Continuous cerebroventricular administration of dopamine: A new treatment for severe dyskinesia in Parkinson’s disease?

In Parkinson’s disease (PD) depletion of dopamine in the nigro-striatal pathway is a main pathological hallmark that requires continuous and focal restoration. Current predominant treatment with intermittent oral administration of its precursor, Levodopa (l-dopa), remains the gold standard but pharmacological drawbacks trigger motor fluctuations and dyskinesia. Continuous intracerebroventricular (i.c.v.) administration of dopamine previously failed as a therapy because of an inability to resolve the accelerated dopamine oxidation and tachyphylaxia. We aim to overcome prior challenges by demonstrating treatment feasibility and efficacy of continuous i.c.v. of dopamine close to the striatum. Dopamine prepared either anaerobically (A-dopamine) or aerobically (O-dopamine) in the presence or absence of a conservator (sodium metabisulfite, SMBS) was assessed upon acute MPTP and chronic 6-OHDA lesioning and compared to peripheral l-dopa treatment. A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal tyrosine hydroxylase positive neurons in mice after 7 days of MPTP insult that was not evident with either O-dopamine or l-dopa. In the 6-OHDA rat model, continuous circadian i.c.v. injection of A-dopamine over 30 days also improved motor activity without occurrence of tachyphylaxia. This safety profile was highly favorable as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral l-dopa treatment. Indicative of a new therapeutic strategy for patients suffering from l-dopa related complications with dyskinesia, continuous i.c.v. of A-dopamine has greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxia

Oligophore and Semaphore for extrahepatic delivery of therapeutic RNA

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Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson's disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms

Neuroplasticity and neurorestoration in the treatment of Parkinson's Disease: Experimental studies in the mouse

Neuroplasticity is the brain´s capacity to respond to inner and outer challenges with functional and structural reorganizations. An aberrant activation of neuroplasticity pathways may contribute to the development of neurological disease. In the case of Parkinson’s disease (PD), the induction of motor complications by L-DOPA pharmacotherapy is generally regarded as an example of maladaptive plasticity. Indeed, L-DOPA-induced dyskinesia is associated with an aberrant striatal activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), a pathway that normally governs processes of synaptic plasticity and motor learning. The term neurorestoration refers to a stimulation of brain´s endogenous regenerative mechanisms either by neurotrophic factor delivery or by treatments that increase the production of trophic factors. These treatments recruit some of the same pathways that are involved in neuroplasticity. In this thesis work, we have used mice with 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) projections as a model of PD in order to examine the modulation of neuroplasticity pathways by both symptomatic and neurorestorative treatments. In a first study, we optimized the 6-OHDA lesion model in mice by examining the molecular and behavioural effects of 6-OHDA injections performed either in the medial forebrain bundle (MFB), in the substantia nigra, or in the striatum. The results showed that MFB lesions are the most suitable model for studying L-DOPA-induced dyskinesia, while intrastriatal 6-OHDA lesions should be the model of choice to study the effects of neurorestorative treatments. The second study focuses on the role of striatal Ras-ERK1/2 signaling in the development of L-DOPA-induced dyskinesia. Genetic ablation of Ras-GRF1 (a neuronal-specific activator of Ras-ERK1/2 signaling downstream of G-protein-coupled receptors) resulted in a reduced development of dyskinesia in the mouse. A collaborative study was undertaken to assess the role of Ras-ERK1/2 signaling in a monkey model of PD. The results of this study show that the severity of L-DOPA-induced dyskinesia can be reduced through lentiviral-mediated inactivation of Ras-GRF1 and ERK2 in the striatum. We did also utilize mice with intrastriatal 6-OHDA lesions in order to examine the effects of potential neurorestorative treatments for PD. In the third study of thesis, we evaluated the time course of behavioural recovery and nigrostriatal neurorestoration induced by striatal lentiviral delivery of the neurotrophic factor, GDNF. The intervention caused a progressive increase in the levels of phosphorylated ERK1/2 both in nigrostriatal neurons and in their projection areas, and this effect correlated with a local neuritic sprouting response. In the last study we evaluated the effects of PRE-084, a selective agonist of the sigma-1 receptor (which is an intracellular protein involved in many cellular functions). Chronic treatment with PRE-084 for 5 weeks resulted in a gradual and significant motor recovery, partial neuroprotective and neurorestorative effects on the nigrostriatal DA pathway. This was accompanied by striatal and nigral upregulation of GDNF and activation of ERK1/2. Taken together, the results of this thesis indicate that treatments stimulating a physiological activation of neuroplasticity pathways (such as ERK1/2 signaling) have neurorestorative potential in PD, while an excessive activation of these pathway by dopaminergic therapies may result in unwanted effects, such as dyskinesia

