Inflammatory responses have been proposed as important factors in dopaminergic neuro-degeneration in Parkinsonism. Increasing evidence suggests that the alteration of the glial microenvironment induced by neuronal degeneration could be deleterious to the remaining neurons. The activation of microglia/macrophages and reactive astrocytes may have a negative effect on the surrounding parenchyma, perpetuating the neurodegenerative process. However, this alteration may also go beyond the brain parenchyma and stimulate other inflammatory changes in other systems, inducing the release of proinflammatory cytokines and probably Acute Phase Proteins (APP) and Glucocorticoids (GC). In this work we review the latest advances in the field to provide a picture of the state of the art of studies of inflammatory responses and Parkinsonism, hopefully opening up new therapeutic perspectives for patients with Parkinson’s disease.
This study was designed to examine the type of changes experienced by the CB1 receptor, a key element of the cannabinoid signaling system, in the basal ganglia of different mouse mutants generated by deletion of specific genes associated with the development of Parkinson's disease in humans [PARK1 (alpha-synuclein), PARK2 (parkin) or PARK6 (PINK1)]. We observed that CB1 receptor-mRNA levels were significantly reduced in the caudate-putamen in the three models under examination when animals were analyzed at early phases (<= 12 months of age). This decrease was, in general, associated with a reduction in CB1 receptor binding in the substantia nigra and the globus pallidus, particularly in the case of alpha-synuclein-deficient mice. By contrast, both parameters, mRNA levels and binding for the CB1 receptor, showed an elevation in the same areas when animals were analyzed at older ages, mainly in the case of the CB1 receptor binding in the substantia nigra. In summary, our data revealed the existence of a biphasic response for CB1 receptors, with losses at early phases, when dopaminergic dysfunction is possibly the major event that takes place, followed by upregulatory responses at advanced phases characterized by the occurrence of evident nigrostriatal pathology including neuronal death in some cases.
The roles of the nigrostriatal pathway are far beyond the simple control of motor functions. The tonic release of dopamine in the dorsal and ventral striatum controls the choice of proper actions toward a given environmental situation. In the striatum, a specific action is triggered by a specific stimulus associated with it. When the subject faces a novel and salient stimulus, the phasic release of dopamine allows synaptic plasticity in the cortico-striatal synapses. Neurons of different regions of cortical areas make synapses that converge to the same medium spine neurons of the striatum. The convergent associations form functional units encoding body parts, objects, locations, and symbolic representations of the subject's world. Such units emerge in the striatum in a repetitive manner, like a mosaic of broken mirrors. The phasic release of dopamine allows the association of units to encode an action of the subject directed to an object or location with the outcome of this action. Reinforced stimulus-action-outcome associations will affect future decision making when the same stimulus (object, location, idea) is presented to the subject in the future. In the absence of a minimal amount of striatal dopamine, no action is initiated as seen in Parkinson's disease subjects. The abnormal and improper association of these units leads to the initiation of unpurposeful and sometimes repetitive actions, as those observed in dyskinetic patients. The association of an excessive reinforcement of some actions, like drug consumption, leads to drug addiction. Improper associations of ideas and unpleasant outcomes may be related to traumatic and depressive symptoms common in many diseases, including Parkinson's disease. The same can be said about the learning and memory impairments observed in demented and nondemented Parkinson's disease patients.
Dopaminergic neurons in the substantia nigra pars compacta modulate complex motor control. Nigral dopaminergic neurons exhibit three different firing patterns in vivo: a pacemaker mode, a random mode, and a burst mode. These firing patterns are closely related to motor control. However, the changes in the proportion of the firing patterns with respect to age have not been fully established. To clarify the age-dependent changes in the proportion of dopaminergic firing patterns, we used single unit extracellular recordings in male F344/N rats. We observed that, with age, the distribution of the spikes fired by dopaminergic neurons shifts from pacemaker to random mode, and then from random to burst mode. These results suggest that the age-dependent changes in the proportion of nigral dopaminergic firing patterns may have an effect on motor function.
