1,721,222 research outputs found
Excitotoxicity
No full textParkinson’s disease (PD) is a multisystem, complex disorder with an uncertain etiology characterized by the involvement of selected neuronal populations throughout the central and peripheral nervous systems. The main pathological feature of the disease is degeneration of dopaminergic, melanized neurons of the substantia nigra pars compacta (SNc) projecting to the corpus striatum; this is associated with the presence of intracytoplasmic, proteinaceous inclusions termed Lewy bodies (LBs), presenting as spherical, eosinophilic structures with a central, granular core surrounded by a fibrillary halo (Betarbet et al., 2002; Hirsch, 1999; Jellinger, 1998; Riederer and Lange, 1992). The striatal dopaminergic denervation resulting from the SNc cell loss triggers complex functional modifications within the basal ganglia circuitry that cause the typical motor symptoms of the disease (tremor, rigidity, and bradykinesia) (Blandini et al., 2000). Although PD is the prototypical movement disorder, the disease is also characterized by numerous nonmotor symptoms, which include autonomic dysfunction, sleep disorders, psychiatric symptoms, gastrointestinal dysfunction, and cognitive dysfunction (Poewe, 2008)
Neural and immune mechanisms in the pathogenesis of Parkinson's disease
No full textAlthough almost 50 years have passed since impaired dopaminergic transmission was identified as the main neurochemical defect in Parkinson's disease (PD), the cause of the disease remains unknown. A restricted number of biological mechanisms are likely to contribute to the process of cell death in the nigrostriatal pathway. These mechanisms include mitochondrial defects and enhanced formation of reactive oxygen species - leading to oxidative damage - and abnormal protein aggregation. In addition to or, possibly, intermingled with these mechanisms of neuronal damage there is another crucial factor: neuroinflammation. The inflammatory response associated with cell loss in the dopaminergic nigrostriatal tract and, more in general, the role of immune mechanisms are increasingly recognized in PD pathogenesis. Neuroinflammatory changes have been repeatedly demonstrated, in both neurotoxic and transgenic animal models of PD, as well as in PD patients. Transgenic models based on α-synuclein overexpression, in particular, have provided crucial insights into the correlation between this protein and the dichotomous response that microglia can activate, with the polarization toward a cytotoxic (M1) or cytoprotective (M2) phenotype. Full understanding of such mechanisms may set the ground for a fine tuning of the neuroinflammatory process that accompanies and sustains neurodegeneration, thereby opening new therapeutic perspectives for PD. © 2013 Springer Science+Business Media New York
Adenosine receptors and L-DOPA-induced dyskinesia in Parkinson's disease: Potential targets for a new therapeutic approach
No full textNeuroprotection by Rasagiline: A New Therapeutic Approach to Parkinson's Disease?
No full textNeuronal death in Parkinson's disease (PD) may originate from the reciprocal interactions of a restricted number of conditions, such as mitochondrial defects, oxidative stress and protein mishandling, which would favor a state of apoptotic cell death in the nigrostriatal pathway. The search for pharmacological treatments able to counteract the nigrostriatal degeneration, possibly by interfering with these phenomena, has recently raised considerable interest in rasagiline [R(+)-N-propargyl-l-aminoindan], a potent, selective, and irreversible inhibitor of monoamine oxidase B (MAO-B). Rasagiline, like selegiline, is a propargylamine, but is ∼10 times more potent. Unlike selegiline, rasagiline is not metabolized to amphetamine and/or methamphetamine and is devoid of sympathomimetic activity. Numerous experimental studies, conducted both in vitro and in vivo, have shown that rasagiline possesses significant protective properties on neuronal populations. The pro-survival effects of the drug appear to be linked to its propargyl moiety, rather than to the inhibitory effect on MAO-B. Rasagiline's major metabolite, aminoindan - which possesses intrinsic neuroprotective activity - may also contribute to the beneficial effects of the parent compound. Rasagiline has been recently evaluated in early PD patients, with results that are consistent with slowing the progression of the disease. Therefore, the neuroprotective activity shown by the drug under experimental conditions may be reflected in the clinic, thus providing new perspectives for the treatment of PD. © 2005 Neva Press, Branford, Connecticut
In vivo modeling of prodromal stage of Parkinson's disease
No full textParkinson's disease (PD) has a long prodromal period that precedes the appearance of typical motor symptoms. This phase is extremely heterogeneous and is characterized by a wide range of non-motor alterations including REM sleep behavior disorders, constipation, olfactory and urinary dysfunctions. The increasing clinical and experimental knowledge on prodromal PD has led to the development of novel animal models recapitulating this disease stage as well as to a new use and interpretation of existing models. Prodromal animal models of PD represent an important tool for testing new therapeutic strategies and shedding light on the early pathogenic steps that set the ground for the extensive dopaminergic cell death observed in the midbrain. This review summarizes the new insights that these models have provided into the comprehension of a complex and still unexplored stage of PD
An update on the use of non-ergot dopamine agonists for the treatment of Parkinson’s disease
