntary movement (AIM) inhibition assay using unilateral 6-hydroxydopamine lesioned (hemiparkinsonian) rats. Compound 6a was found to be active in both assays. This compound could lead to a better understanding of how a bitopic D3 dopamine receptor selective ligand might lead to the development of pharmacotherapeutics for the treatment of levodopa-induced dyskinesia (LID) in patients with Parkinson’s disease. Full article

Rhes is one of the most interesting genes regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. Rhes mRNA is expressed at high levels in the dorsal striatum, with a medial-to-lateral expression gradient reflecting that of both dopamine D₂ and adenosine A_2A receptors. Rhes transcript is also present in the hippocampus, cerebral cortex, olfactory tubercle and bulb, substantia nigra pars compacta (SNc) and ventral tegmental area of the rodent brain. In line with Rhes-dependent regulation of dopaminergic transmission, data showed that lack of Rhes enhanced cocaine- and amphetamine-induced motor stimulation in mice. Previous studies showed that pharmacological depletion of dopamine significantly reduces Rhes mRNA levels in rodents, non-human primates and Parkinson’s disease (PD) patients, suggesting a link between dopaminergic innervation and physiological Rhes mRNA expression. Rhes protein binds to and activates striatal mTORC1, and modulates L-DOPA-induced dyskinesia in PD rodent models. Finally, Rhes is involved in the survival of mouse midbrain dopaminergic neurons of SNc, thus pointing towards a Rhes-dependent modulation of autophagy and mitophagy processes, and encouraging further investigations about mechanisms underlying dysfunctions of the nigrostriatal system. Full article