Nigrostriatal Dopamine Depletion Research Articles

Rewarding properties of L-Dopa in experimental parkinsonism are mediated by sensitized dopamine D1 receptors in the dorsal striatum.

Treatment of Parkinson's disease (PD) is based on the use of dopaminergic drugs, such as L-Dopa and dopamine receptor agonists. These substances counteract motor symptoms, but their administration is accompanied by motor and non-motor complications. Among these latter conditions a neurobehavioral disorder similar to drug abuse, known as dopamine dysregulation syndrome (DDS), is attracting increasing interest because of its profound negative impact on the patients' quality of life. Here we replicate DDS in a PD mouse model based on a bilateral injection of 6-hydroxydopamine (6-OHDA) into the dorsal striatum. Administration of L-Dopa induced locomotor sensitization and conditioned place preference in 6-OHDA lesion, but not in control mice, indicative of the acquisition of addictive-like properties following nigrostriatal dopamine depletion. These behavioral effects were accompanied by abnormal dopamine D1 receptor (D1R) signaling in the medium spiny neurons of the dorsal striatum, leading to hyperactivation of multiple signaling cascades and increased expression of ΔFosB, a stable transcription factor involved in addictive behavior. Systemic administration of the D1R antagonist, SCH23390, abolished these effects and the development of place preference, thereby counteracting the psychostimulant-like effect of L-Dopa. The rewarding properties of L-Dopa were also prevented by chemogenetic inactivation of D1R-expressing neurons in the dorsal striatum. Our results indicate the association between abnormal D1R-mediated transmission and DDS in PD and identify potential approaches for the treatment of this disorder.

Machine Learning Identifies a Rat Model of Parkinson’s Disease via Sleep-Wake Electroencephalogram

Alpha-synuclein induced degeneration of the midbrain substantia nigra pars compact (SNc) dopaminergic neurons causes Parkinson’s disease (PD). Rodent studies demonstrate that nigrostriatal dopamine stimulates pallidal neurons which, via the topographical pallidocortical pathway, regulate cortical activity and functions. We hypothesize that nigrostriatal dopamine acting at the basal ganglia regulates cortical activity in sleep and wake state, and its depletion systemically alters electroencephalogram (EEG) across frequencies during sleep-wake state. Compared to control rats, 6-hydroxydopamine induced selective SNc lesions increased overall EEG power (positive synchronization) across 0.5–60 Hz during wake, NREM (non-rapid eye movement) sleep, and REM sleep. Application of machine learning (ML) to seven EEG features computed at a single or combined spectral bands during sleep-wake differentiated SNc lesions from controls at high accuracy. ML algorithms construct a model based on empirical data to make predictions on subsequent data. The accuracy of the predictive results indicate that nigrostriatal dopamine depletion increases global EEG spectral synchronization in wake, NREM sleep, and REM sleep. The EEG changes can be exploited by ML to identify SNc lesions at a high accuracy.

Coronarin D attenuates MPTP-induced Parkinson’s disease in mice by inhibition of oxidative stress and apoptosis

Parkinson’s disease (PD) is a brain-related disease condition, globally it is the second most common neurodegenerative disease that mostly disturbs the brain motor control and action of the aged populations. It involves a tiny, dark portion of the brain denoted as substantia nigra. Dopamine is produced in the substantia nigra for the usage of the brain. This dopamine communicates messages among nerves and controls muscle movements. Coronarin D is a diterpenoid with exclusive pharmacological possessions and its effectiveness over a few neurogenerative diseases exposed to some intense properties. The present study was intended to exhibit the neuroprotective efficacy of Coronarin D over MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced animals. Oral management of Coronarin D (10 and 20 mg/kg body wt.) protects the MPTP-induced nigrostriatal dopamine (DA) depletion and its intermediate substances. Behavioral studies like narrow beam walk test, open field test and hang test were conducted to study the movement and actions of Coronarin D treated MPTP induced experimental animals, in which Coronarin D treated group III & IV animals showed better behavioral alterations. Our compound as well attenuated MPTP persuaded oxidative pressure in experimental animals. Apoptotic marker studies displayed that management with Coronarin D upturned MPTP induced programmed cell death, which might be its anti-apoptotic properties. Ultimately to conclude, Coronarin D recovered oxidative pressure, neurochemical alterations, apoptosis, and functional irregularities in investigational mice and propose a potential approach to disease management of neurodegenerative and its related disease.

