Multi-facetted impulsivity following nigral degeneration and dopamine replacement therapy.

Impulse control disorders (ICDs) are debilitating side effects of dopamine replacement therapy (DRT) in Parkinson's disease (PD) that severely affect the quality of life of patients. While DRT, the pattern and extent of neurodegeneration, and prodromic factors of vulnerability (e.g. impulsivity) have all been hypothesized to play a role in the development of ICDs, their respective, and potentially interacting, contributions remain to be established. High impulsive (HI), Intermediate (Int) or low impulsive (LI) rats were identified based on their performance in both a differential reinforcement of low rate of responding (DRL) and a fixed consecutive number (FCN) schedules, that operationalize two independent facets of impulsivity, waiting and action inhibition (motor impulsivity). We investigated whether high impulsivity trait influenced the progressive development of a parkinsonian state induced by viral-mediated overexpression of α-synuclein, and whether impulsivity trait and nigrostriatal neurodegeneration independently or jointly influenced the effects of DRT on impulse control. α-synuclein-induced nigrostriatal neurodegeneration increased both waiting and motor impulsivity. The D2/D3 dopamine receptor agonist pramipexole exacerbated motor impulsivity more than waiting. However, the pramipexole-induced increase in waiting impulsivity observed in both sham and lesioned rats, was more pronounced in HI lesioned rats, which displayed a restricted α-synuclein-induced dopaminergic neurodegeneration. Thus, a PD-like nigrostriatal lesion increases both motor and waiting impulsivity, but its interaction with a pre-existing impulsivity trait, which, at the cellular level, confers resilience to dopaminergic neurodegeneration, worsens the detrimental effects of D2/D3 dopamine receptor agonists on inhibitory control.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S0028390816302118

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. Thus, results of these studies may have been affected by factors other than the primary biological process investigated. METHODOLOGY/PRINCIPAL FINDINGS: We tested the possibility that L-DOPA might interfere with DAT binding. Post-mortem DAT binding was conducted in normal and MPTP-treated macaque monkeys that were administered L-DOPA, acutely or chronically. In parallel, DAT SPECT was conducted in MPTP-treated animals that were administered chronic L-DOPA. [99mTc]TRODAT-1 SPECT binding was similarly reduced in all MPTP monkeys regardless of L-DOPA treatment. L-DOPA had no significant effect on post-mortem DAT binding either in saline or in MPTP-lesioned animals. CONCLUSIONS/SIGNIFICANCE: These data indicate that L-DOPA does not induce modifications of DAT expression detectable by SPECT of by DAT binding autoradiography, suggesting that differences between clinical assessment and radiotracer imaging in clinical trials may not be specifically related to L-DOPA treatment

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (α-syn) aggregates in affected oligodendrocytes. Several studies point to α-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of α-syn in vitro and in neuronal cell models of α-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate α-syn pathology and to mediate neuroprotection in proteolipid protein α-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP-SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of α-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated α-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX-765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting α-syn accumulation

Analogues expérimentaux de dégénérescence striatonigrique et développement d'un modèle systémique chez la souris

La dégénérescence striatonigrique (DSN) est une maladie neurodégénérative qui associe l'atteinte de la substance noire pars compacta (SNc) et du striatum. Après avoir validé un test de mesure de la longueur du pas chez la souris, nous avons étudié les conséquences de lésions induites par l'acide 3-nitropropionique (3-NP) et avons caractérisé un syndrome moteur spécifique corrélé au degré d'atteinte striatale ainsi qu'une altération des performances motrices et une perte neuronale dans la SNc dose-dépendantes. Nous avons ensuite étudié le rôle de la dopamine sur l'intégrité striatale et avons mis en évidence une augmentation de l'effet du 3-NP chez des souris hyperdopaminergiques ainsi que des troubles moteurs spontanés associés à une atteinte striatale modérée. Nous avons ensuite développé un modèle de DSN par intoxication combinée au 3-NP+MPTP, caractérisé par une absence d'interactions entre les deux neurotoxiques et une augmentation des troubles moteurs et de l'atteinte striatale.Striatonigral degeneration (SND) is a neurodegenerative disease combining loss of substantia nigra pars compacta (SNc) and striatal neurons. We first validated a stride length test in the mouse and studied the consequences of 3-nitropropionic acid (3-NP) induced lesions and demonstrated a characteristic motor syndrome correlated with the extent of striatal neuronal loss while a dose-dependant motor impairment and neuronal loss in the SNc. We then studied the role of dopamine upon striatal functioning and demonstrated a hypersensitivity to 3-NP in hyperdopaminergic mice, together with spontaneous motor deficits and striatal neuronal loss. Finally, we developped a model of SND using combined MPTP+3-NP intoxication and characterized by a lack of interactions between the two neurotoxins, increased behavioural troubles, motor impairments and striatal injury.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Premotor parkinsonism models.

