Left Substantia Nigra Pars Compacta Research Articles

Hydroxychloroquine attenuated motor impairment and oxidative stress in a rat 6-hydroxydopamine model of Parkinson’s disease

Purpose Parkinson’s disease (PD) is associated with the destruction of dopaminergic neurons in the substantia nigra (SN). Hydroxychloroquine (HCQ) has the capability to cross the blood–brain barrier and promote a neuroprotective potential. This study evaluated the effects of HCQ on the 6-hydroxydopamine (6-OHDA)-induced PD model in rats. Methods Wistar rats were randomly divided into sham, PD, PD + levodopa and PD + HCQ groups. The PD model was induced by a stereotactic administration of 6-OHDA into the left SN pars compacta (SNpc) and confirmed by rotation and the Murprogo’s tests. HCQ (100 mg/kg, p.o.) and levodopa (12 mg/kg, p.o.) were administered once a day for 21 days. Three weeks after surgery, the behavioral tests were performed. Brain lipid peroxidation index (MDA), glutathione peroxidase activity (GPx), total antioxidant capacity (TAC) levels and α-synuclein protein expression in the SN were also measured. Results The behavioral tests demonstrated that induction of PD increased the muscle rigidity and the number of rotations, which were reversed by HCQ treatment. Also, induction of PD was associated with an increase in α-synuclein protein levels and MDA and decreased TAC levels and GPx activity. However, HCQ decreased α-synuclein and MDA levels while increased TAC levels and GPx activity. In addition, histopathological data showed that HCQ protects dopaminergic neurons against 6-OHDA-induced toxicity. Conclusion According to the results, HCQ has a beneficial effect in improving PD-related pathophysiology, in part, by mitigating oxidative stress and protecting the dopaminergic neurons in the SN.

Mesenchymal Stem Cells with Granulocyte Colony-Stimulating Factor Reduce Stress Oxidative Factors in Parkinson's Disease

Background:Recent studies have shown that BMSCs have a putative ability to promote neurogenesis and produce behavioral and functional improvement. Our previous study demonstrated that co-treatment of G-CSF and BMSCs have beneficial effects on Parkinson's models. The main purpose of this research was to investigate the effects of these two factors on oxidative stress factors in the brain of Parkinson's rat. Methods:Adult male Wistar rats (weighing 200–250 g) were used and randomly divided into five groups of seven each. To create the Parkinson's model, 6-OHDA was injected into the left SNpc. The BMSCs (2 × 106) and G-CSF (75 µg/kg) were used for treatment after creating the PD model. After four weeks, the brains of rats were removed and processed for immunohistochemical studies, such as TH-positive neurons as well as analysis of oxidative stress factors. Results:The results showed that the injected BMSCs could cross the BBB. The injected cells are also able to settle in different areas of the brain. Analyses of the brain oxidative stress factors showed that G-CSF and BMSCs reduced the expression of MDA and induced the activity of SOD, GSH-Px, and FRAP. Conclusion:Co-administration of G-CSF and BMSCs reduced the expression of pro-inflammatory cytokines and induced the activity of antioxidant enzymes; however, neurogenesis increased in the brain.

Microstructural abnormalities of substantia nigra in Parkinson's disease: A neuromelanin sensitive MRI atlas based study.

Microstructural changes associated with degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) have been studied using Diffusion Tensor Imaging (DTI). However, these studies show inconsistent results, mainly due to methodological variations in delineation of SNc. To mitigate this, our work aims to construct a probabilistic atlas of SNc based on a 3D Neuromelanin Sensitive MRI (NMS‐MRI) sequence and demonstrate its applicability to investigate microstructural changes on a large dataset of PD. Using manual segmentation and deformable registration we created a novel SNc atlas in the MNI space using NMS‐MRI sequences of 27 healthy controls (HC). We first quantitatively evaluated this atlas and then employed it to investigate the micro‐structural abnormalities in SNc using diffusion MRI from 133 patients with PD and 99 HCs. Our results demonstrated significant increase in diffusivity with no changes in anisotropy. In addition, we also observed an asymmetry of the diffusion metrics with a higher diffusivity and lower anisotropy in the left SNc than the right. Finally, a multivariate classifier based on SNc diffusion features could delineate patients with PD with an average accuracy of 71.7%. Overall, from this work we establish a normative baseline for the SNc region of interest using NMS‐MRI while the application on PD data emphasizes on the contribution of diffusivity measures rather than anisotropy of white matter in PD.

