Nigrostriatal Dopaminergic Pathway Research Articles

Photobiomodulation Mitigates Cerebrovascular Leakage Induced by the Parkinsonian Neurotoxin MPTP.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson’s disease (PD) as it specifically damages the nigrostriatal dopaminergic pathway. Recent studies in mice have, however, provided evidence that MPTP also compromises the integrity of the brain’s vasculature. Photobiomodulation (PBM), the irradiation of tissue with low-intensity red light, mitigates MPTP-induced loss of dopaminergic neurons in the midbrain, but whether PBM also mitigates MPTP-induced damage to the cerebrovasculature has not been investigated. This study aimed to characterize the time course of cerebrovascular disruption following MPTP exposure and to determine whether PBM can mitigate this disruption. Young adult male C57BL/6 mice were injected with 80 mg/kg MPTP or isotonic saline and perfused with fluorescein isothiocyanate FITC-labelled albumin at various time points post-injection. By 7 days post-injection, there was substantial and significant leakage of FITC-labelled albumin into both the substantia nigra pars compacta (SNc; p < 0.0001) and the caudate-putamen complex (CPu; p ≤ 0.0003); this leakage partly subsided by 14 days post-injection. Mice that were injected with MPTP and treated with daily transcranial PBM (670 nm, 50 mW/cm2, 3 min/day), commencing 24 h after MPTP injection, showed significantly less leakage of FITC-labelled albumin in both the SNc (p < 0.0001) and CPu (p = 0.0003) than sham-treated MPTP mice, with levels of leakage that were not significantly different from saline-injected controls. In summary, this study confirms that MPTP damages the brain’s vasculature, delineates the time course of leakage induced by MPTP out to 14 days post-injection, and provides the first direct evidence that PBM can mitigate this leakage. These findings provide new understanding of the use of the MPTP mouse model as an experimental tool and highlight the potential of PBM as a therapeutic tool for reducing vascular dysfunction in neurological conditions.

Effect of stromal cell-derived factor-1/CXCR4 axis in neural stem cell transplantation for Parkinson's disease.

Previous studies have shown that neural stem cell transplantation has the potential to treat Parkinson's disease, but its specific mechanism of action is still unclear. Stromal cell-derived factor-1 and its receptor, chemokine receptor 4 (CXCR4), are important regulators of cell migration. We speculated that the CXCR4/stromal cell-derived factor 1 axis may be involved in the therapeutic effect of neural stem cell transplantation in the treatment of Parkinson's disease. A Parkinson's disease rat model was injected with 6-hydroxydopamine via the right ascending nigrostriatal dopaminergic pathway, and then treated with 5 μL of neural stem cell suspension (1.5 × 104/L) in the right substantia nigra. Rats were intraperitoneally injected once daily for 3 days with 1.25 mL/kg of the CXCR4 antagonist AMD3100 to observe changes after neural stem cell transplantation. Parkinson-like behavior in rats was detected using apomorphine-induced rotation. Immunofluorescence staining was used to determine the immunoreactivity of tyrosine hydroxylase, CXCR4, and stromal cell-derived factor-1 in the brain. Using quantitative real-time polymerase chain reaction, the mRNA expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra were measured. In addition, western blot assays were performed to analyze the protein expression of stromal cell-derived factor-1 and CXCR4. Our results demonstrated that neural stem cell transplantation noticeably reduced apomorphine-induced rotation, increased the mRNA and protein expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra, and enhanced the immunoreactivity of tyrosine hydroxylase, CXCR4, and stromal cell-derived factor-1 in the brain. Injection of AMD3100 inhibited the aforementioned effects. These findings suggest that the stromal cell-derived factor-1/CXCR4 axis may play a significant role in the therapeutic effect of neural stem cell transplantation in a rat model of Parkinson's disease. This study was approved by the Animal Care and Use Committee of Kunming Medical University, China (approval No. SYXKK2015-0002) on April 1, 2014.