International audienceAside from motor symptoms, Parkinson's disease is associated with a number of non-motor symptoms arising many years before motor signs. The most prevalent and predictive premotor symptoms include olfactory dysfunction, REM sleep behaviour disorder (RBD) and constipation. Several studies in toxin- or gene-based models have specifically investigated these non-motor signs in a premotor context. Altered olfactory discrimination has been reproduced both in toxin- and in gene-based models, and genetic models may also reproduce the underlying pathophysiological mechanisms. Sleep alterations have also been demonstrated, mostly in toxin-based models, and RBD-like features can be demonstrated in non-human primates. Gastrointestinal dysfunction and associated enteric pathology are reproduced both in toxin and genetic models displaying reduced colonic motility and enteric α-synuclein accumulation. This review describes the main premotor symptoms that are recapitulated both in toxin- and in gene-based models, their relevance to the human disease, and their potential to understand the underlying mechanisms of early symptoms and disease progression

Impulse control disorders in Parkinson’s disease

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Insulin, IGF-1 and GLP-1 signaling in neurodegenerative disorders: targets for disease modification?

International audienceInsulin and Insulin Growth Factor-1 (IGF-1) play a major role in body homeostasis and glucose regulation. They also have paracrine/autocrine functions in the brain. The Insulin/IGF-1 signaling pathway contributes to the control of neuronal excitability, nerve cell metabolism and cell survival. Glucagon like peptide-1 (GLP-1), known as an insulinotropic hormone has similar functions and growth like properties as insulin/IGF-1. Growing evidence suggests that dysfunction of these pathways contribute to the progressive loss of neurons in Alzheimer's disease (AD) and Parkinson's disease (PD), the two most frequent neurodegenerative disorders. These findings have led to numerous studies in preclinical models of neurodegenerative disorders targeting insulin/IGF-1 and GLP-1 signaling with currently available anti-diabetics. These studies have shown that administration of insulin, IGF-1 and GLP-1 agonists reverses signaling abnormalities and has positive effects on surrogate markers of neurodegeneration and behavioral outcomes. Several proof-of-concept studies are underway that attempt to translate the encouraging preclinical results to patients suffering from AD and PD. In the first part of this review, we discuss physiological functions of insulin/IGF-1 and GLP-1 signaling pathways including downstream targets and receptors distribution within the brain. In the second part, we undertake a comprehensive overview of preclinical studies targeting insulin/IGF-1 or GLP-1 signaling for treating AD and PD. We then detail the design of clinical trials that have used anti-diabetics for treating AD and PD patients. We close with future considerations that treat relevant issues for successful translation of these encouraging preclinical results into treatments for patients with AD and PD

Unlucky punches: the vulnerability-stress model for the development of impulse control disorders in Parkinson's disease

Impulse-control disorders are commonly observed during dopamine-replacement therapy in Parkinson's disease, but the majority of patients seems immune to this side effect. Epidemiological evidence suggests that a major risk factor may be a specific difference in the layout of the dopaminergic-reinforcement system, of which the ventral striatum is a central player. A series of imaging studies of the dopaminergic system point toward a presynaptic reduction of dopamine-reuptake transporter density and dopamine synthesis capacity. Here, we review current evidence for a vulnerability-stress model in which a relative reduction of dopaminergic projections to the ventral striatum and concomitant sensitization of postsynaptic neurons represent a predisposing (hypodopaminergic) vulnerability. Stress (hyperdopaminergic) is delivered when dopamine replacement therapy leads to a relative overdosing of the already-sensitized ventral striatum. These alterations are consistent with consecutive changes in reinforcement mechanisms, which stimulate learning from reward and impede learning from punishment, thereby fostering the development of impulse-control disorders. This vulnerability-stress model might also provide important insights into the development of addictions in the non-Parkinsonian population