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

Dramatic differences in susceptibility to L-DOPA-induced dyskinesia between mice that are aged before or after a nigrostriatal dopamine lesion

Mice with striatal 6-hydroxydopamine (6-OHDA) lesions are widely used as a model to study the effects of neurorestorative, symptomatic, or antidyskinetic treatments for Parkinson's disease (PD). The standard praxis is to utilize young adult mice with relatively acute 6-OHDA lesions. However, long post-lesion intervals may be required for longitudinal studies of treatment interventions, and the long-term stability of the model's behavioral and cellular phenotypes is currently unknown. In this study, C57Bl/6J mice sustained unilateral striatal 6-OHDA lesions at approx. 2 months of age, and were allowed to survive for 1, 10 or 22 months. Another group of mice sustained the lesion at the age of 23 months and survived for one month thereafter. Baseline and drug-induced motor behaviors were examined using a battery of tests (utilizing also a novel video-based methodology). The extent of nigral dopamine cell loss was stable across post-lesion intervals and ages. However, a prominent sprouting of both dopaminergic and serotonergic fibers was detected in the caudate-putamen in animals that survived until 10 and 22 months post-lesion. This phenomenon was associated with a recovery of baseline motor deficits, and with a lack of dyskinetic responses upon treatment with either L-DOPA or apomorphine. By contrast, mice sustaining the lesion at 23 months of age showed a striking susceptibility to the dyskinetic effects of both L-DOPA and apomorphine, which was associated with a pronounced drug-induced upregulation of ∆FosB in the ventrolateral striatum. The results reveal a remarkable compensatory capacity of a damaged nigrostriatal pathway in ageing mice, and how this impacts on the response to dopaminergic therapies for PD

Animal models of l-DOPA-induced dyskinesia: an update on the current options.

Major limitations to the pharmacotherapy of Parkinson's disease (PD) are the motor complications resulting from l-DOPA treatment. Abnormal involuntary movements (dyskinesia) affect a majority of the patients after a few years of l-DOPA treatment and can become troublesome and debilitating. Once dyskinesia has debuted, an irreversible process seems to have occurred, and the movement disorder becomes almost impossible to eliminate with adjustments in peroral pharmacotherapy. There is a great need to find new pharmacological interventions for PD that will alleviate parkinsonian symptoms without inducing dyskinesia. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate model is an excellent symptomatic model of PD and was the first model used to reproduce l-DOPA-induced dyskinesia experimentally. As it recapitulates the motor features of human dyskinesia, that is, chorea and dystonia, it is considered a reliable animal model to define novel therapies. Over the last decade, rodent models of l-DOPA-induced dyskinesia have been developed, having both face validity and predictive validity. These models have now become the first-line experimental tool for therapeutic screening purposes. The application of classical 6-hydroxydopamine (6-OHDA) lesion procedures to produce rodent models of dyskinesia has provided the field with more dynamic tools, since the versatility of toxin doses and injection coordinates allows for mimicking different stages of PD. This article will review models developed in non-human primate and rodents to reproduce motor complications induced by dopamine replacement therapy. The recent breakthroughs represented by mouse models and the relevance of rodents in relation to non-human primate models will be discussed. This article is part of a Special Issue entitled: Neuroscience Disease Models

Neuroprotection and neurorestoration as experimental therapeutics for Parkinson's disease

Disease-modifying treatments remain an unmet medical need in Parkinson's disease (PD). Such treatments can be operationally defined as interventions that slow down the clinical evolution to advanced disease milestones. A treatment may achieve this outcome by either inhibiting primary neurodegenerative events ("neuroprotection") or boosting compensatory and regenerative mechanisms in the brain ("neurorestoration"). Here we review experimental paradigms that are currently used to assess the neuroprotective and neurorestorative potential of candidate treatments in animal models of PD. We review some key molecular mediators of neuroprotection and neurorestoration in the nigrostriatal dopamine pathway that are likely to exert beneficial effects on multiple neural systems affected in PD. We further review past and current strategies to therapeutically stimulate these mediators, and discuss the preclinical evidence that exercise training can have neuroprotective and neurorestorative effects. A future translational task will be to combine behavioral and pharmacological interventions to exploit endogenous mechanisms of neuroprotection and neurorestoration for therapeutic purposes. This type of approach is likely to provide benefit to many PD patients, despite the clinical, etiological, and genetic heterogeneity of the disease

Chapter 22 - Rodent Models of Treatment-Related Complications in Parkinson Disease

Dopamine replacement therapy effectively relieves the typical motor features of Parkinson disease (PD), but it can cause complications that limit its utility. Dyskinesia (abnormal involuntary movements) and motor fluctuations (abrupt changes in the patients' motor status) occur in most PD patients after a few years of 3,4-dihydroxyphenyl-. l-alanine (l-DOPA) pharmacotherapy. Animal models reproducing these motor complications can be obtained in mice and rats if the nigrostriatal dopamine pathway is severely damaged. Within the large arsenal of neurotoxic and genetic models of PD, rodents with unilateral 6-hydroxydopamine lesions have the best characteristics for the sake of modeling l-DOPA-induced dyskinesia. When treated chronically with high doses of l-DOPA, these rodent models may also display motor response alterations reminiscent of the wearing-off fluctuations that occur in PD patients. Because of research performed on these animal models, our understanding of the molecular and biochemical mechanisms of l-DOPA-induced dyskinesia has made great advances, and several pharmacological approaches to treatment have been recently identified and successfully tested in proof-of-concept trials in PD patients. It is now well recognized that dopaminergic therapies for PD also cause nonmotor fluctuations (e.g., abrupt changes in mood and cognitive performance) and impulse control disorders. Valid rodent models of these nonmotor complications need to be developed as an important tool for basic and translational research on the cognitive and psychiatric features of PD

Rodent models of impulsive compulsive behaviors in Parkinson's disease: how far have we reached?

There is increasing awareness that the medications used to treat the motor symptoms of Parkinson's disease (PD) contribute to the development of behavioral addictions, which have been clinically defined as impulsive compulsive behaviors (ICBs). These features include pathological gambling, compulsive sexual behavior, binge eating, compulsive shopping, excessive hobbyism or punding, and the excessive use of dopaminergic medication. ICBs frequently have devastating effects on the social and occupational function of the affected individuals as well as their families. Although ICBs are an important clinical problem in PD, the number of studies in which these symptoms have been modeled in rodents is still limited. This may depend on uncertainties regarding, on one hand, the pathophysiology of these behaviors and, on the other hand, the experimental paradigms with which similar features can be induced in rodents. To help compose these uncertainties, we will here review the characteristics of ICBs in PD patients and then describe behavioral methods to approximate them in rodents. We will discuss both the challenges and the possibilities of applying these methods to animals with PD-like lesions, and review the recent progress made to this end. We will finally highlight important questions deserving further investigation. Rodent models having both face validity and construct validity to parkinsonian ICBs will be essential to further pathophysiological and therapeutic investigations into this important area