In vivo detection of metabolic changes in the striatum of proteasomal inhibition-induced Parkinson’s disease in rats using proton MR spectroscopy at 9.4 T

Purpose: Parkinson’s disease is a progressive disorder. To investigate the biochemical alterations in the striatum of rats with different stages of Parkinson’s disease induced by proteasomal inhibition, we quantified neurochemical profiles of the striatum using proton magnetic resonance spectroscopyusing 9.4 T ultra-high field imaging.Methods: In this study, 10 μg/2 μl lactacystin, a selective proteasome inhibitor, was unilaterally injected stereotaxically into the left substantia nigra pars compacta of rats. An equal volume of saline was injected into the same region and side in the control group. Changes in motor behaviour were observed. The morphological changes of tyrosine hydroxylase-positive cells in substantia nigra pars compacta were visualized using immunohistochemistry. Tyrosine hydroxylase-positive nerve fibers were quantified. Alterations of N-acetylaspartate, choline, creatine, taurine in the different stages of Parkinson’s disease rats were detected using proton magnetic resonance spectroscopy.Results: Application of in vivo 1H magnetic resonance spectroscopy was repeated in both the six Parkinson’s disease rats and the six control rats across three time points during the first, second and fourth weekend after administration. In Parkinson’s disease rats, increased N-acetylaspartate and decreased taurine concentrations were observed in the left striatum at the first week after administration. The increased N-acetylaspartate and choline concentrations were observed at the second weekend. At the fourth weekend, increased creatine concentrations in the left side were observed, while other metabolites were not significantly changed.Conclusions: Neurochemical alterations occurred in the striatum during different stages of the Parkinson’s disease model in rats. Also, 9.4 T 1H magnetic resonance spectroscopy may be a useful tool for elucidating the progression of Parkinson’s disease through the variation of these metabolites.

Predictive markers for Parkinson's disease using deep neural nets on neuromelanin sensitive MRI.

Neuromelanin sensitive magnetic resonance imaging (NMS-MRI) has been crucial in identifying abnormalities in the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) as PD is characterized by loss of dopaminergic neurons in the SNc. Current techniques employ estimation of contrast ratios of the SNc, visualized on NMS-MRI, to discern PD patients from the healthy controls. However, the extraction of these features is time-consuming and laborious and moreover provides lower prediction accuracies. Furthermore, these do not account for patterns of subtle changes in PD in the SNc. To mitigate this, our work establishes a computer-based analysis technique that uses convolutional neural networks (CNNs) to create prognostic and diagnostic biomarkers of PD from NMS-MRI. Our technique not only performs with a superior testing accuracy (80%) as compared to contrast ratio-based classification (56.5% testing accuracy) and radiomics classifier (60.3% testing accuracy), but also supports discriminating PD from atypical parkinsonian syndromes (85.7% test accuracy). Moreover, it has the capability to locate the most discriminative regions on the neuromelanin contrast images. These discriminative activations demonstrate that the left SNc plays a key role in the classification in comparison to the right SNc, and are in agreement with the concept of asymmetry in PD. Overall, the proposed technique has the potential to support radiological diagnosis of PD while facilitating deeper understanding into the abnormalities in SNc.

Motor asymmetry and neuromelanin imaging: Concordance in Parkinson's disease

BackgroundThe onset of motor symptoms in Parkinson's disease (PD) is characteristically asymmetric and correlates with dopaminergic deficit of contralateral basal ganglia. This study explored the concordance between motor asymmetry and changes of substantia nigra pars compacta (SNc) using neuromelanin-sensitive imaging. MethodsForty-four subjects with PD and fifteen healthy controls were included in this study. Clinical laterality (CL) was based on the motor sub scores of the Unified Parkinson's Disease Rating Scale-Part III. All subjects underwent neuromelanin-sensitive imaging and imaging laterality (IL) was based on the differences between contrast ratios of the right and left lateral SNc. Concordance was evaluated by correlating CL and IL. ResultsMotor asymmetry at disease onset was reported in 97.72% of subjects with PD, of which 65.90% reported right-sided onset. Forty-three subjects were right-handed and 68.18% reported onset of symptoms on dominant side. Right CL was observed in 59.09%, left CL in 40.90%, right IL in 11.36% and left IL in 88.63%. Concordance was established in 61.36%, majority of whom had a combination of right CL and left IL. In healthy controls, a significantly lower contrast ratio of the left lateral SNc was also noted. ConclusionsHandedness may correlate with motor asymmetry and left hemisphere may have a predilection for neurodegeneration. The finding of significant neuronal loss of left SNc in controls warrants further evaluation for better understanding of motor asymmetry in PD. Neuromelanin sensitive imaging can be a useful tool to study the relationship between motor asymmetry and nigrostriatal dysfunction.

Levetiracetam attenuates rotenone-induced toxicity: A rat model of Parkinson's disease.