Cytosolic non-vesicular dopamine accumulation as the predominant mechanism for developing non-DOPA responsive parkinsonism in late-stage Huntington disease

Disturbances in motor movement can have similar clinical presentations, albeit having different pathways and temporal onset. Hypokinetic movements present with rigidity, resting tremors, postural instability and bradykinesia, as seen in parkinsonism, while hyperkinetic movements typically present with chorea, ballismus, tic, athetosis and dystonia. Nonetheless, movement disorders are thought to be a continuum. Long-term therapy of parkinsonism with L-DOPA or dopamine (DA) agonists leads to late-onset dyskinesia – a hyperkinetic movement disorder, while patients with late-stage Huntington disease (HD) often develop non-DOPA responsive parkinsonism. In this paper, it is proposed that late-onset parkinsonism is driven by the overactivity of the nigrostriatal dopaminergic pathway. The excessive synthesis, storage, release, reuptake and degradation of dopamine in the presynaptic terminal and synaptic clefts lead to cellular stress and damage, resulting to progressive neuroapoptosis aggravated by pro-parkinsonism drugs used to treat hyperkinesia. Glutamate excitotoxicity may provide initial stress to neurons during early HD – but as the disease advances, lower glutamate levels are observed, making it less likely to cause the hypokinetic shift on its own. Over time, dopaminergic neurons are depleted and cholinergic influence to striatal GABA release is unopposed, leading to late-onset parkinsonism that is unresponsive to DOPA challenge, due to drastic DA neuron loss previously masked by the dominating choreic presentation. This paper thus provides a mechanism of action to a common clinical sequela and complication of long-term choreic diseases, whose pathophysiologic mechanism is presently lacking.

Mice deficient in protein tyrosine phosphatase receptor type Z (PTPRZ) show reduced responsivity to methamphetamine despite an enhanced response to novelty.

Methamphetamine (METH), a commonly abused drug, elevates extracellular dopamine (DA) levels by inducing DA efflux through the DA transporter (DAT). Emerging evidence in rodent models suggests that locomotor responses to a novel inescapable open field may predict behavioral responses to abused drugs; METH produces more potent stimulant effects in high responders to novelty than in low responders. We herein found that mice deficient in protein tyrosine phosphatase receptor type Z (Ptprz-KO) exhibited an enhanced behavioral response to novelty; however, METH-induced hyperlocomotion was significantly lower in Ptprz-KO than in wild-type mice when METH was administered at a non-toxic dose of 1 mg per kg body weight (bdw). Single-cell RT-PCR revealed that the majority of midbrain DA neurons expressed PTPRZ. No histological alterations were observed in the mesolimbic or nigrostriatal dopaminergic pathways in Ptprz-KO brains; however, a significant decrease was noted in brain DA turnover, suggesting functional alterations. In vivo microdialysis experiments revealed that METH-evoked DA release in the nucleus accumbens was significantly lower in Ptprz-KO mice than in wild-type mice. Consistent with this result, Ptprz-KO mice showed significantly fewer cell surface DAT as well as weaker DA uptake activity in striatal synaptosomes prepared 1 hr after the administration of METH than wild-type mice, while no significant differences were observed in the two groups treated with saline. These results indicate that the high response phenotype of Ptprz-KO mice to novelty may not be simply attributed to hyper-dopaminergic activity, and that deficits in PTPRZ reduce the effects of METH by reducing DAT activity.

Methyl jasmonate abrogates rotenone-induced parkinsonian-like symptoms through inhibition of oxidative stress, release of pro-inflammatory cytokines, and down-regulation of immnopositive cells of NF-κB and α-synuclein expressions in mice