Parkinson’s disease is characterized by the degeneration of the nigrostriatal dopaminergic neurons with the manifestation of tremor, rigidity, akinesia, and disturbances of postural reflexes. Medication using L-DOPA and surgeries including deep brain stimulation are the established therapies for Parkinson’s disease. Cell therapies are also effective and have rapidly developed with the recent advancement in molecular biological technology including gene transfer. In this review, ex vivo gene therapy using genetically engineered cell transplantation for Parkinson’s disease model of animals is described, including catecholamine/neurotrophic factor-secreting cell transplantation with or without encapsulation, as well as in vivo gene therapy using direct injection of viral vector to increase dopamine-production, ameliorate the survival of dopaminergic neurons, correct the deteriorated microenvironment, or normalize genetic abnormality. Furthermore, the future directions for clinical application are described together with recent clinical trials of gene therapy.
Nitric oxide (NO) plays an important role in the integration of information processed by the basal ganglia nuclei. Accordingly, considerable evidence has emerged indicating a role for NO in pathophysiological conditions such as Parkinson's disease (PD) and other neurodegenerative disorders. Despite these recent advances, the nitrergic modulation of the dopamine (DA) nigrostriatal system is still unclear. In order to fill this gap, in this study we used in vivo electrophysiology and ex vivo neurochemical analysis to further investigate the effect of NO signaling in rat substantia nigra pars compacta (SNc) and the striatum. Acute and subchronic (4 days) pharmacological manipulation of the NO system using 7-nitroindazole (7-NI, 50 mg kg(-1) i.p.) and molsidomine (MOL, 40 mg kg(-1) i.p.) treatment caused significant changes in both DA SNc neurons electrophysiological properties and striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. It is worth noting that acute inhibition of NO production decreased DA nigrostriatal neurotransmission while its subchronic inhibition was instead excitatory. Thus, a crucial role for NO in the modulation of nigrostriatal DA function is suggested together with a potential role for inhibitors of NO sythase in the treatment of PD.
Parkinson's disease (PD) is a neurodegenerative disorder caused by a progressive degeneration of the midbrain dopamine (DA) neurons in the substantia nigra pars compacta (SNc) that predominantly affects the ventral population projecting to the dorsal striatum and leads to a gradual dysfunction of the motor system. There is currently no cure for PD. Pharmacological and surgical (e.g. deep brain stimulation) interventions can alleviate some of the symptoms, but lose their efficacy over time. The distinct loss of DA neurons in the SN offers the opportunity to assay neuronal cell replacement, and the clinical transplantation of fetal midbrain neuroblasts in PD patients has shown that this approach is feasible. However, there are multiple problems associated with the use of fetus-derived material, including limited availability. DA neurons derived from stem cells (SC) represent an alternative and unlimited cell source for cell replacement therapies. Currently, human pluripotent SC, such as embryonic (ES), and most recently, induced pluripotent stem cells (iPS), and multipotent (tissue-specific) adult SC are available, although the methodology for a reliable and efficient production of DA neurons necessary for biomedical applications is still underdeveloped. Here, we discuss some essentials for SC and SC-derived DA neurons to become therapeutic agents.
This paper reviews two of the major features of the nigrostriatal pathway, its axonal collateralization, and compartmental specificity, as revealed by single-axon labeling experiments in rodents and immunocytological analysis of human postmortem tissue. The dorsal and ventral tiers of the substantia nigra pars compacta harbor various types of neurons the axons of which branch not only within the striatum but also in other major components of the basal ganglia. Furthermore, some nigrostriatal axons send collaterals both to thalamus and to brainstem pedunculopontine tegmental nucleus. In humans, the compartmental specificity of the nigrostriatal pathway is revealed by the fact that the matrix compartment is densely innervated by dopaminergic fibers, whereas the striosomes display different densities of dopaminergic terminals depending on their location within the striatum. The nigral neurons most severely affected in Parkinson's disease are the ventral tier cells that project to the matrix and form deep clusters in the substantia nigra pars reticulata.