Potential Link Between Cognition and Motor Reserve in Patients With Parkinson's Disease.

Objective To investigate whether there is a link between cognitive function and motor reserve (i.e., individual capacity to cope with nigrostriatal dopamine depletion) in patients with newly diagnosed Parkinson’s disease (PD).Methods A total of 163 patients with drug-naïve PD who underwent 18F-FP-CIT PET, brain MRI, and a detailed neuropsychological test were enrolled. We estimated individual motor reserve based on initial motor deficits and striatal dopamine depletion using a residual model. We performed correlation analyses between motor reserve estimates and cognitive composite scores. Diffusion connectometry analysis was performed to map the white matter fiber tracts, of which fractional anisotropy (FA) values were well correlated with motor reserve estimates. Additionally, Cox regression analysis was used to assess the effect of initial motor reserve on the risk of dementia conversion.Results The motor reserve estimate was positively correlated with the composite score of the verbal memory function domain (γ = 0.246) and with the years of education (γ = 0.251). Connectometry analysis showed that FA values in the left fornix were positively correlated with the motor reserve estimate, while no fiber tracts were negatively correlated with the motor reserve estimate. Cox regression analysis demonstrated that higher motor reserve estimates tended to be associated with a lower risk of dementia conversion (hazard ratio, 0.781; 95% confidence interval, 0.576–1.058).Conclusion The present study demonstrated that the motor reserve estimate was well correlated with verbal memory function and with white matter integrity in the left fornix, suggesting a possible link between cognition and motor reserve in patients with PD.

Identifying the white matter structural network of motor reserve in early Parkinson's disease

IntroductionMotor reserve refers to the individual capacity to cope with nigrostriatal dopamine depletion in Parkinson's disease (PD). This study aimed to explore the white matter structural network associated with motor reserve in patients with newly diagnosed PD. MethodsA total of 238 patients with early-stage drug-naïve PD who underwent 18F-FP-CIT PET and brain MRI scans at initial assessment were enrolled. We estimated individual motor reserve based on the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) scores and dopamine transporter availability in the posterior putamen using a residual model. Then, we performed threshold-free network-based statistics (TFNBS) analysis to identify the structural brain network associated with the estimated motor reserve. We also assessed the effect of the network connectivity strength on the longitudinal increase in levodopa-equivalent dose (LED). ResultsThe mean age at PD symptom onset was 69.10 ± 9.03 years and the mean UPDRS-III score at the time of PD diagnosis was 22.44 ± 9.72. TFNBS analysis identified a motor reserve-associated structural network whose nodes were mainly in the frontal region and cerebellum. Higher network strength (i.e., greater motor reserve) was associated with a slower longitudinal increase in LED during a 3-year follow-up period. ConclusionThe structural brain network is associated with motor reserve in patients with PD. Connectivity strength within the identified network indicates the individual's capacity to tolerate PD-related pathologies, which is maintained with disease progression and affects the long-term motor prognosis of PD.

Dopamine-Related Reduction of Semantic Spreading Activation in Patients With Parkinson's Disease.

Impaired performance in verbal fluency (VF) tasks is a frequent observation in Parkinson’s disease (PD). As to the nature of the underlying cognitive deficit, it is commonly attributed to a frontal-type dysexecutive syndrome due to nigrostriatal dopamine depletion. Whereas dopaminergic medication typically improves VF performance in PD, e.g., by ameliorating impaired lexical switching, its effect on semantic network activation is unclear. Data from priming studies suggest that dopamine causes a faster decay of semantic activation spread. The aim of the current study was to examine the impact of dopaminergic medication on the dynamic change of word frequency during VF performance as a measure of semantic spreading activation. To this end, we performed a median split analysis of word frequency during phonemic and semantic VF task performance in a PD group tested while receiving dopaminergic medication (ON) as well as after drug withdrawal (i.e., OFF), and in a sample of age-matched healthy volunteers (both groups n = 26). Dopaminergic medication in the PD group significantly affected phonemic VF with improved word production as well as increased error-rates. The expected decrease of word frequency during VF task performance was significantly smaller in the PD group ON medication than in healthy volunteers across semantic and phonemic VF. No significant group-difference emerged between controls and the PD group in the OFF condition. The comparison between both treatment conditions within the PD group did not reach statistical significance. The observed pattern of results indicates a faster decay of semantic network activation during lexical access in PD patients on dopaminergic medication. In view of improved word generation, this finding is consistent with a concept of more focused neural activity by an increased signal-to-noise ratio due to dopaminergic neuromodulation. However, the effect of dopaminergic stimulation on VF output suggests a trade-off between these beneficial effects and increased error-rates.

