Nigrostriatal Dopaminergic Projection Research Articles

Nigrostriatal dopamine modulates the striatal-amygdala pathway in auditory fear conditioning

The auditory striatum, a sensory portion of the dorsal striatum, plays an essential role in learning and memory. In contrast to its roles and underlying mechanisms in operant conditioning, however, little is known about its contribution to classical auditory fear conditioning. Here, we reveal the function of the auditory striatum in auditory-conditioned fear memory. We find that optogenetically inhibiting auditory striatal neurons impairs fear memory formation, which is mediated through the striatal-amygdala pathway. Using calcium imaging in behaving mice, we find that auditory striatal neuronal responses to conditioned tones potentiate across memory acquisition and expression. Furthermore, nigrostriatal dopaminergic projections plays an important role in modulating conditioning-induced striatal potentiation. Together, these findings demonstrate the existence of a nigro-striatal-amygdala circuit for conditioned fear memory formation and expression.

Adult-specific Reelin expression alters striatal neuronal organization: implications for neuropsychiatric disorders.

In addition to neuronal migration, brain development, and adult plasticity, the extracellular matrix protein Reelin has been extensively implicated in human psychiatric disorders such as schizophrenia, bipolar disorder, and autism spectrum disorder. Moreover, heterozygous reeler mice exhibit features reminiscent of these disorders, while overexpression of Reelin protects against its manifestation. However, how Reelin influences the structure and circuits of the striatal complex, a key region for the above-mentioned disorders, is far from being understood, especially when altered Reelin expression levels are found at adult stages. In the present study, we took advantage of complementary conditional gain- and loss-of-function mouse models to investigate how Reelin levels may modify adult brain striatal structure and neuronal composition. Using immunohistochemical techniques, we determined that Reelin does not seem to influence the striatal patch and matrix organization (studied by μ-opioid receptor immunohistochemistry) nor the density of medium spiny neurons (MSNs, studied with DARPP-32). We show that overexpression of Reelin leads to increased numbers of striatal parvalbumin- and cholinergic-interneurons, and to a slight increase in tyrosine hydroxylase-positive projections. We conclude that increased Reelin levels might modulate the numbers of striatal interneurons and the density of the nigrostriatal dopaminergic projections, suggesting that these changes may be involved in the protection of Reelin against neuropsychiatric disorders.

A Machine Learning Approach to Detect Parkinson’s Disease by Looking at Gait Alterations

Parkinson’s disease (PD) is often detected only in later stages, when about 50% of nigrostriatal dopaminergic projections have already been lost. Thus, there is a need for biomarkers to monitor the earliest phases, especially for those that are at higher risk. In this work, we explore the use of machine learning methods to diagnose PD by analyzing gait alterations via an inertial sensors system that participants in the study wear while walking down a 15 m long corridor in three different scenarios. To achieve this goal, we have trained six well-known machine learning models: support vector machines, logistic regression, neural networks, k nearest neighbors, decision trees and random forest. We thoroughly explored several ways to mitigate the problems derived from the small amount of available data. We found that, while achieving accuracy rates of over 70% is quite common, the accuracy of the best model trained is only slightly above the 80% mark. This model has high precision and specificity (over 90%), but lower sensitivity (only 71%). We believe that these results are promising, especially given the size of the population sample (41 PD patients and 36 healthy controls), and that this research venue should be further explored.

Non-Apoptotic Caspase-3 Activation Mediates Early Synaptic Dysfunction of Indirect Pathway Neurons in the Parkinsonian Striatum.

Non-apoptotic caspase-3 activation is critically involved in dendritic spine loss and synaptic dysfunction in Alzheimer’s disease. It is, however, not known whether caspase-3 plays similar roles in other pathologies. Using a mouse model of clinically manifest Parkinson’s disease, we provide the first evidence that caspase-3 is transiently activated in the striatum shortly after the degeneration of nigrostriatal dopaminergic projections. This caspase-3 activation concurs with a rapid loss of dendritic spines and deficits in synaptic long-term depression (LTD) in striatal projection neurons forming the indirect pathway. Interestingly, systemic treatment with a caspase inhibitor prevents both the spine pruning and the deficit of indirect pathway LTD without interfering with the ongoing dopaminergic degeneration. Taken together, our data identify transient and non-apoptotic caspase activation as a critical event in the early plastic changes of indirect pathway neurons following dopamine denervation.