Oxidative stress and neuroinflammation play key roles in the initiation and progression of Parkinson's disease (PD), a neurodegenerative disorder, associated with the loss of nigrostriatal dopaminergic pathway. Thus, compounds that can mitigate oxidative stress and neuroinflammation are being investigated as promising agents for the treatment of PD. This study was designed to evaluate the effects of methyl jasmonate (MJ), a potent antioxidant and anti-inflammatory compound on parkinsonian-like symptoms and the underlying biochemical changes induced by rotenone (Rot) in mice. To this end, the effects of graded doses of MJ (25, 50 and100 mg/kg, i.p.) on motor dysfunctions, cognitive and depressive-like disorders induced by Rot (2.5 mg/kg, i.p.) were evaluated. The specific brain regions (striatum, prefrontal cortex and hippocampus) of the animals were processed for various biochemical studies. Rot-treated mice showed reduced motor activity, postural instability, cognitive and depressive-like disorders. Rot also increased brain levels of malondialdehyde (MDA), nitrite, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and acetyl-cholinesterase (AChE) activity. Moreover, Rot reduced the concentration of glutathione (GSH) and increased immnopositive cells of NF-κB and α-synuclein expressions in these brain regions. However, pretreatment with MJ, attenuated the parkinsonian-like symptoms and reduced the brain levels of MDA/nitrite, TNF-α and IL-6 induced by Rot. MJ also reduced AChE activity and down-regulate the expressions of NF-κB and α-synuclein in the brain of Rot-treated mice. These findings suggest that MJ has anti-parkinsonian-like activity, which may be related to the inhibition of oxidative stress, release of pro-inflammatory cytokines, and down regulation of NF-κB and α-synuclein expressions.

Remote Monitoring of Treatment Response in Parkinson's Disease: The Habit of Typing on a Computer.

The recent advances in technology are opening a new opportunity to remotely evaluate motor features in people with Parkinson's disease (PD). We hypothesized that typing on an electronic device, a habitual behavior facilitated by the nigrostriatal dopaminergic pathway, could allow for objectively and nonobtrusively monitoring parkinsonian features and response to medication in an at-home setting. We enrolled 31 participants recently diagnosed with PD who were due to start dopaminergic treatment and 30 age-matched controls. We remotely monitored their typing pattern during a 6-month (24 weeks) follow-up period before and while dopaminergic medications were being titrated. The typing data were used to develop a novel algorithm based on recursive neural networks and detect participants' responses to medication. The latter were defined by the Unified Parkinson's Disease Rating Scale-III (UPDRS-III) minimal clinically important difference. Furthermore, we tested the accuracy of the algorithm to predict the final response to medication as early as 21 weeks prior to the final 6-month clinical outcome. The score on the novel algorithm based on recursive neural networks had an overall moderate kappa agreement and fair area under the receiver operating characteristic (ROC) curve with the time-coincident UPDRS-III minimal clinically important difference. The participants classified as responders at the final visit (based on the UPDRS-III minimal clinically important difference) had higher scores on the novel algorithm based on recursive neural networks when compared with the participants with stable UPDRS-III, from the third week of the study onward. This preliminary study suggests that remotely gathered unsupervised typing data allows for the accurate detection and prediction of drug response in PD. © 2019 International Parkinson and Movement Disorder Society.

Sex-related pattern of intrinsic brain connectivity in drug-naïve Parkinson's disease patients.

Sex difference is related to specific clinical features in PD patients over the disease course. To investigate the potential sex-difference effect on the spontaneous neuronal activity within the most reported resting-state networks in early untreated PD patients and its correlation with baseline and longitudinal clinical features. Fifty-six drug-naïve PD patients (30/26 male/female) and 30 (15/15 male/female) matched controls were enrolled in the study. Topological and spectral resting-state functional MRI features of the sensorimotor, dorsal and ventral attention, frontoparietal, and default-mode networks were analyzed for possible sex-difference effects in both PD patients and controls groups. Additionally, a region-of-interest analysis was performed to test for a sex effect on basal ganglia connectivity. Multivariate ordinal regression was used to investigate whether connectivity findings at baseline were predictors of motor impairment over a 2-year follow-up period. Compared to female PD patients and controls, male PD patients showed an abnormal spectral composition of the sensorimotor and dorsal attention networks in the slow-5 band. The region-of-interest analysis showed an increased connectivity within the basal ganglia in female PD patients compared to males. Functional sensorimotor connectivity changes at baseline showed to be an independent predictor of disease severity at 2-year follow-up. Our findings revealed the presence of a disease-related, sex-specific cortical and subcortical connectivity pattern within the sensorimotor network, in the early stage of PD. We hypothesize that these findings may be related to the presence of different sex-specific nigrostriatal dopaminergic pathways and might predict PD progression. © 2019 International Parkinson and Movement Disorder Society.