Interrelation of striatal dopamine, brain metabolism and cognition in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB), the second most common neurodegenerative dementia, is characterized by cognitive decline, fluctuation of cognition and alertness, visual hallucinations, rapid eye movement sleep behaviour disorder and parkinsonism. Imaging biomarkers are of great importance in diagnosing patients with DLB and associated with characteristic clinical features including cognitive decline. In this study, we investigate interrelation between nigrostriatal dopamine depletion, brain metabolism and cognition in DLB. We enrolled 55 patients with probable DLB (15 with prodromal DLB and 40 with DLB) and 13 healthy controls. All subjects underwent N-(3-[18F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane PET/CT, 18F-fluorodeoxyglucose PET/CT, 18F-florbetaben PET/CT and detailed neuropsychological testing. The relationship between striatal dopamine transporter availability and regional brain metabolism was assessed using general linear models, and the effect of striatal dopamine transporter availability and brain metabolism on specific cognitive function was evaluated by multivariate linear regression analysis. Path analyses were used to evaluate the relationship between striatal dopamine transporter availability, fluorodeoxyglucose uptake and cognitive function scores. Additionally, a linear mixed model was used to investigate the association between baseline dopamine transporter availability or brain metabolism and longitudinal cognitive decline. Independent of amyloid deposition, caudate and putamen dopamine transporter availabilities were positively correlated with brain metabolism in the DLB-specific hypometabolic regions, most prominently in the occipital and lateral parietal cortices. Both reduced caudate dopamine and brain hypometabolism were associated with low z-scores of Rey-Osterrieth Complex Figure Test copy, Seoul Verbal Learning Test immediate recall and Controlled Oral Word Association Test (COWAT)-animal. Path analyses showed that the effect of reduced caudate dopamine on the Rey-Osterrieth Complex Figure Test copy z-score was completely mediated by brain hypometabolism, whereas it affected the Seoul Verbal Learning Test immediate recall z-score both directly and via the mediation of brain hypometabolism. Caudate dopamine depletion was directly associated with the COWAT-animal z-score, not mediated by brain hypometabolism. Both baseline caudate dopamine transporter availability and brain hypometabolism were associated with longitudinal cognitive decline, with brain hypometabolism being more relevant. Our findings suggest that in DLB, striatal dopaminergic depletion and brain hypometabolism are closely related, and they differentially affect cognitive dysfunction in an item-specific manner. Additionally, brain hypometabolism would be more relevant to longitudinal cognitive outcomes than striatal dopaminergic degeneration.

Glucocerebrosidase Mutations and Motor Reserve in Parkinson's Disease.

The concept of motor reserve explains the individual differences in motor deficits despite similar degrees of nigrostriatal dopamine depletion in Parkinson's disease (PD). To investigate glucocerebrosidase (GBA) variants as potential determinants of motor reserve for exploratory purposes. A total of 408 patients with drug-naïve PD were enrolled from the Parkinson's Progression Markers Initiative cohort database. All patients underwent SPECT dopamine transporter (DAT) scans and had results for Sanger sequencing of GBA. Parkinsonian motor deficits were assessed using the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III). We compared MDS-UPDRS-III scores while adjusting for DAT availability in the putamen (i.e., motor reserve) between the PD groups according to the presence of GBA mutations. Fifty-four (13.2%) patients carried GBA mutations. PD patients with GBA mutations were younger than those without mutations. There were no significant differences in sex, disease duration, years of education, and striatal DAT availability between the PD groups. PD patients with GBA mutations had higher MDS-UPDRS-III scores for the less affected side than those without mutations, despite similar levels of DAT availability in the contralateral putamen. The MDS-UPDRS-III sub-scores of the more affected side did not differ between the two PD groups. The results of this study demonstrated the detrimental effect of GBA variants on individual capacity to cope with PD-related pathologies, with different impacts depending on the motor laterality.