This chapter consists of four sections. The first section provides a general description of the electrophysiological characteristics of dopamine (DA) neurons in both the substantia nigra and ventral tegmental area. Emphasis is placed on the differences between DA and neighboring non-DA neurons. The second section discusses the ionic mechanisms underlying the generation of action potential in DA cells. Evidence is provided to suggest that these mechanisms differ not only between DA and non-DA neurons but also between DA cells located in different areas, with different projection sites and at different developmental stages. Some of the differences may play a critical role in the vulnerability of a DA neuron to cell death. The third section describes the firing patterns of DA cells. Data are presented to show that the current "80/160 ms" criteria for burst identification need to be revised and that the burst firing, originally described by Bunney et al., can be described as slow oscillations in firing rate. In the ventral tegmental area, the slow oscillations are, at least partially, derived from the prefrontal cortex and part of prefrontal information is transferred to DA cells indirectly through inhibitory neurons. The final section focuses on the feedback regulation of DA cells. New evidence suggests that DA autoreceptors are coupled to multiple effectors, and both D1 and D2-like receptors are involved in long-loop feedback control of DA neurons. Because of the presence of multiple feedback and nonfeedback pathways, the effect of a drug on a DA neuron can be far more complex than an inhibition or excitation. A better understanding of the intrinsic properties of DA neurons and their regulation by afferent input will, in time, help to point to the way to more effective and safer treatments for disorders including schizophrenia, drug addiction, and Parkinson's disease.
We have observed in previous studies that 6-hydroxydopamine (6-OHDA)-induced lesions in the nigrostriatal dopamine (DA) system promote increases of the astroglial basic fibroblast growth factor (FGF-2, bFGF) synthesis in the ascending DA pathways, event that could be modified by adrenosteroid hormones. Here, we first evaluated the changes of microglial reactivity in relation to the FGF-2-mediated trophic responses in the lesioned nigrostriatal DA system. 6-OHDA was injected into the left side of the rat substantia nigra. The OX42 immunohistochemistry combined with stereology showed the time course of the microglial activation. The OX42 immunoreactivity (IR) was already increased in the pars compacta of the substantia nigra (SNc) and ventral tegmental area (VTA) 2 h after the 6-OHDA injection, peaked on day 7, and remained increased on the 14th day time-interval. In the neostriatum, OX42 immunoreactive (ir) microglial profiles increased at 24 h, peaked at 72 h, was still increased at 7 days but not 14 days after the 6-OHDA injection. Two-colour immunofluorescence analysis of the tyrosine hydroxylase (TH) and OX42 IRs revealed the presence of small patches of TH IR within the activated microglia. A decreased FGF-2 IR was seen in the cytoplasm of DA neurons of the SNc and VTA as soon as 2 h after 6-OHDA injection. The majority of the DA FGF-2 ir cells of these regions had disappeared 72 h after neurotoxin. The astroglial FGF-2 IR increased in the SNc and VTA, which peaked on day 7. Two-colour immunofluorescence and immunoperoxidase analyses of the FGF-2 and OX42 IRs revealed no FGF-2 IR within the reactive or resting microglia. Second, we have evaluated in a series of biochemical experiments whether adrenocortical manipulation can interfere with the nigral lesion and the state of local astroglial reaction, looking at the TH and GFAP levels respectively. Rats were adrenalectomized (ADX) and received a nigral 6-OHDA stereotaxical injection 2 days later and sacrificed up to 3 weeks after the DA lesion. Western blot analysis showed time-dependent decrease and elevation of TH and GFAP levels, respectively, in the lesioned versus contralateral midbrain sides, events potentiated by ADX and worsened by corticosterone replacement. ADX decreased the levels of FGF-2 protein (23 kDa isoform) in the lesioned side of the ventral midbrain compared contralaterally. The results indicate that reactive astroglia, but not reactive microglia, showed an increased FGF-2 IR in the process of DA cell degeneration induced by 6-OHDA. However, interactions between these glial cells may be relevant to the mechanisms which trigger the increased astroglial FGF-2 synthesis and thus may be related to the trophic state of DA neurons and the repair processes following DA lesion. The findings also gave further evidence that adrenocortical hormones may regulate astroglial-mediated trophic mechanisms and wound repair events in the lesioned DA system that may be relevant to the progression of Parkinson's disease.
Parkinson's disease (PD) is the second most common neurodegenerative disease, which unfortunately is still fatal. Since the discovery of dopamine (DA) neuronal cell loss within the substantia nigra in PD, the past decades have seen the understanding of the pathophysiological mechanisms underlying the degenerative process advance at a very impressive rate. Nevertheless, there is at present no cure for PD. Although there are no proven therapies for prevention, a large body of evidence from animal studies has highlighted the paramount role of dietary factors in counteracting DA degeneration. Consistently, associations between the risk of developing PD and the intake of nutrients, individual foods, and dietary patterns have been recently shown. Therefore, promoting healthy lifestyle choices such as a Mediterranean diet might be the key to reducing the risk of PD.