Therapeutic Applications of Induced Pluripotent Stem Cell Use in Parkinson’s Disease Models

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder resulting from the loss of particular nigrostriatal dopaminergic (DA) neuron projections. Current treatments only address the symptoms of PD and do not work to repair the causative neurodegeneration. Using both Ovid MEDLINE (n = 10) and Google Scholar (n = 10), we conducted a literature search relevant to treating the underlying causes of this disease with induced pluripotent stem cell (iPSC) therapy. In vitro studies of iPSC lines have demonstrated their ability to model neurodegeneration in DA neurons in addition to specific genetic risk factors, allowing for personalized pharmacological testing and treatment. In vivo studies have progressed over the last decade demonstrating the clinical safety and efficacy of iPSC transplantation in primate and human models. We present research that improves limitations of current methods, such as purification techniques, specific differentiation markers, cryopreservation of iPSCs, and CORIN sorting technology for large-scale production. Due to the evolution and improvement of these methods, we encourage the advancement and expansion of domestic PD-focused iPSC clinical trials.

AAV-Mediated Expression of Dominant-Negative ULK1 Increases Neuronal Survival and Enhances Motor Performance in the MPTP Mouse Model of Parkinson's Disease.

Loss of nigrostriatal projections by axonal degeneration is a key early event in Parkinson's disease (PD) pathophysiology, being accountable for the lack of dopamine in the nigrostriatal system and resulting in motor symptoms such as bradykinesia, rigidity, and tremor. Since autophagy is an important mechanism contributing to axonal degeneration, we aimed to evaluate the effects of competitive autophagy inhibition in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD in vivo. Adeno-associated viral vector (AAV)-mediated overexpression of a dominant-negative form of the unc-51 like autophagy-initiating kinase (ULK1.DN) in the substantia nigra was induced 3weeks before MPTP treatment. Analysis of motor behavior demonstrated a significant improvement of ULK1.DN expressing mice after MPTP treatment. Immunohistochemical analyses of dopaminergic nigral neurons and nigrostriatal projections revealed a significant protection from MPTP-induced neurotoxicity after ULK1.DN expression. Western blot analysis linked these findings to an activation of mTOR signaling. Taken together, our results indicate that expression of ULK1.DN can attenuate MPTP-induced axonal neurodegeneration, suggesting that ULK1 could be a promising novel target in the treatment of PD.

The Importance of Rehabilitation Treatment in Patients with Parkinson’s Disease

Parkinson’s disease (PD) is a chronic neurodegenerative disease with a slowly progressive course, having an average duration of about 15 years. It is characterized by akinesia/ bradykinesia, tremor, rigidity and postural instability. For the diagnosis of PD at least two of these four characteristics are required. There is a whole spectrum of non-motor symptoms (mood disorders, different levels of cognitive deficit, sleep disorders, fatigue, autonomic dysfunction). The patomorphologic base of PD is a disorder of the nigrostriatal dopaminergic mechanisms, metabolic damages, structural changes (hydrocephalus, tumors) or degenerative processes of presynaptic nigrostriatal dopaminergic projections or the striatum. Although the pharmacological approach is still essential, more systematic reviews and meta-analysis support the hypothesis on the positive effects of physiotherapy and intensive kinesiotherapy in PD patients. The main rehabilitation method for these patients is kinesiotherapy in its various forms, related to the individual therapeutic target, based on functional limits. Rehabilitation programs contain kinesiotherapeutic procedures for balance, posture, the range of motions- especially rotation of the trunk, strength, elongation, as well as exercise for functionally reduced motion types. The greatest emphasis in the rehabilitation process should be on the re-education of gait, which involves the optimization of initiation, speed, and length of steps. The aim of kinesiotherapy and occupational therapy is to bring the maximum functional independence of the patient and the occurrence of complications to a minimum.In neurodegenerative disorders, all modalities for improving the gait function are essentially a lifelong activity. Therapeutic strategy comes down to the combination of pharmacotherapy and neurorehabilitation methods.