Exercise Improves Movement by Regulating the Plasticity of Cortical Function in Hemiparkinsonian Rats.

Aberrant cortical spike-local field potential (LFP) coupling leads to abnormal basal ganglia activity, disruption of cortical function, and impaired movement in Parkinson's disease (PD). Here, the primary motor cortex mediated plasticity mechanism underlying behavioral improvement by exercise intervention was investigated. Exercise alleviates motor dysfunction and induces neuroplasticity in PD. In this study, Sprague-Dawley (SD) rats were injected with 6-hydroxydopamine (6-OHDA) to induce unilateral nigrostriatal dopamine depletion. Two weeks later, a 4-week exercise intervention was initiated in the PD + exercise (Ex) group. Multichannel recording technology recorded spikes and LFPs in rat motor cortices, and balanced ability tests evaluated behavioral performance. The balanced ability test showed that the total crossing time/front leg error/input latency time was significantly lower in PD + Ex rats than in PD rats (P < 0.05). Scalograms and LFP power spectra indicated increased beta-range LFP power in lesioned hemispheres, with exercise reducing LFP power spectral density. Spike-triggered LFP waveform averages showed strong phase-locking in PD motor cortex cells, and exercise reduced spike-LFP synchronization. Our results suggest that exercise can suppress overexcitability of LFPs and minimize spike-LFP synchronization in the motor cortex, leading to motor-improving effects in PD.

A subcortical network for implicit visuo-spatial attention: Implications for Parkinson's Disease

Recent studies in humans and animal models suggest a primary role of the basal ganglia in the extraction of stimulus-value regularities, then exploited to orient attentional shift and build up sensorimotor memories. The tail of the caudate and the posterior putamen both receive early visual input from the superficial layers of the superior colliculus, thus forming a closed-loop. We portend that the functional value of this circuit is to manage the selection of visual stimuli in a rapid and automatic way, once sensory–motor associations are formed and stored in the posterior striatum. In Parkinson's Disease, the nigrostriatal dopamine depletion starts and tends to be more pronounced in the posterior putamen. Thus, at least some aspect of the visuospatial attention deficits observed since the early stages of the disease could be the behavioral consequences of a cognitive system that has lost the ability to translate high-level processing in stable sensorimotor memories.

White Matter Hyperintensities, Dopamine Loss, and Motor Deficits in De Novo Parkinson's Disease.

White matter hyperintensities, prevalent in patients with Parkinson's disease (PD), significantly affect parkinsonian motor symptoms. The objective of this study was to investigate the relationship between white matter hyperintensities and nigrostriatal dopamine depletion and their interaction or mediating effects on motor symptoms in patients with drug-naive early-stage PD. This cross-sectional study enrolled 501 patients with de novo PD who initially underwent [18 F] N-(3-fluoropropyl)-2β-carbonethoxy-3β-(4-iodophenyl) nortropane positron emission tomography and brain magnetic resonance imaging scans between April 2009 and September 2015 in a tertiary-care university hospital. We quantified dopamine transporter availability in each striatal subregion and assessed the severity of periventricular and lobar white matter hyperintensities using the Scheltens scale. The relationship between white matter hyperintensities, dopamine transporter availability in the posterior putamen, and Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was assessed using multivariate linear regression and mediation analyses. Periventricular and frontal white matter hyperintensities were generally associated with dopamine transporter availability in striatal subregions after adjusting for age at symptom onset, sex, disease duration, and vascular risk factors. There was an interaction effect between periventricular white matter hyperintensities and dopamine transporter availability in the posterior putamen for the axial motor score. The effect of white matter hyperintensities on UPDRS total score and bradykinesia subscore was indirectly mediated by dopamine transporter availability in the posterior putamen, whereas the axial sub-score was directly affected by white matter hyperintensities. This study suggests that the detrimental effect of white matter hyperintensities on parkinsonian motor symptoms is more relevant and independent for axial motor impairments in the status of mildly decreased striatal dopamine transporter availability. © 2021 International Parkinson and Movement Disorder Society.