Levetiracetam (LEV), a second-generation anti-epileptic drug, is used for treatment of both focal and generalized epilepsy. Growing body of evidence suggests that LEV may have neuroprotective effects. The present study was undertaken to investigate the neuroprotective effects of LEV on rotenone-induced Parkinson's disease (PD) in rats. Twenty-four adult Sprague-Dawley rats were infused with rotenone (3 μg/μl in DMSO) or vehicle (1 μl DMSO) into the left substantia nigra pars compacta (SNc) under stereotaxic surgery. PD model was assessed by rotational test ten days after drug infusion. The valid PD rats were randomly distributed into two groups; Group 1 (n=8) and Group 2 (n=8) were administered saline (1 ml/kg/day, i.p.) and LEV (600 mg/kg/day, i.p.) through 21 days, respectively. The effects of LEV treatment were evaluated by behavioral (rotation score), biochemical (brain homovalinic acid level and oxidant/antioxidant status) and immunohistochemical (tyrosine hydroxylase) parameters. Apomorphine-induced rotations in PD rats were significantly suppressed by LEV treatment. While unilateral rotenone lesion induced a dramatic loss of dopaminergic neurons both in the striatum and SNc, LEV treatment significantly attenuated the degenerative changes in dopaminergic neurons. Furthermore, LEV significantly decreased lipid peroxide levels, a marker of lipid peroxidation, and induced glutathione levels, catalase and superoxide dismutase activity in PD rats compared with saline group. We conclude that LEV may have beneficial effects on dopaminergic neurons against rotenone-induced injury. The underlying mechanism may be associated with the attenuation of oxidative stress.

Losartan pretreatment reduces neurodegeneration and behavioural symptoms in 6-hydroxydopamine induced unilateral rat model of Parkinson's disease

Losartan is an angiotensin II receptor antagonist which is mainly used to treat hypertension. It has been shown that angiotensin II involves in NADPH-dependent oxidase activation. In this study, the effect of losartan in 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease was investigated. The rats were daily pre-treated i.p. with losartan (90mg/kg), for the duration of six days before the 6-OHDA injection in the left substantia nigra pars compacta (SNC), until one day afterwards. Losartan administration caused a significant decrease in the rotational and rigidity score in the lesioned rats after 2 weeks. Furthermore, the pretreatment with losartan significantly lowered the value of the markers of oxidative stress after 24h. Moreover, losartan protected SNC dopaminergic neurons against toxicity of 6-OHDA. The results therefore suggested that losartan pretreatment attenuated the symptoms of Parkinson's disease probably by preventing 6-OHDA induced oxidative stress and neurodegeneration.

Amelioration of rotenone-induced dopaminergic cell death in the striatum by oxytocin treatment

Oxytocin (OT) is essentially associated with uterine contraction during parturition and milk ejection reflex. Although several studies implicate the role of OT in anti-inflammatory, anti-oxidative and anti-apoptotic pathways, there is a lack of data with regard to the protective effects of oxytocin in neurodegenerative models such as Parkinson's disease (PD). The present study was undertaken to investigate the neuroprotective effects of oxytocin (OT) on rotenone-induced PD in rats. Twenty adult Sprague-Dawley rats were injected with rotenone (3μg/μl in DMSO) or vehicle (1μl DMSO) into the left substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) under stereotaxic surgery, and PD model was assessed by rotational test ten days after drug infusion. The valid PD rats were randomly divided into two groups; Group 1 (n=7) and Group 2 (n=7) were administered saline (1ml/kg/day, i.p.) and oxytocin (160μg/kg/day, i.p.) through 20 days, respectively. The effects of OT treatment were evaluated by behavioral, histological and immunohistochemical parameters. Apomorphine-induced stereotypic rotations in PD rats were significantly inhibited by OT treatment (p<0.05). In addition, immunohistochemical studies clearly demonstrated the suppression of Bax, caspase-3, caspase-8 and elevation of Bcl-2 and tyrosine hydroxylase immunoexpression in OT-treated rats compared to saline group. Our findings suggest that oxytocin may have cytoprotective and restorative effects on dopaminergic neurons against rotenone-induced injury. The underlying mechanism may be associated with the inhibition of apoptotic pathways.

The effect of red grape juice and exercise, and their combination on parkinson(')s disease in rats.