Upregulation of Cysteine Protease Cathepsin X in the 6-Hydroxydopamine Model of Parkinson's Disease.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of midbrain dopaminergic neurons in the substantia nigra pars compacta (SNc). In vitro, a contribution to neuroinflammation and neurotoxicity has been shown for the lysosomal protease cathepsin X; however, its expression and its role in PD remain unknown. Therefore, the current study was designed to address the regional, cellular, and subcellular localization and activity of cathepsin X in hemi-parkinsonian rats with 6-hydroxydopamine (6-OHDA)-induced excitotoxicity in the unilateral medial forebrain bundle (MFB) lesion. We report for the first time that cathepsin X expression and activity are rapidly increased in the ipsilateral SNc after injection of 6-OHDA into the MFB reaching a maximum after 12 h but seem to stay strongly upregulated after 4 weeks after injection. At early time points of 6-OHDA injection into the MFB, the increased cathepsin X is localized in the lysosomes in the neuronal, predominantly tyrosine hydroxylase-positive dopaminergic cells. After 12 h of 6-OHDA induced lesion, only a few activated microglial cells are positive for cathepsin X whereas, in 4 weeks post-lesion accompanied with complete loss of dopaminergic neurons, there is persistent cathepsin X upregulation restricted to activated glia cells. Taken together, our results demonstrate that cathepsin X upregulation in the lesioned dopaminergic system may play a role as a pathogenic factor in PD. Moreover, inhibition of cathepsin X expression or activity may be useful in protecting the nigrostriatal dopaminergic projection in the PD.

Epothilone B Benefits Nigral Dopaminergic Neurons by Attenuating Microglia Activation in the 6-Hydroxydopamine Lesion Mouse Model of Parkinson's Disease.

Parkinson’s disease (PD) is characterized by loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and a subsequent reduction in striatal DA levels. Recent studies have shown that systemic administration of subtoxic doses of epothilone B (EpoB), a microtubule stabilizing agent, enhances axonal regeneration. However, the underlying alterations in cellular mechanisms remain undetermined. In the present study, we investigated the neuroprotective effects of EpoB on DA neurons in mouse model of PD induced by 6-hydroxyDA (6-OHDA) and in vitro. The results indicated that EpoB improved behavioral deficits, protected the nigrostriatal dopaminergic projections and restored DA level in the striatum of mice exposed to 6-OHDA. Meanwhile, EpoB attenuated microglia activation in the SNc of PD mice. Furthermore, EpoB treatment ameliorated 6-OHDA induced cytotoxicity to MN9D dopaminergic cells in a co-culture transwell system of BV2/MN9D cells, and redistributed the cytoskeleton of microglial BV2 and caused the morphological transition, inhibited the polarization to the M1 phenotype by suppressing expression of pro-inflammatory factors including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α. Overall, our study suggested that EpoB treatment protects nigral DA neurons and projections through limiting the cytotoxicity of activated microglia in 6-OHDA lesioned mice.

43. BUILDING ON GENETICS AND PATHOPHYSIOLOGY OF SCHIZOPHRENIA TO GUIDE DISCOVERY OF NEW TREATMENTS

Overall : Current treatments for schizophrenia (SCZ) are partially effective in treating positive symptoms, but many patients are refractory to available medications and they are ineffective in the treatment of negative symptoms and cognitive impairment. There is a tremendous need to develop novel approaches to the treatment of SCZ that have broader efficacy and fewer adverse effects than existing dopamine D2 receptor and mixed D2/5-HT2A antagonists. To achieve fundamental breakthroughs that provide efficacy for refractory patients and across multiple symptom domains, it will be critical to rely on rigorous studies in SCZ patients that guide development of novel treatment approaches. Major recent advances in the genetics, imaging, and molecular pathophysiology of SCZ point to new potential treatment strategies, and may guide patient selection and outcome measures. Speakers in this symposium will summarize examples of translational studies that may offer novel therapeutic approaches that have the potential to fundamentally change the standard of care for SCZ patients. Jeff Conn (Vanderbilt Univ., USA) will summarize recent genetic studies that point to loss of function mutations in two novel G protein-coupled receptors in SCZ patients, and the discovery of novel positive allosteric modulators for these receptors that are providing a strong proof of concept for advancing selective agents to clinical evaluation in patients, including those that bear these specific mutations. Brian Dean (Univ. Melbourne, Australia) will then review clinical studies showing that a subgroup of SCZ patients show a marked loss of cortical muscarinic M1 receptors and translational studies suggesting that selective activators of M1 receptors could provide benefits in treating this disorder. In addition, he will summarize changes in molecular cytoarchitecture in the cortex of subjects with SCZ that provide important insights in considering M1 activators as a treatment strategy. Clare Beasley (Univ. British Columbia, Canada), will review mounting evidence from postmortem tissue that implicates immune dysregulation and the complement system in SCZ and the potential utility of complement inhibitors in the treatment of this disorder. Finally, Anissa Abi-Dargham (Stony Brook Univ., USA) will discuss recent advances in the use of molecular imaging for discovery of patients with alterations in specific targets that may guide clinical development. Specifically, imaging studies suggest that nigro-striatal dopaminergic projections may play a more important role relative to mesolimbic dopaminergic projections than previously appreciated, and suggest a blunting of dopamine release in extra-striatal areas. These observations can be linked to clinical treatment response or particular domains of pathology and fit nicely with new data suggesting that activation of targets outlined in the first presentation selectively inhibit dopaminergic signaling in nigrostriatal but not in other dopaminergic pathways. In summary, this panel will highlight new therapeutic leads derived from novel insights gathered through imaging, genetic and molecular studies of SCZ patients.