Minimal parkinsonism in the elderly is associated with striatal dopamine loss and pontine structural damage

IntroductionTo investigate whether neurodegeneration underlying Parkinson's disease (PD) accounts for a substantial proportion of cases of minimal parkinsonism in the elderly. MethodsWe recruited 48 consecutive subjects with minimal parkinsonism who visited the clinic with cognitive complaints. All subjects did not show findings compatible with PD on 18F-FP-CIT PET scans, and had no evidence of other neurodegenerative disorders. Striatal dopamine transporter (DAT) availability was quantified, and mean diffusivity (MD) values in the pons were calculated to characterize structural damage using diffusion tensor imaging. Additionally, 35 patients with PD and 21 healthy controls were included as reference groups. ResultsIndividuals with minimal parkinsonism (mean age, 73.23 ± 7.03 years) exhibited mild decrease in DAT availability in the posterior putamen, which was at a level between that of healthy controls and patients with PD. DAT availability in the caudate and anterior putamen was also mildly decreased in the minimal parkinsonism group. Individuals with minimal parkinsonism also tended to have higher MD values in the pons compared to healthy controls. ConclusionsOur results suggest that a substantial proportion of minimal parkinsonism is associated with nigrostriatal dopamine depletion and pontine structural damage, which may be related to the disease process of prodromal PD.

Network degeneration in Parkinson's disease: multimodal imaging of nigro-striato-cortical dysfunction.

The spreading hypothesis of neurodegeneration assumes an expansion of neural pathologies along existing neural pathways. Multimodal neuroimaging studies have demonstrated distinct topographic patterns of cerebral pathologies in neurodegeneration. For Parkinson's disease the hypothesis so far rests largely on histopathological evidence of α-synuclein spreading in a characteristic pattern and progressive nigrostriatal dopamine depletion. Functional consequences of nigrostriatal dysfunction on cortical activity remain to be elucidated. Our goal was to investigate multimodal imaging correlates of degenerative processes in Parkinson's disease by assessing dopamine depletion and its potential effect on striatocortical connectivity networks and cortical metabolism in relation to parkinsonian symptoms. We combined 18F-DOPA-PET, 18F-fluorodeoxyglucose (FDG)-PET and resting state functional MRI to multimodally characterize network alterations in Parkinson's disease. Forty-two patients with mild-to-moderate stage Parkinson's disease and 14 age-matched healthy control subjects underwent a multimodal imaging protocol and comprehensive clinical examination. A voxel-wise group comparison of 18F-DOPA uptake identified the exact location and extent of putaminal dopamine depletion in patients. Resulting clusters were defined as seeds for a seed-to-voxel functional connectivity analysis. 18F-FDG metabolism was compared between groups at a whole-brain level and uptake values were extracted from regions with reduced putaminal connectivity. To unravel associations between dopaminergic activity, striatocortical connectivity, glucose metabolism and symptom severity, correlations between normalized uptake values, seed-to-cluster β-values and clinical parameters were tested while controlling for age and dopaminergic medication. Aside from cortical hypometabolism, 18F-FDG-PET data for the first time revealed a hypometabolic midbrain cluster in patients with Parkinson's disease that comprised caudal parts of the bilateral substantia nigra pars compacta. Putaminal dopamine synthesis capacity was significantly reduced in the bilateral posterior putamen and correlated with ipsilateral nigral 18F-FDG uptake. Resting state functional MRI data indicated significantly reduced functional connectivity between the dopamine depleted putaminal seed and cortical areas primarily belonging to the sensorimotor network in patients with Parkinson's disease. In the inferior parietal cortex, hypoconnectivity in patients was significantly correlated with lower metabolism (left P = 0.021, right P = 0.018). Of note, unilateral network alterations quantified with different modalities corresponded with contralateral motor impairments. In conclusion, our results support the hypothesis that degeneration of nigrostriatal fibres functionally impairs distinct striatocortical connections, disturbing the efficient interplay between motor processing areas and impairing motor control in patients with Parkinson's disease. The present study is the first to reveal trimodal evidence for network-dependent degeneration in Parkinson's disease by outlining the impact of functional nigrostriatal pathway impairment on striatocortical functional connectivity networks and cortical metabolism.