It has been proposed that the basal ganglia are important to the temporal processing of milliseconds- and seconds-range intervals, both within the motor and perceptual domains. This review summarizes and discuses evidence from animal, pharmacological, clinical, and imaging research that supports this proposal, with particular reference to the role of the substantia nigra (SN).
There is extensive evidence that oxidative damage of dopamine (DA)-containing neurons in the substantia nigra pars compacta (SNc) may contribute to the pathogenesis of Parkinson's disease (PD). We evaluated the potential neuroprotective effect of diets enriched with wild-type Red Setter (RS) tomato or transgenic High Carotene (HC) tomato, rich in beta-carotene, obtained by the activation of lycopene beta-cyclase (tlcy-b), in an animal model of PD. Male Fischer 344 rats were fed for 14 days with standard Altromin(MT) diet, 5% RS- or 5% HC-enriched diet. Seven days after the beginning of this diet regimen, the rats were lesioned by 6-hydroxydopamine (6-OHDA) injected into the left SNc. After further 7 days, the rats were sacrificed, and DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in both the left (ipsilateral) and the right (contralateral) striata were measured. Striatal DA levels were reduced by 86.5 +/- 5.0% in control, 86.2 +/- 5.0% in HC-, and 56.0 +/- 9.0% in RS- fed group. Striatal DOPAC was decreased by 85.6 +/- 5.0% in controls, 83.0 +/- 6.0% in HC-, and 58.9 +/- 10.0% in RS- fed group. Blood was obtained from the rats on day 14 and the plasma level of licopene and beta-carotene was measured by liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (LC-APCI-MS) for the determination of lycopene and beta-carotene levels. The plasma level of lycopene was 4.7 +/- 0.2 ng/ml in 5% RS- fed rats, while it was undetectable (< 2.5 ng ml(-1)) in control and HC- fed rats. The efficacy of RS diet to preserve striatal dopaminergic innervation can be attributed to the ability of lycopene to prevent the degeneration of DA-containing neurons in the SNc.
The degeneration of nigral dopaminergic (DA-) neurons is the histopathologic hallmark of Parkinson’s disease (PD), but not all nigral DA-cells show the same susceptibility to degeneration. This starts in DA-cells in the ventrolateral and caudal regions of the susbtantia nigra (SN) and progresses to DA-cells in the dorsomedial and rostral regions of the SN and the ventral tegmental area, where many neurons remain intact until the final stages of the disease. This fact indicates a relationship between the topographic distribution of midbrain DA-cells and their differential vulnerability, and the possibility that this differential vulnerability is associated with phenotypic differences between different subpopulations of nigral DA-cells. Studies carried out during the last two decades have contributed to establishing the existence of different compartments of nigral DA-cells according to their neurochemical profile, and a possible relationship between the expression of some factors and the relative vulnerability or resistance of DA-cell subpopulations to degeneration. These aspects are reviewed and discussed here.
Understanding the ontogeny of A9 dopamine (DA) neurons is critical not only to determining basic developmental events that facilitate the emergence of the substantia nigra pars compacta (SNc) but also to the extraction and de novo generation of DA neurons as a potential cell therapy for Parkinson's disease. Recent research has identified a precise window for DA cell birth (differentiation) in the ventral mesencephalon (VM) as well as a number of factors that may facilitate this process. However, application of these factors in vitro has had limited success in specifying a dopaminergic cell fate from undifferentiated cells, suggesting that other cell/molecular signals may as yet remain undiscovered. To resolve this, current work seeks to identify particularly potent and novel DA neuron differentiation factors within the developing VM specifically at the moment of ontogeny. Through such (past and present) studies, a catalog of proteins that play a pivotal role in the generation of nigral DA neurons during normal CNS development has begun to emerge. In the future, it will be crucial to continue to evaluate the critical developmental window where DA neuron ontogeny occurs, not only to facilitate our potential to protect these cells from degeneration in the adult brain but also to mimic the developmental environment in a way that enhances our ability to generate these cells anew either in vitro or in vivo. Here we review our present understanding of factors that are thought to be involved in the emergence of the A9 dopamine neuron group from the ventral mesencephalon.