Establishment of a novel evaluation system for dopaminergic axonal outgrowth and its regulatory factor

The nigrostriatal dopaminergic pathway is implicated with Parkinson's disease. Elucidation of this projection mechanism is not only important for considering developmental brain formation, but also contributes to the development of a therapy for regenerating the lost neural circuit. Although several axon guidance cues have been reported to induce dopaminergic axons from the substantia nigra to the striatum, the mechanisms by which the dopaminergic axons extend in the striatum remain unclear. An excellent culture system is necessary for studying the formation process of a neural circuit. Therefore, we tried to establish an in vitro model for the quantitative analysis of dopaminergic innervation of striatal neurons using primary dissociated cells. Mesencephalic cells prepared from rat embryos were seeded on the opposite side to striatal cells with the isolation wall in between. When the isolation wall was removed, the dopaminergic axons extended toward the striatal cell region and formed synapses with striatal neurons. The dopaminergic innervation of striatal neurons was suppressed by inhibiting integrin α5β1 expressed on dopaminergic neurons. Furthermore, dopaminergic neurons overexpressing integrin α5 exhibited a longer neurite outgrowth on striatal cells than normal dopaminergic neurons did. Because this evaluation system using dissociated cell culture has relatively high throughput and is easy to be pharmacologically and genetically manipulated, it is considered to be a useful tool in the study of neural circuit formation. In addition, as a result, we found integrin α5β1 as a molecule promoting striatal innervation by dopaminergic neuron, which is expected to contribute to regeneration of the nigrostriatal dopaminergic projection.

Establishment of a novel evaluation system for dopaminergic axonal outgrowth and its regulatory factor

The nigrostriatal dopaminergic pathway is implicated with Parkinson's disease. Elucidation of this projection mechanism is not only important for considering developmental brain formation, but also contributes to the development of a therapy for regenerating the lost neural circuit. Although several axon guidance cues have been reported to induce dopaminergic axons from the substantia nigra to the striatum, the mechanisms by which the dopaminergic axons extend in the striatum remain unclear. An excellent culture system is necessary for studying the formation process of a neural circuit. Therefore, we tried to establish an in vitro model for the quantitative analysis of dopaminergic innervation of striatal neurons using primary dissociated cells. Mesencephalic cells prepared from rat embryos were seeded on the opposite side to striatal cells with the isolation wall in between. When the isolation wall was removed, the dopaminergic axons extended toward the striatal cell region and formed synapses with striatal neurons. The dopaminergic innervation of striatal neurons was suppressed by inhibiting integrin α5β1 expressed on dopaminergic neurons. Furthermore, dopaminergic neurons overexpressing integrin α5 exhibited a longer neurite outgrowth on striatal cells than normal dopaminergic neurons did. Because this evaluation system using dissociated cell culture has relatively high throughput and is easy to be pharmacologically and genetically manipulated, it is considered to be a useful tool in the study of neural circuit formation. In addition, as a result, we found integrin α5β1 as a molecule promoting striatal innervation by dopaminergic neuron, which is expected to contribute to regeneration of the nigrostriatal dopaminergic projection.

Montelukast treatment protects nigral dopaminergic neurons against microglial activation in the 6-hydroxydopamine mouse model of Parkinson's disease.