Dopamine agonist treatment increases sensitivity to gamble outcomes in the hippocampus in de novo Parkinson’s disease

BackgroundParkinson’s disease is associated with severe nigro-striatal dopamine depletion, leading to motor dysfunction and altered reward processing. We previously showed that drug-naïve patients with Parkinson’s disease had a consistent attenuation of reward signalling in the mesolimbic and mesocortical system. Here, we address the neurobiological effects of dopaminergic therapy on reward sensitivity in the mesolimbic circuitry, and how this may contribute to neuropsychiatric symptoms. ObjectivesWe tested the hypothesis that (1) dopaminergic treatment would restore the attenuated, mesolimbic and mesocortical responses to reward; and (2) restoration of reward responsivity by dopaminergic treatment would predict motor performance and the emergence of impulse control symptoms. MethodsIn 11 drug-naïve Parkinson patients, we prospectively assessed treatment-induced changes in reward processing before, and eight weeks after initiation of monotherapy with dopamine agonists. They were compared to 10 non-medicated healthy controls who were also measured longitudinally. We used whole-brain functional magnetic resonance imaging at 3 Tesla to assess the reward responsivity of the brain to monetary gains and losses, while participants performed a simple consequential gambling task. ResultsIn patients, dopaminergic treatment improved clinical motor symptoms without significantly changing task performance. Dopamine agonist therapy induced a stronger reward responsivity in the right hippocampus with higher doses being less effective. None of the patients developed impulse control disorders in the follow-up period of four years. ConclusionsShort-term treatment with first-ever dopaminergic medication partially restores deficient reward-related processing in the hippocampus in de novo Parkinson’s disease.

3,4-Dihydroxyphenylacetaldehyde Is More Efficient than Dopamine in Oligomerizing and Quinonizing α-Synuclein.

Lewy body diseases such as Parkinson's disease involve intraneuronal deposition of the protein α-synuclein (AS) and depletion of nigrostriatal dopamine (DA). Interactions of AS with DA oxidation products may link these neurohistopathologic and neurochemical abnormalities via two potential pathways: spontaneous oxidation of DA to dopamine-quinone and enzymatic oxidation of DA catalyzed by monoamine oxidase to form 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is then oxidized to DOPAL-Q. We compared these two pathways in terms of the ability of DA and DOPAL to modify AS. DOPAL was far more potent than DA both in oligomerizing and forming quinone-protein adducts with (quinonizing) AS. The DOPAL-induced protein modifications were enhanced similarly by pro-oxidation with Cu(II) or tyrosinase and inhibited similarly by antioxidation with N-acetylcysteine. Dopamine oxidation evoked by Cu(II) or tyrosinase did not quinonize AS. In cultured MO3.13 human oligodendrocytes DOPAL resulted in the formation of numerous intracellular quinoproteins that were visualized by near-infrared spectroscopy. We conclude that of the two routes by which oxidation of DA modifies AS and other proteins the route via DOPAL is more prominent. The results support developing experimental therapeutic strategies that might mitigate deleterious modifications of proteins such as AS in Lewy body diseases by targeting DOPAL formation and oxidation. SIGNIFICANCE STATEMENT: Interactions of the protein α-synuclein with products of dopamine oxidation in the neuronal cytoplasm may link two hallmark abnormalities of Parkinson disease: Lewy bodies (which contain abundant AS) and nigrostriatal DA depletion (which produces the characteristic movement disorder). Of the two potential routes by which DA oxidation may alter AS and other proteins, the route via the autotoxic catecholaldehyde 3,4-dihydroxyphenylacetaldehyde is more prominent; the results support experimental therapeutic strategies targeting DOPAL formation and DOPAL-induced protein modifications.

L-alpha-aminoadipic acid restricts dopaminergic neurodegeneration and motor deficits in an inflammatory model of Parkinson's disease in male rats.