Modeling Parkinson's disease and treatment complications in rodents : Potentials and pitfalls of the current options

Animal models of neurological deficits are essential to assess new therapeutic options and reduce treatment complications. Over the last decades, several rodent models of Parkinson's disease have been developed, and have now become the first-line experimental tool for therapeutic screening purposes. Which model is the most predictive for identifying the efficacy of symptomatic or disease-modifying interventions is still a matter of debate. None of the models so far available is able to recapitulate all the features of the human disease, but several well-characterized models with complementary features currently provide a valuable repertoire of tools to address specific scientific hypotheses. This article reviews the rodent models of Parkinson's disease currently available, with a particular focus on symptomatic models used to mimic parkinsonian motor deficits and treatment-related complications. Advantages and disadvantages of each model are presented and discussed to assist the decision of investigators who wonder which model may be the most suitable for their particular research project

Animal models of l-DOPA-induced dyskinesia : the 6-OHDA-lesioned rat and mouse

Appearance of l-DOPA-induced dyskinesia (LID) represents a major limitation in the pharmacological therapy with the dopamine precursor l-DOPA. Indeed, the vast majority of parkinsonian patients develop dyskinesia within 9–10 years of l-DOPA oral administration. This makes the discovery of new therapeutic strategies an important need. In the last decades, several animal models of Parkinson’s disease (PD) have been developed, to both study mechanisms underlying PD pathology and treatment-induced side effects (i.e., LID) and to screen for new potential anti-parkinsonian and anti-dyskinetic treatments. Among all the models developed, the 6-OHDA-lesioned rodents represent the models of choice to mimic PD motor symptoms and LID, thanks to their reproducibility and translational value. Under l-DOPA treatment, rodents sustaining 6-OHDA lesions develop abnormal involuntary movements with dystonic and hyperkinetic features, resembling what seen in dyskinetic PD patients. These models have been extensively validated by the evidence that dyskinetic behaviors are alleviated by compounds reducing dyskinesia in patients and non-human primate models of PD. This article will focus on the translational value of the 6-OHDA rodent models of LID, highlighting their main features, advantages and disadvantages in preclinical research

Investigating the molecular mechanisms of L-DOPA-induced dyskinesia in the mouse

L-DOPA-induced dyskinesia (LID) is a major complication of the pharmacotherapy of Parkinson's disease (PD). Animal models of LID are essential for investigating pathogenic pathways and therapeutic targets. While non-human primates have been the preferred species for pathophysiological studies, mouse models of LID have been recently produced and characterized to facilitate molecular investigations. Most of these studies have used mice with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal projection sustaining treatment with L-DOPA for 1-4 weeks. Mice with complete medial forebrain bundle lesions have been found to develop dyskinetic movements of maximal severity associated with a pronounced post-synaptic supersensitivity of D1-receptor dependent signaling pathways throughout the striatum. In contrast, mice with striatal 6-OHDA lesions have been found to exhibit a variable susceptibility to LID and a regionally restricted post-synaptic supersensitivity. Genetic mouse models of PD have just started to be used for studies of LID, providing an opportunity to dissect the impact of genetic factors on the maladaptive neuroplasticity that drives the development of treatment-induced involuntary movements in PD