Although the main cause of degeneration of the nigrostriatal dopaminergic (DA) projection in Parkinson's disease (PD) is still controversial, many reports suggest that excessive inflammatory responses mediated by activated microglia can induce neurotoxicity in the nigrostriatal DA system in vivo. Montelukast, which plays an anti-inflammatory role, is used to treat patients with asthma. In addition, recent studies have reported that its administration could reduce neuroinflammatory activities, showing beneficial effects against various neuropathological conditions. These results suggest that montelukast may be a useful drug to alleviate inflammatory responses in PD, even though there are no reports showing its beneficial effects against neurotoxicity in the nigrostriatal DA system. In the present study, our results showed that treatment with montelukast could protect DA neurons against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity and its administration significantly attenuated the production of neurotoxic cytokines such as tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) from activated microglia in the substantia nigra (SN) and striatum following 6-OHDA treatment. Therefore, we suggest that montelukast can be used as a potential inhibitor of microglial activation to protect DA neurons in the adult brain against PD.

Naringin as a beneficial natural product against degeneration of the nigrostriatal dopaminergic projection in the adult brain.

Naringin as a beneficial natural product against degeneration of the nigrostriatal dopaminergic projection in the adult brain.

Neurometabolic profiles of the substantia nigra and striatum of MPTP-intoxicated common marmosets: An in vivo proton MRS study at 9.4T.

Given the strong coupling between the substantia nigra (SN) and striatum (STR) in the early stage of Parkinson's disease (PD), yet only a few studies reported to date that have simultaneously investigated the neurochemistry of these two brain regions in vivo, we performed longitudinal metabolic profiling in the SN and STR of 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated common marmoset monkey models of PD (n=10) by using proton MRS (1 H-MRS) at 9.4T. T2 relaxometry was also performed in the SN by using MRI. Data were classified into control, MPTP_2weeks, and MPTP_6-10weeks groups according to the treatment duration. In the SN, T2 of the MPTP_6-10weeks group was lower than that of the control group (44.33±1.75 versus 47.21±2.47ms, p<0.05). The N-acetylaspartate to total creatine ratio (NAA/tCr) and γ-aminobutyric acid to tCr ratio (GABA/tCr) of the MPTP_6-10weeks group were lower than those of the control group (0.41±0.04 versus 0.54±0.08 (p<0.01) and 0.19±0.03 versus 0.30±0.09 (p<0.05), respectively). The glutathione to tCr ratio (GSH/tCr) was correlated with T2 for the MPTP_6-10weeks group (r=0.83, p=0.04). In the STR, however, GABA/tCr of the MPTP_6-10weeks group was higher than that of the control group (0.25±0.10 versus 0.16±0.05, p<0.05). These findings may be an in vivo depiction of the altered basal ganglion circuit in PD brain resulting from the degeneration of nigral dopaminergic neurons and disruption of nigrostriatal dopaminergic projections. Given the important role of non-human primates in translational studies, our findings provide better understanding of the complicated evolution of PD.

Topography of Dopamine Transporter Availability in the Cerebellar Variant of Multiple System Atrophy.

Voxel-wise comparison of [123I]-2β-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I]β-CIT) radioligand distribution measured by single-photon emission computed tomography (SPECT) revealed distinct patterns of reduced dopamine transporter (DAT) availability in the Parkinson's variant of MSA (MSA-P). The aim of this study was to identify the monoamine transporter distribution pattern in patients with the cerebellar variant of MSA (MSA-C). Additionally, monoamine transporter availability was investigated in a small cohort of patients with sporadic adult-onset ataxia (SAOA). [123I]β-CIT SPECT was performed in patients with MSA-C (n = 12), MSA-P (n = 14), SAOA (n = 5), and controls (n = 15) matched for age. Parametric images of [123I]β-CIT binding potential (BPND) were generated and analyzed by statistical parametric mapping (SPM) and region of interest (ROI) analysis. SPM localized significant reductions of [123I]β-CIT BPND in the striatum, midbrain, and pons in MSA-C compared to controls. When compared with MSA-P, the striatal DAT decline was significantly less affected in MSA-C. ROI analysis revealed reductions of striatal and midbrain [123I]β-CIT binding in MSA-C compared to SAOA, whereas no significant difference was apparent between the SAOA and control groups. Midbrain and pontine monoaminergic transporter binding was severely impaired in MSA-C, matching the underlying pathological features. Striatal DAT availability was relatively less affected in MSA-C compared to MSA-P, reflecting measureable, but less-profound, degeneration of the nigrostriatal dopaminergic projections. Preliminary results of reduced striatal and midbrain [123I]β-CIT binding in MSA-C, compared to SAOA, suggest that the potential of DAT-SPECT as a surrogate marker in the diagnostic workup of patients with adult-onset cerebellar ataxia should be further investigated.