Parkinson's disease (PD) is a severe neurodegenerative disorder of complex etiology and enigmatic physiopathology. In the past decade, the identification of genes involved in rare familial Parkinsonian syndromes has brought hope that understanding the functions of their products will provide insight into the molecular mechanisms responsible for neurodegeneration. The knowledge accumulated thus far has delineated two putative, potentially interconnected, disease-causing pathways: alpha-synuclein accumulation may be central to Parkinsonism due to alpha-synuclein gene defects, but possibly also to sporadic PD and other genetic forms presenting with Lewy bodies; altered mitochondrial physiology may be pivotal to Parkinsonian syndromes caused by parkin, PINK1, and possibly DJ-1 gene mutations. Adding new pieces to this fragmentary picture to determine to what extent sporadic PD and Parkinsonism due to distinct genetic causes share common pathogenic mechanisms remains a major challenge toward the development of future therapeutic strategies for these disabling disorders.
The clinical motor dysfunction in Parkinson's disease is primarily the consequence of a progressive degeneration of dopaminergic neurons in the substantia nigra of the nigrostriatal pathway. The degeneration of this tract provokes a depletion of dopamine in the striatum, where it is required as a permissive factor for normal motor function. Despite intense investigations, no effective therapy is available to prevent the onset or to halt the progression of the neuronal cell loss. Therefore, recent years have seen research into the mechanisms of endogenous repair processes occurring in the adult brain, particularly in the substantia nigra. Neurogenesis occurs in the adult brain in a constitutive manner under physiological circumstances within two regions: the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. In contrast to these two so-called neurogenic areas, the remainder of the brain is considered to be primarily nonneurogenic in nature, implying that no new neurons are produced there under normal conditions. The occurrence of adult neurogenesis in the substantia nigra under the pathological conditions of Parkinson's disease, however, remains controversial. Here, we review the published evidence of whether adult neurogenesis exists or not within the substantia nigra, where dopaminergic neurons are lost in Parkinson's disease.
The firing pattern of midbrain dopamine neurons is thought to have important behavioral consequences. Although these neurons fire regularly in vitro when deprived of their afferent inputs, they usually fire irregularly in vivo. It is not known whether the irregularity is functionally important and whether it derives from the intrinsic properties of dopamine neurons or network interactions. It is also not known whether the irregular firing pattern is fundamentally stochastic or deterministic in nature. Distinguishing between the deterministic nonlinear structure associated with chaos and other sources of structure including correlated noise is an inherently nontrivial problem. Here we explain the geometric tools provided by the field of nonlinear dynamics and their application to the analysis of interspike interval (ISI) data from midbrain dopamine neurons. One study failed to find strong evidence of nonlinear determinism, but others have identified such a structure and correlated it with network interactions.
The specific loss of substantia nigra compacta (SNc) neurons in Parkinson's disease (PD) has been the main driving force in initiating research efforts to unravel the apparent SNc-specific vulnerability. Initially, metabolic constraints due to high dopamine turnover have been the main focus in the attempts to solve this issue. Recently, it has become clear that fundamental differences in the molecular signature are adding to the neuronal vulnerability and provide specific molecular dependencies. Here, the different processes that define the molecular background of SNc vulnerability are summarized.
Nigral dopaminergic areas from Parkinsonian patients show an increase of reactive astrocytes and active microglia. The reaction of these two cell types is a clear evidence of inflammatory response associated with dopaminergic cell loss. However, the function of this glial reaction remains unclear. This histological hallmark is also reproduced in induced Parkinsonian animals such as MPTP-treated monkeys. In this work, we analyze with confocal microscopy the number of processes of microglial cells and astrocytes in the SNpc of MPTP-treated monkeys and compare with control animals. We observe that secondary branches from microglia and astrocytes increase in MPTP-treated animals, while the scaffold of primary branches does not change. These results demonstrate that glial reaction in MPTP-treated monkeys is characterized by the emission of new filaments after the dopaminergic degeneration, suggesting that glial cells may increase their scanning progress and modify their microanatomy after dopaminergic injury.