Amelioration of the nigrostriatal pathway facilitated by ultrasound-mediated neurotrophic delivery in early Parkinson's disease

The blood-brain barrier (BBB) prevents most drugs from gaining access to the brain parenchyma, which is a recognized impediment to the treatment of neurodegenerative disorders like Parkinson's disease (PD). Focused ultrasound (FUS), in conjunction with systemically administered microbubbles, opens the BBB locally, reversibly and non-invasively. Herein, we show that neither FUS applied over both the striatum and the ventral midbrain, without neurotrophic factors, nor intravenous administration of neurotrophic factors (either through protein or gene delivery) without FUS, ameliorates the damage to the nigrostriatal dopaminergic pathway in the sub-acute MPTP mouse model of early-stage PD. Conversely, the combination of FUS and intravenous neurotrophic (protein or gene) delivery attenuates the damage to the nigrostriatal dopaminergic pathway, by allowing the entry of these agents into the brain parenchyma. Our findings provide evidence that the application of FUS at the early stages of PD facilitates critical neurotrophic delivery that can curb the rapid progression of neurodegeneration while improving the neuronal function, seemingly opening new therapeutic avenues for the early treatment of diseases of the central nervous system.

Disturbed neurotransmitter homeostasis in ether lipid deficiency.

Plasmalogens, the most prominent ether (phospho)lipids in mammals, are structural components of most cellular membranes. Due to their physicochemical properties and abundance in the central nervous system, a role of plasmalogens in neurotransmission has been proposed, but conclusive data are lacking. Here, we targeted this issue in the glyceronephosphate O-acyltransferase (Gnpat) KO mouse, a model of complete deficiency in ether lipid biosynthesis. Throughout the study, focusing on adult male animals, we found reduced brain levels of various neurotransmitters. In the dopaminergic nigrostriatal tract, synaptic endings but not neuronal cell bodies were affected. Neurotransmitter turnover was altered in ether lipid-deficient murine as well as human post-mortem brain tissue. A generalized loss of synapses did not account for the neurotransmitter deficits, since the levels of several presynaptic proteins appeared unchanged. However, reduced amounts of vesicular monoamine transporter indicate a compromised vesicular uptake of neurotransmitters. As exemplified by norepinephrine, the release of neurotransmitters from Gnpat KO brain slices was diminished in response to strong electrical and chemical stimuli. Finally, addressing potential phenotypic correlates of the disturbed neurotransmitter homeostasis, we show that ether lipid deficiency manifests as hyperactivity and impaired social interaction. We propose that the lack of ether lipids alters the properties of synaptic vesicles leading to reduced amounts and release of neurotransmitters. These features likely contribute to the behavioral phenotype of Gnpat KO mice, potentially modeling some human neurodevelopmental disorders like autism or attention deficit hyperactivity disorder.

Effects of Silibinin Against Prothrombin Kringle-2-Induced Neurotoxicity in the Nigrostriatal Dopaminergic System In Vivo.

Parkinson's disease (PD) and Alzheimer's disease exhibit common features of neurodegenerative diseases and can be caused by numerous factors. A common feature of these diseases is neurotoxic inflammation by activated microglia, indicating that regulation of microglial activation is a potential mechanism for preserving neurons in the adult brain. Recently, we reported that upregulation of prothrombin kringle-2 (pKr-2), one of the domains that make up prothrombin and which is cleaved and generated by active thrombin, induces nigral dopaminergic (DA) neuronal death through neurotoxic microglial activation in the adult brain. In this study, we show that silibinin, a flavonoid found in milk thistle, can suppress the production of inducible nitric oxide synthase and neurotoxic inflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, after pKr-2 treatment by downregulating the extracellular signal-regulated kinase signaling pathway in the mouse substantia nigra. Moreover, as demonstrated by immunohistochemical staining, measurements of the dopamine and metabolite levels, and open-field behavioral tests, silibinin treatment protected the nigrostriatal DA system resulting from the occurrence of pKr-2-triggered neurotoxic inflammation in vivo. Thus, we conclude that silibinin may be beneficial as a natural compound with anti-inflammatory effects against pKr-2-triggered neurotoxicity to protect the nigrostriatal DA pathway and its properties, and thus, may be applicable for PD therapy.