Prothrombin Kringle-2: A Potential Inflammatory Pathogen in the Parkinsonian Dopaminergic System.

Although accumulating evidence suggests that microglia-mediated neuroinflammation may be crucial for the initiation and progression of Parkinson's disease (PD), and that the control of neuroinflammation may be a useful strategy for preventing the degeneration of nigrostriatal dopaminergic (DA) projections in the adult brain, it is still unclear what kinds of endogenous biomolecules initiate microglial activation, consequently resulting in neurodegeneration. Recently, we reported that the increase in the levels of prothrombin kringle-2 (pKr-2), which is a domain of prothrombin that is generated by active thrombin, can lead to disruption of the nigrostriatal DA projection. This disruption is mediated by neurotoxic inflammatory events via the induction of microglial Toll-like receptor 4 (TLR4) in vivo , thereby resulting in less neurotoxicity in TLR4-deficient mice. Moreover, inhibition of microglial activation following minocycline treatment, which has anti-inflammatory activity, protects DA neurons from pKr-2-induced neurotoxicity in the substantia nigra (SN) in vivo. We also found that the levels of pKr-2 and microglial TLR4 were significantly increased in the SN of PD patients compared to those of age-matched controls. These observations suggest that there may be a correlation between pKr-2 and microglial TLR4 in the initiation and progression of PD, and that inhibition of pKr-2-induced microglial activation may be protective against the degeneration of the nigrostriatal DA system in vivo. To describe the significance of pKr-2 overexpression, which may have a role in the pathogenesis of PD, we have reviewed the mechanisms of pKr-2-induced microglial activation, which results in neurodegeneration in the SN of the adult brain.

Pathogenic Upregulation of Glial Lipocalin-2 in the Parkinsonian Dopaminergic System

Lipocalin-2 (LCN2) is a member of the highly heterogeneous secretory protein family of lipocalins and increases in its levels can contribute to neurodegeneration in the adult brain. However, there are no reports on the role of LCN2 in Parkinson's disease (PD). Here, we report for the first time that LCN2 expression is increased in the substantia nigra (SN) of patients with PD. In mouse brains, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment for a neurotoxin model of PD significantly upregulated LCN2 expression, mainly in reactive astrocytes in both the SN and striatum. The increased LCN2 levels contributed to neurotoxicity and neuroinflammation, resulting in disruption of the nigrostriatal dopaminergic (DA) projection and abnormal locomotor behaviors, which were ameliorated in LCN2-deficient mice. Similar to the effects of MPTP treatment, LCN2-induced neurotoxicity was also observed in the 6-hydroxydopamine (6-OHDA)-treated animal model of PD. Moreover, treatment with the iron donor ferric citrate (FC) and the iron chelator deferoxamine mesylate (DFO) increased and decreased, respectively, the LCN2-induced neurotoxicity in vivo In addition to the in vivo results, 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity in cocultures of mesencephalic neurons and astrocytes was reduced by LCN2 gene deficiency in the astrocytes and conditioned media derived from MPP(+)-treated SH-SY5Y neuronal enhanced glial expression of LCN2 in vitro Therefore, our results demonstrate that astrocytic LCN2 upregulation in the lesioned DA system may play a role as a potential pathogenic factor in PD and suggest that inhibition of LCN2 expression or activity may be useful in protecting the nigrostriatal DA system in the adult brain. Lipocalin-2 (LCN2), a member of the highly heterogeneous secretory protein family of lipocalins, may contribute to neuroinflammation and neurotoxicity in the brain. However, LCN2 expression and its role in Parkinson's disease (PD) are largely unknown. Here, we report that LCN2 is upregulated in the substantia nigra of patients with PD and neurotoxin-treated animal models of PD. Our results suggest that LCN2 upregulation might be a potential pathogenic mechanism of PD, which would result in disruption of the nigrostriatal dopaminergic system through neurotoxic iron accumulation and neuroinflammation. Therefore, inhibition of LCN2 expression or activity may be useful in protecting the nigrostriatal dopaminergic projection in PD.