Neuroinflammation is a contributory factor underlying the progressive nature of dopaminergic neuronal loss within the substantia nigra (SN) of Parkinson's disease (PD) patients, albeit the role of astrocytes in this process has been relatively unexplored to date. Here, we aimed to investigate the impact of midbrain astrocytic dysfunction in the pathophysiology of intra-nigral lipopolysaccharide (LPS)-induced experimental Parkinsonism in male Wistar rats via simultaneous co-injection of the astrocytic toxin L-alpha-aminoadipic acid (L-AAA). Simultaneous intra-nigral injection of L-AAA attenuated the LPS-induced loss of tyrosine hydroxylase-positive (TH+ ) dopamine neurons in the SNpc and suppressed the affiliated degeneration of TH+ dopaminergic nerve terminals in the striatum. L-AAA also repressed LPS-induced nigrostriatal dopamine depletion and provided partial protection against ensuing motor dysfunction. L-AAA abrogated intra-nigral LPS-induced glial fibrillary acidic protein-positive (GFAP+ ) reactive astrogliosis and attenuated the LPS-mediated increases in nigral S100β expression levels in a time-dependent manner, findings which were associated with reduced ionized calcium binding adaptor molecule 1-positive (Iba1+ ) microgliosis, thus indicating a role for reactive astrocytes in sustaining microglial activation at the interface of dopaminergic neuronal loss in response to an immune stimulus. These results indicate that midbrain astrocytic dysfunction restricts the development of dopaminergic neuropathology and motor impairments in rats, highlighting reactive astrocytes as key contributors in inflammatory associated degeneration of the nigrostriatal tract.

Quantitative Analysis of Catecholamines in the Pink1 −/− Rat Model of Early-onset Parkinson’s Disease

Parkinson’s disease (PD) related to homozygous mutations in the Pink1 gene is associated with nigrostriatal dopamine depletion and a wide range of sensorimotor deficits. In humans and animal models of PD, not all sensorimotor deficits are levodopa-responsive. We hypothesized that the underlying mechanisms of locomotion, limb control, and vocal communication behavior include other pathologies. Here, Pink1 −/− rats were treated with an oral dose of levodopa and limb motor and vocal communication behaviors were measured. Levodopa significantly improved some aspects of locomotion but did not improve ultrasonic vocalization intensity or frequency. Catecholamine concentrations in the striatum (SR), substantia nigra (SN), and locus coeruleus (LC) were analyzed to test the hypothesis that behavioral deficits would correlate to altered protein levels. There were no differences in dopamine concentrations in the SR and SN of Pink1 −/− animals compared to wild-type controls. There was a significant increase in norepinephrine concentration in the SN of Pink1 −/− animals. Moreover, an observed decrease in norepinephrine concentrations in the LC is consistent with the hypothesis that early-stage PD includes noradrenergic loss in the brainstem, and is congruent with a significant increase in catechol-O-methyltransferase expression in the LC of Pink1 −/− animals. Pearson’s correlations showed that increases in time to traverse a tapered balance beam are significantly associated with reductions in striatal dopamine. Ultrasonic vocalization complexity was positively correlated with LC norepinephrine concentrations. These data support the evolving hypothesis that differences in neural substrates and early-onset noradrenergic mechanisms in the brainstem may contribute to pathogenesis in the Pink1 −/− rat.

Cerebrospinal fluid biomarkers of central dopamine deficiency predict Parkinson's disease

BackgroundConsistent with nigrostriatal dopamine depletion, low cerebrospinal fluid (CSF) concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, characterize Parkinson's disease (PD) even in recently diagnosed patients. Whether low CSF levels of DOPAC or DOPA, the precursor of dopamine, identify pre-clinical PD in at-risk healthy individuals has been unknown. MethodsParticipants in the intramural NINDS PDRisk study entered information about family history of PD, olfactory dysfunction, dream enactment behavior, and orthostatic hypotension at a protocol-specific website. After at least 3 risk factors were confirmed by on-site screening, 26 subjects had CSF sampled for levels of catechols and were followed for at least 3 years. ResultsOf 26 PDRisk subjects, 4 were diagnosed with PD (Pre-Clinical PD group); 22 risk-matched (mean 3.2 risk factors) subjects remained disease-free after a median of 3.7 years (No-PD group). The Pre-Clinical PD group had lower initial DOPA and DOPAC levels than did the No-PD group (p = 0.0302, p = 0.0190). All 3 subjects with both low DOPA (<2.63 pmol/mL) and low DOPAC (<1.22 pmol/mL) levels, based on optimum cut-off points using the minimum distance method, developed PD, whereas none of 14 subjects with both normal DOPA and DOPAC levels did so (75% sensitivity at 100% specificity, p = 0.0015 by 2-tailed Fisher's exact test). ConclusionsIn people with multiple PD risk factors, those with low CSF DOPA and low CSF DOPAC levels develop clinical disease during follow-up. We suggest that neurochemical biomarkers of central dopamine deficiency identify the disease in a pre-clinical phase.