Complementary motivational roles of nigroaccumbens and nigrostriatal dopaminergic pathways.

Movement DisordersVolume 34, Issue 1 p. 45-45 Hot Topics Complementary motivational roles of nigroaccumbens and nigrostriatal dopaminergic pathways Roger L. Albin MD, Corresponding Author Roger L. Albin MD ralbin@umich.edu Neurology Service & Geriatrics Research, Education, and Clinical Center, Veterans Affairs Ann Arbor Health System and Department of Neurology, University of Michigan, Ann Arbor, Michigan, USACorrespondence to: Roger L. Albin, 5023 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200; ralbin@umich.eduSearch for more papers by this author Roger L. Albin MD, Corresponding Author Roger L. Albin MD ralbin@umich.edu Neurology Service & Geriatrics Research, Education, and Clinical Center, Veterans Affairs Ann Arbor Health System and Department of Neurology, University of Michigan, Ann Arbor, Michigan, USACorrespondence to: Roger L. Albin, 5023 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200; ralbin@umich.eduSearch for more papers by this author First published: 17 January 2019 https://doi.org/10.1002/mds.27504Citations: 2 Relevant conflicts of interest/financial disclosures: none. Funding agencies: P50NS091856, P30AG053760, Michael J. Fox Foundation. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume34, Issue1January 2019Pages 45-45 RelatedInformation

Sleep-State Dependent Alterations in Brain Functional Connectivity under Urethane Anesthesia in a Rat Model of Early-Stage Parkinson's Disease.

Parkinson’s disease (PD) is characterized by the gradual degeneration of dopaminergic neurons in the substantia nigra, leading to striatal dopamine depletion. A partial unilateral striatal 6-hydroxydopamine (6-OHDA) lesion causes 40–60% dopamine depletion in the lesioned rat striatum, modeling the early stage of PD. In this study, we explored the connectivity between the brain regions in partially 6-OHDA lesioned male Wistar rats under urethane anesthesia using functional magnetic resonance imaging (fMRI) at 5 weeks after the 6-OHDA infusion. Under urethane anesthesia, the brain fluctuates between the two states, resembling rapid eye movement (REM) and non-REM sleep states. We observed clear urethane-induced sleep-like states in 8/19 lesioned animals and 8/18 control animals. 6-OHDA lesioned animals exhibited significantly lower functional connectivity between the brain regions. However, we observed these differences only during the REM-like sleep state, suggesting the involvement of the nigrostriatal dopaminergic pathway in REM sleep regulation. Corticocortical and corticostriatal connections were decreased in both hemispheres, reflecting the global effect of the lesion. Overall, this study describes a promising model to study PD-related sleep disorders in rats using fMRI.

Neurotransplantation: the time has come?

Problems in curing disorders of the brain are caused by several characteristic features of the nervous tissue, such as postmitotic nature of neurons, their limited reparative potential, significant energy dependence, etc. Because of special vulnerability and extremely high specialization, neurons are very sensitive to the action of any pathological factors, while existing possibilities of their trophic and metabolic support are scanty. Therefore, the creation of new reparative strategies, including substitutive cell technologies, is immediate task in neurology. Neurodegenerative disorders, Parkinson’s disease (PD), Huntington’s disease and others, are an “ideal” model for elaborating such strategies. As main motor symptoms of PD are related to degeneration of the dopaminergic nigrostriatal pathway, treatment of these patients, theoretically, may be based on transplantation of dopamine-producing neurons into the striatum. In the paper, analyzed are the results of many-year experimental (on models of parkinsonism) and preliminary clinical trials of neurotransplantation with the use of fetal tissues (dopaminergic cells of the ventral midbrain) and dopaminergic neurons differentiated from embryonal stem cells and induced pluripotent. Newest scientific achievements in this field, improvement of cell protocols and successful resolving of a number of technical and medical problems allow saying that neurotransplantation becomes clinical reality just before our eyes.