Molecular imaging of movement disorders.

Positron emission tomography measures the activity of radioactively labeled compounds which distribute and accumulate in central nervous system regions in proportion to their metabolic rate or blood flow. Specific circuits such as the dopaminergic nigrostriatal projection can be studied with ligands that bind to the pre-synaptic dopamine transporter or post-synaptic dopamine receptors (D1 and D2). Single photon emission computerized tomography (SPECT) measures the activity of similar tracers labeled with heavy radioactive species such as technetium and iodine. In essential tremor, there is cerebellar hypermetabolism and abnormal GABAergic function in premotor cortices, dentate nuclei and ventral thalami, without significant abnormalities in dopaminergic transmission. In Huntington's disease, there is hypometabolism in the striatum, frontal and temporal cortices. Disease progression is accompanied by reduction in striatal D1 and D2 binding that correlates with trinucleotide repeat length, disease duration and severity. In dystonia, there is hypermetabolism in the basal ganglia, supplementary motor areas and cerebellum at rest. Thalamic and cerebellar hypermetabolism is seen during dystonic movements, which can be modulated by globus pallidus deep brain stimulation (DBS). Additionally, GABA-A receptor activity is reduced in motor, premotor and somatosensory cortices. In Tourette's syndrome, there is hypermetabolism in premotor and sensorimotor cortices, as well as hypometabolism in the striatum, thalamus and limbic regions at rest. During tics, multiple areas related to cognitive, sensory and motor functions become hypermetabolic. Also, there is abnormal serotoninergic transmission in prefrontal cortices and bilateral thalami, as well as hyperactivity in the striatal dopaminergic system which can be modulated with thalamic DBS. In Parkinson's disease (PD), there is asymmetric progressive decline in striatal dopaminergic tracer accumulation, which follows a caudal-to-rostral direction. Uptake declines prior to symptom presentation and progresses from contralateral to the most symptomatic side to bilateral, correlating with symptom severity. In progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), striatal activity is symmetrically and diffusely decreased. The caudal-to-rostral pattern is lost in PSP, but could be present in MSA. In corticobasal degeneration (CBD), there is asymmetric, diffuse reduction of striatal activity, contralateral to the most symptomatic side. Additionally, there is hypometabolism in contralateral parieto-occipital and frontal cortices in PD; bilateral putamen and cerebellum in MSA; caudate, thalamus, midbrain, mesial frontal and prefrontal cortices in PSP; and contralateral cortices in CBD. Finally, cardiac sympathetic SPECT signal is decreased in PD. The capacity of molecular imaging to provide in vivo time courses of gene expression, protein synthesis, receptor and transporter binding, could facilitate the development and evaluation of novel medical, surgical and genetic therapies in movement disorders.

Naringin treatment induces neuroprotective effects in a mouse model of Parkinson's disease in vivo, but not enough to restore the lesioned dopaminergic system

We recently reported that treatment with naringin, a major flavonoid found in grapefruit and citrus fruits, attenuated neurodegeneration in a rat model of Parkinson's disease (PD) in vivo. In order to investigate whether its effects are universally applied to a different model of PD and whether its treatment induces restorative effects on the lesioned nigrostriatal dopaminergic (DA) projection, we observed the effects of pre-treatment or post-treatment with naringin in a mouse model of PD. For neuroprotective effects, 6-hydroxydopamine (6-OHDA) was unilaterally injected into the striatum of mouse brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. Our results showed that naringin protected the nigrostriatal DA projection from 6-OHDA-induced neurotoxicity. Moreover, similar to the effects in rat brains, this treatment induced the activation of mammalian target of rapamycin complex 1 (mTORC1), which is well known as an important survival factor for DA neurons, and inhibited microglial activation in the substantia nigra (SN) of mouse brains treated with 6-OHDA. However, there was no significant change of DA phenotypes in the SN and striatum post-treated with naringin compared with 6-OHDA-lesioned mice, despite the treatment being continued for 12 weeks. These results suggest that post-treatment with naringin alone may not be enough to restore the nigrostriatal DA projection in a mouse model of PD. However, our results apparently suggest that naringin is a beneficial natural product to prevent DA degeneration, which is involved in PD.