No full textIntroduction: Long-term treatment of Parkinson’s disease (PD) with levodopa is hampered by motor complications related to the inability of residual nigrostriatal neurons to convert levodopa to dopamine (DA) and use it appropriately. This generated a tendency to postpone levodopa, favoring the initial use of DA agonists, which directly stimulate striatal dopaminergic receptors. Use of DA agonists, however, is associated with multiple side effects and their efficacy is limited by suboptimal bioavailability. Areas covered: This paper reviewed the latest preclinical and clinical findings on the efficacy and adverse effects of non-ergot DA agonists, discussing the present and future of this class of compounds in PD therapy. Expert opinion: The latest findings confirm the effectiveness of DA agonists as initial treatment or adjunctive therapy to levodopa in advanced PD, but a more conservative approach to their use is emerging, due to the complexity and repercussions of their side effects. As various factors may increase the individual risk to side effects, assessing such risk and calibrating the use of DA agonists accordingly may become extremely important in the clinical management of PD, as well as the availability of new DA agonists with better profiles of safety and efficacy
Role of autophagy in Parkinson’s disease
No full textAutophagy is an essential catabolic mechanism that delivers misfolded proteins and damaged organelles to the lysosome for degradation. Autophagy pathways include macroautophagy, chaperone-mediated autophagy and microautophagy, each involving different mechanisms of substrate delivery to lysosome. Defects of these pathways and the resulting accumulation of protein aggregates represent a common pathobiological feature of neurodegenerative disorders such as Alzheimer, Parkinson and Huntington disease. This review provides an overview of the role of autophagy in Parkinson’s disease (PD) by summarizing the most relevant genetic and experimental evidence showing how this process can contribute to disease pathogenesis. Given lysosomes take part in the final step of the autophagic process, the role of lysosomal defects in the impairment of autophagy and their impact on disease will also be discussed. A glance on the role of non-neuronal autophagy in the pathogenesis of PD will be included. Moreover, we will examine novel pharmacological targets and therapeutic strategies that, by boosting autophagy, may be theoretically beneficial for PD. Special attention will be focused on natural products, such as phenolic compounds, that are receiving increasing consideration due to their potential efficacy associated with low toxicity. Although many efforts have been made to elucidate autophagic process, the development of new therapeutic interventions requires a deeper understanding of the mechanisms that may lead to autophagy defects in PD and should take into account the multifactorial nature of the disease as well as the phenotypic heterogeneity of PD patients
Protective and symptomatic strategies for therapy of Parkinson's disease
No full textParkinson's disease (PD) is a neurodegenerative disorder characterized by loss of the capacity to execute voluntary movements appropriately. PD develops as a consequence of the degeneration of dopamine-containing neurons in the substantia nigra pars compacta (SNc). SNc is a component of the basal ganglia nuclei, the network that controls the neural signaling underlying voluntary movements. The nigral cell loss triggers a cascade Of functional modifications in the basal ganglia circuit, the most important of which is hyperactivity of another component of the circuit, the subthalamic nucleus (STN). Subthalamic hyperactivity represents a major neural substrate of PD motor symptoms. The etiopathogenesis of PD is probably multifactorial. Various mechanisms - including mitochondrial defects, oxidative stress, glutamate toxicity and genetic factors - are likely to contribute to the degenerative process. Current therapy for PD is essentially symptomatic. L- dopa, the direct precursor of dopamine, is still the gold standard'. However, long-term therapy with L-dopa is associated with significant side effects. Therefore, there is a need for new therapeutic strategies aimed at relieving motor symptoms and slowing the progression of neuronal degeneration. The excitatory amino acid glutamate plays a central role in the functional modifications that affect the basal ganglia in PD. In particular, it mediates the enhanced excitatory drive of the STN to the output nuclei of the basal ganglia, which leads to the expression of PD symptoms. Furthermore, since the STN projects to the SNc, the excessive glutamatergic stimulation on residual nigral neurons may sustain the degenerative process, generating a self- maintaining vicious circle. From these considerations, it ensues that the use of drugs capable of antagonizing the effects of glutamate may provide new symptomatic and neuroprotective strategies for therapy of PD
Prospects of glutamate antagonists in the therapy of Parkinson's disease
No full textIt has been suggested that the excitatory amino acid glutamate, acting as both a neurotoxin and a neurotransmitter, might play a central role in the pathophysiology of Parkinson's disease (PD). Intrinsic energetic defects of the neurons of the substantia nigra pars compacta, the brain area where the degenerative process of PD takes place, may render nigral neurons highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. Degeneration of dopamine nigral neurons and striatal dopaminergic denervation cause a cascade of functional modifications in the activity of basal ganglia nuclei. Due to the close relationship that links dopaminergic and glutamatergic neurotransmission, glutamate is directly involved in the functional alterations of basal ganglia circuitry that lead to the development of parkinsonian motor symptoms. Drugs counteracting the effects of glutamate might therefore provide new protective and symptomatic strategies for therapy of PD
- …