Imaging of Motor Cortex Physiology in Parkinson's Disease.

ABSTRACTThere is abundant evidence that the pathophysiology of Parkinson's disease (PD) is not confined to the nigrostriatal dopaminergic pathway but propagates along the cortico‐basal ganglia‐thalamo‐cortical neural network. A critical node in this functional circuit impacted by PD is the primary motor cortex (M1), which plays a key role in generating neural impulses that regulate movements. The past several decades have lay witness to numerous in vivo neuroimaging techniques that provide a window into the function and structure of M1. A consistent observation from numerous studies is that during voluntary movement, but also at rest, the functional activity of M1 is altered in PD relative to healthy individuals, and it relates to many of the motor signs. Although this abnormal functional activity can be partially restored with acute dopaminergic medication, it continues to deteriorate with disease progression and may predate structural degeneration of M1. The current review discusses the evidence that M1 is fundamental to the pathophysiology of PD, as measured by neuroimaging techniques such as positron emission tomography, single‐photon emission computed tomography, electroencephalography, magnetoencephalography, and functional and structural MRI. Although novel treatments that target the cortex will not cure PD, they could significantly slow down and alter the progressive course of the disease and thus improve clinical care for this degenerative disease. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Protein kinase C ζ‐dependent upregulation of GDNF by metformin

Parkinson's disease is the second most common neurodegenerative disorder characterized by prominent loss of the dopaminergic neurons in the substantia nigra (SN). The substantial demise of the dopaminergic neurons in the SN is followed by depletion of dopamine in the striatum manifesting typical motor symptoms including resting tremor, bradykinesia, and rigidity. In spite of effort to develop therapies for the disease, there is still no way to cure or halt the neurodegeneration. Recently, we have demonstrated that metformin rescued the nigrostriatal dopaminergic pathway from MPTP neurotoxicity by inducing neurotrophic factors. In this study, we attempted to address how metformin upregulates neurotrophic factors in the brain which might contribute to the neuroprotection. We observed the increase in the levels of brain derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF) in the SN and striatum of C57BL6 mice via immunohistochemistry and western blotting. These results were recapitulated in vitro study using SH‐SY5Y cells. Upregulation of the neurotrophic factors was accompanied by the activation of AKT/ERK/CREB pathway. Furthermore, we found that inhibition of protein kinase (PK) C ζ attenuated metformin‐induced GDNF elevation, but not BDNF. Tyrosine hydroxylase phosphorylation by metformin was also blocked by PKC ζ inhibition. These results suggest that metformin increase GDNF through induction of PKC ζ activity, which might exert neuroprotection. Although further research is required to identify the metformin's action mechanism, metformin might be a potential neuroprotective therapy for Parkinson's disease treatment.Support or Funding InformationThis work was supported by the Korea Foundation for the Advancement of Science &amp; Creativity (KOFAC) grant funded by the Korean Government.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Influence of the DRD2/ANKK1 Taq1A polymorphism on caudate volume in older adults without dementia

Dopaminergic neuromodulation is critically important for brain and cognitive integrity. The DRD2/ANKK1 Taq1A polymorphism is associated with striatal dopamine (DA) D2 receptor availability. Some previous studies have found that the A allele of the Taq1A polymorphism influences brain structure, but the results are inconsistent, likely due to population heterogeneity and small sample sizes. We investigated the genetic effect on caudate volume in a large sample of older adults without dementia. Results show that A-allele carriers have smaller caudate volume compared to non-carriers in relatively older adults (n = 167; Mage = 77.8 years), whereas the genotype did not influence caudate volume in a younger age group (n = 220; Mage = 62.8 years). Cognitive performance was not significantly affected by the DRD2 gene. Our findings extend previous observations by showing magnified genetic effects on brain volume in old age, and provide evidence for a link between a DA-related genetic polymorphism and grey matter volume in a brain region within the nigrostriatal dopaminergic pathway.