Parkinson(')s disease (PD) is one of the most common neurodegenerative disorders which is characterized by tremor, rigidity, bradykinesia and postural disturbances. Studies indicate that grape juice and exercise may have beneficial effects on neurodegenerative disorders. Therefore, in the present study, we evaluated the effects of red grape juice (GJ) together with treadmill running on animal model of PD. Materials and Methods : 30 male Wistar rats were divided randomly into Sham, PD, PD treated with GJ (PD-GJ), PD treated with exercise (PD-Ex), and PD treated with GJ associated with exercise (PD-GJ-Ex) groups with six rats in each. In order to obtain the PD model, 6-OHDA was infused into left substantia nigra pars compacta. In order to prove that the lesions are created and to estimate their extent, apomorphine was administered (i.p.) and total number of induced rotations was recorded during 60 minutes. Exercise was applied by treadmill and GJ was added into drinking water for 30 days and rotations test was performed again. Our results indicate that there was a significant difference in number of rotations between PD and Sham groups (p<0.05). At the end of experiment, number of rotations decreased significantly in both PD-GJ and PD-GJ-Ex groups (p<0.05). Exercise alone increased the number of rotations non- significantly. Grape juice reduced rotations probably via the antioxidant agents.

Effects of Aspirin and Celecoxib on Rigidity in a Rat Model of Parkinson`s Disease

Parkinson's disease (PD) is a degenerative neurodopaminergic disease in nigrostriatum pathway of human and is responsible for most of the movement disorders. Increasing evidence suggests that an inflammatory reaction accompanies the pathological processes caused by Cyclooxygenase (COX) seen in many neurodegenerative disorders, including PD and according to the recent researches chronic use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) decreases the risk of PD in human. In the study the rat left Substantia Nigra Pars Compacta (SNc) have been destroyed using electrical lesion (1 mA; DC; 8 Sec) to induce PD model. Then aspirin (30, 60 mg kg(-1)) and celecoxib (4, 8 mg kg(-1)) have been administrated orally to parkinsonian rats. When the animals were suffered to PD Murprogo's Method evaluated the rigidity ofparkinsonian rats. Both selective COX-2 inhibitor (celecoxib) and non-selective COX-2 inhibitor (aspirin) decreased the rigidity of parkinsonian rats p<0.05 but rigidity recovery after administration the selective COX-2 inhibitor was more than non-selective COX-2 inhibitor. These findings are additional pharmacological information which has suggested the use of NSAIDs as alternative way to treat the rigidity of PD.

Is the unilateral lesion of the left substantia nigra pars compacta sufficient to induce working memory impairment in rats?

Adult male Wistar rats with a substantia nigra pars compacta (SNc) lesion induced by intranigral administration of 1 μmol 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were used as a model of early phase Parkinson’s disease (PD). This lesion caused a partial depletion of striatal dopamine (DA). The animals were submitted to a spatial working memory version of the water maze task in which they had to find a hidden (submersed) platform using online-maintained information that the platform remains in the same place during four consecutive trials, but that it is moved to another place every training day. Left, but not right SNc-lesioned rats were impaired in finding the platform in the second trial. This result suggests that the left SNc plays a key role in spatial working memory. Control experiments ruled out the possibility that motor impairment, sensory neglect, and/or impairment in the mental representation of the contralateral spatial environment had affected performance of the SNc-lesioned rats.

Dopamine transporter function assessed by antisense knockdown in the rat: protection from dopamine neurotoxicity.

The plasma membrane dopamine transporter is located on presynaptic nerve terminals and is responsible for the termination of dopaminergic neurotransmission via dopamine reuptake. The dopamine transporter may also contribute to the pathogenesis of Parkinson disease. Dopamine transporter expression correlates well with susceptibility to neuronal degeneration in 1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine (MPTP)-induced parkinsonism. Recent studies have implicated the dopamine transporter in the uptake of both this neurotoxin and its metabolite, MPP(+), as well as another experimental neurotoxin, 6-hydroxydopamine. In these studies we examined the role of the dopamine transporter in the neurotoxicity of both MPP(+) and 6-hydroxydopamine in the rat brain using in vivo administration of phosphorothioate antisense oligonucleotides targeting dopamine transporter mRNA. Infusion of dopamine transporter antisense (1 nmol/day, 7 days) into the left substantia nigra pars compacta resulted in reduced (3)H-WIN 35-428 binding in the left striatum and significant levodopa and amphetamine-induced contralateral rotations. Unilateral pretreatment with dopamine transporter antisense prior to bilateral intrastriatal infusion of either MPP(+) or 6-hydroxydopamine resulted in asymmetrical striatal (3)H-WIN 35-428 binding and dopamine content as well as significant apomorphine-induced ipsilateral rotations, suggesting neuroprotection of nigrostriatal neurons on the antisense-treated side. Thus, the dopamine transporter appears to play a critical role in determining susceptibility to the experimental neurotoxins MPP(+) and 6-hydroxydopamine. In light of this, the dopamine transporter may prove useful, both as a marker for susceptibility to Parkinson's disease and as a target for therapeutic intervention.