Voluntary Physical Exercise Improves Subsequent Motor and Cognitive Impairments in a Rat Model of Parkinson's Disease.

Background: Parkinson’s disease (PD) is typically characterized by impairment of motor function. Gait disturbances similar to those observed in patients with PD can be observed in animals after injection of neurotoxin 6-hydroxydopamine (6-OHDA) to induce unilateral nigrostriatal dopamine depletion. Exercise has been shown to be a promising non-pharmacological approach to reduce the risk of neurodegenerative disease. Methods: In this study, we investigated the long-term effects of voluntary running wheel exercise on gait phenotypes, depression, cognitive, rotational behaviors as well as histology in a 6-OHDA-lesioned rat model of PD. Results: We observed that, when compared with the non-exercise controls, five-week voluntary exercise alleviated and postponed the 6-OHDA-induced gait deficits, including a significantly improved walking speed, step/stride length, base of support and print length. In addition, we found that the non-motor functions, such as novel object recognition and forced swim test, were also ameliorated by voluntary exercise. However, the rotational behavior of the exercise group did not show significant differences when compared with the non-exercise group. Conclusions: We first analyzed the detailed spatiotemporal changes of gait pattern to investigate the potential benefits after long-term exercise in the rat model of PD, which could be useful for future objective assessment of locomotor function in PD or other neurological animal models. Furthermore, these results suggest that short-term voluntary exercise is sufficient to alleviate cognition deficits and depressive behavior in 6-OHDA lesioned rats and long-term treatment reduces the progression of motor symptoms and elevates tyrosine hydroxylase (TH), Brain-derived neurotrophic factor (BDNF), bone marrow tyrosine kinase in chromosome X (BMX) protein expression level without affecting dopaminergic (DA) neuron loss in this PD rat model.

Bidirectional Neural Interaction Between Central Dopaminergic and Gut Lesions in Parkinson's Disease Models.

The exact mechanism of gut dysfunction in Parkinson's disease and, conversely, the role of gut pathology in brain dopaminergic degeneration are controversial. We investigated the effects of nigral lesions on the colonic neurotransmission, the effect of gut inflammation on the nigrostriatal dopaminergic function, and the possible involvement of the vagus nerve and the local renin-angiotensin system (RAS). Nigrostriatal dopamine depletion was performed by bilateral injection 6-hydroxydopamine, and gut inflammation was induced by dextran sulfate sodium salt treatment in rats and mice, respectively, with or without vagal disruption. A decrease in central dopamine levels induced a decrease in colonic dopamine types 1 and 2 receptor expression together with an increase in the colonic levels of dopamine and a decrease in the levels of acetylcholine, which may explain a decrease in gut motility. Central dopaminergic depletion also induced an increase in the colonic levels of inflammatory and oxidative stress markers together with activation of the pro-inflammatory arm of the local RAS. Mice with acute (1week) or subchronic (3weeks) gut inflammation did not show a significant increase in colonic α-synuclein and phosphorylated α-synuclein expression during this relatively short survival period. Interestingly, we observed early changes in the nigrostriatal dopaminergic homeostasis, dopaminergic neuron death, and increased levels of nigral pro-inflammatory markers and RAS pro-inflammatory activity. The present results show that a dysregulation of the neural bidirectional gut-brain interaction may explain the early gut disturbances observed in parkinsonian patients, and also the increase in vulnerability of nigral dopaminergic neurons after gut inflammation.