Serum metabolomics study in a group of Parkinson's disease patients from northern India

BackgroundParkinson's disease (PD) is the result of progressive degeneration of the nigrostriatal dopaminergic pathway and depletion of neurotransmitter dopamine in the striatum. MethodsWe included 17 patients with PD along with 7 patients of progressive supranuclear palsy (PSP), 6 patients of multiple system atrophy (MSA) and 22 age and sex-matched healthy controls. We analyzed metabolite profiles in the serum of these patients and controls using 1H NMR spectroscopy. ResultsIsoleucine, valine, alanine, glutamine and histidine in PD, PSP and MSA were significantly (P < 0.001) higher than controls, whereas, glutamate and glucose were significantly increased in PD (P < 0.001), PSP and MSA (P < 0.05) vs. control. Citrate was increased in PD, PSP and MSA (P < 0.05) vs. control. While, acetone, lactate and formate were higher at P < 0.001, threonine is increased at P < 0.05. The 3D scattered score plot of OPLS-DA model revealed clear differentiation among the groups, R2 = 0.92 and Q2 = 0.78. ConclusionSignificant differences in various metabolite levels were found between control and disease groups. Common amino acids that are significantly higher in all groups include branched chain amino acids, which could increase neuronal excitability.

Brain structural changes in cynomolgus monkeys administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: A longitudinal voxel-based morphometry and diffusion tensor imaging study.

In animal models of Parkinson's disease (PD), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the most widely used agents that damages the nigrostriatal dopaminergic pathway. However, brain structural changes in response to MPTP remain unclear. This study aimed to investigate in vivo longitudinal changes in gray matter (GM) volume and white matter (WM) microstructure in primate models administered with MPTP. In six cynomolgus monkeys, high-resolution magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) scans were acquired 7 times over 32 weeks, and assessments of motor symptoms were conducted over 15 months, before and after the MPTP injection. Changes in GM volume and WM microstructure were estimated on a voxel-by-voxel basis. Mixed-effects regression models were used to examine the trajectories of these structural changes. GM volume initially increased after the MPTP injection and gradually decreased in the striatum, midbrain, and other dopaminergic areas. The cerebellar volume temporarily decreased and returned to its baseline level. The rate of midbrain volume increase was positively correlated with the increase rate of motor symptom severity (Spearman rho = 0.93, p = 0.008). Mean, axial, and radial diffusivity in the striatum and frontal areas demonstrated initial increases and subsequent decreases. The current multi-modal imaging study of MPTP-administered monkeys revealed widespread and dynamic structural changes not only in the nigrostriatal pathway but also in other cortical, subcortical, and cerebellar areas. Our findings may suggest the need to further investigate the roles of inflammatory reactions and glial activation as potential underlying mechanisms of these structural changes.

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.

Neuroimaging Applications in Restless Legs Syndrome.

Neuroimaging studies provide information useful to understand the pathophysiology of restless legs syndrome. Molecular PET and SPECT imaging findings mainly supported dysfunction of dopaminergic pathways involving not only the nigrostriatal but also mesolimbic pathways. Magnetic resonance imaging (MRI) studies have used different techniques. Studies using iron-sensitive sequences supported the presence of a regionally variable low brain iron content, mainly at the level of substantia nigra and thalamus. The search for brain structural or microstructural abnormalities by voxel-based morphometry, diffusion tensor imaging or cortical thickness analysis has reported none or variable findings in restless legs syndrome patients, most of them in regions belonging to sensorimotor and limbic/nociceptive networks. Functional MRI studies have substantially demonstrated activation or connectivity changes in the same networks. Magnetic resonance spectroscopy studies showed metabolic changes in the thalamus, which is a hub of these networks. In summary, neuroimaging findings in restless legs syndrome support the presence of reduction of brain iron content, of dysfunction of mesolimbic and nigrostriatal dopaminergic pathways, and of abnormalities at level of limbic/nociceptive and sensorimotor networks.