A Sequential Intrastriatal Dopaminergic Graft Strategy in the Rodent Model for Parkinson's Disease: Implications for Graft Survival and Targeting

Optimal placement of intrastriatal dopaminergic grafts is likely crucial to optimize clinical recovery in Parkinson's disease (PD). The target sites of dopaminergic grafts vary among clinical trials and may partially explain the variable results in clinical efficacy reported thus far. In this study we hypothesized that a subsequent dopaminergic graft may promote functional recovery following a suboptimal initial graft. To test this hypothesis, rats with unilateral 6-hydroxydopamine lesions of the right nigrostriatal pathway were randomly divided into three groups. The first group received 900,000 fetal nigral cells in the medial striatum only (n = 6). The second group received 900,000 cells in both the medial and lateral striatum simultaneously (1.8 million total; n = 8). The final group received a second graft of 900,000 cells in the lateral striatum 6 weeks following initial transplantation of a medial graft (n = 6). Amphetamine-induced circling behavior was significantly reduced in both simultaneous and sequential graft groups at 9 and 12 weeks following transplantation of the initial graft. However, no recovery was noted in the single medial graft group at those time points. Furthermore, increased survival of dopaminergic cells was observed in the lateral graft of sequentially grafted animals compared with the medial graft. We conclude that a well-positioned subsequent graft can restore function in animals with a suboptimal initial graft and that the initial graft may improve survival of the second graft. These results are further discussed in relation to their important clinical implication for neural transplantation in PD.

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Effect of 6-OHDA on hypercapnic ventilatory response in the rat model of Parkinson’s disease

Physiological Research ◽

10.33549/physiolres.933949 ◽

2019 ◽

pp. 285-293 ◽

Cited By ~ 4

Author(s):

K. Andrzejewski ◽

K. Budzińska ◽

K. Kaczyńska

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Tidal Volume ◽

Ventilatory Response ◽

Minute Ventilation ◽

Sleep Apnoea ◽

Respiratory Pattern ◽

Nigrostriatal Pathway ◽

6 Hydroxydopamine ◽

The Right

Breathing impairments, such as an alteration in breathing pattern, dyspnoea, and sleep apnoea, are common health deficits recognised in Parkinson’s disease (PD). The mechanism that underlies these disturbances, however, remains unclear. We investigated the effect of the unilateral damage to the rat nigrostriatal pathway on the central ventilatory response to hypercapnia, evoked by administering 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle (MFB). The respiratory experiments were carried out in conscious animals in the plethysmography chamber. The ventilatory parameters were studied in normocapnic and hyperoxic hypercapnia before and 14 days after the neurotoxin injection. Lesion with the 6-OHDA produced an increased tidal volume during normoxia. The magnified response of tidal volume and a decrease of breathing frequency to hypercapnia were observed in comparison to the pre-lesion and sham controls. Changes in both respiratory parameters resulted in an increase of minute ventilation of the response to CO(2) by 28% in comparison to the pre-lesion state at 60 s. Our results demonstrate that rats with implemented unilateral PD model presented an altered respiratory pattern most often during a ventilatory response to hypercapnia. Preserved noradrenaline and specific changes in dopamine and serotonin characteristic for this model could be responsible for the pattern of breathing observed during hypercapnia.

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KDS2010, a Newly Developed Reversible MAO-B Inhibitor, as an Effective Therapeutic Candidate for Parkinson’s Disease

Neurotherapeutics ◽

10.1007/s13311-021-01097-4 ◽

2021 ◽

Author(s):

Min-Ho Nam ◽

Jong-Hyun Park ◽

Hyo Jung Song ◽

Ji Won Choi ◽

Siwon Kim ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Therapeutic Potential ◽

Motor Dysfunction ◽

Monoamine Oxidase B ◽

Nigrostriatal Pathway ◽

Neuroprotective Effects ◽

Mao B ◽

6 Hydroxydopamine ◽

Mptp Model

AbstractMonoamine oxidase-B (MAO-B) is a well-established therapeutic target for Parkinson’s disease (PD); however, previous clinical studies on currently available irreversible MAO-B inhibitors have yielded disappointing neuroprotective effects. Here, we tested the therapeutic potential of KDS2010, a recently synthesized potent, selective, and reversible MAO-B inhibitor in multiple animal models of PD. We designed and synthesized a series of α-aminoamide derivatives and found that derivative KDS2010 exhibited the highest potency, specificity, reversibility, and bioavailability (> 100%). In addition, KDS2010 demonstrated significant neuroprotective and anti-neuroinflammatory efficacy against nigrostriatal pathway destruction in the mouse MPTP model of parkinsonism. Treatment with KDS2010 also alleviated parkinsonian motor dysfunction in 6-hydroxydopamine-induced and A53T mutant α-synuclein overexpression rat models of PD. Moreover, KDS2010 showed virtually no toxicity or side effects in non-human primates. KDS2010 could be a next-generation therapeutic candidate for PD.

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Moxibustion Exerts a Neuroprotective Effect through Antiferroptosis in Parkinson’s Disease

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/2735492 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Juan Lu ◽

Xuelei Liu ◽

Ye Tian ◽

Hang Li ◽

Zhenxing Ren ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuroprotective Effect ◽

Disease Model ◽

Protective Mechanism ◽

Neural Cells ◽

Ferritin Heavy Chain ◽

Functional Pathway ◽

6 Hydroxydopamine ◽

The Right

The objective of this study was to explore the neuroprotective effect of moxibustion on rats with Parkinson’s disease (PD) and its mechanism. A Parkinson’s disease model was established in rats using a two-point stereotactic 6-hydroxydopamine injection in the right substantia nigra (SN) and ventral tegmental area. The rats received moxibustion at the Baihui (GV20) and Sishencong (EX-HN1) acupoints for 20 minutes, six times a week, for 6 weeks. The right SN tissue was histologically and immunohistochemically examined. Differentially expressed genes (DEGs) were identified through RNA sequencing. In addition, the levels of tyrosine hydroxylase (TH), glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) in SN were measured. In comparison to the model group, the moxibustion group showed a significantly greater TH immunoreactivity and a higher behavioural score. In particular, moxibustion led to an increase in the number and morphological stability of SN neural cells. The functional pathway analysis showed that DEGs are closely related to the ferroptosis pathway. GPX4 and FTH1 in the SN were significantly overexpressed in the moxibustion-treated rats with PD. Moxibustion can effectively reduce the death of SN neurons, decrease the occurrence of ferroptosis, and increase the TH activity to protect the neurons in rats with PD. The protective mechanism may be associated with suppression of the ferroptosis.

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Treadmill Exercise Improves Motor Dysfunction and Hyperactivity of the Corticostriatal Glutamatergic Pathway in Rats with 6-OHDA-Induced Parkinson’s Disease

Neural Plasticity ◽

10.1155/2017/2583910 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Wei Chen ◽

Decai Qiao ◽

Xiaoli Liu ◽

Kaixuan Shi

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Motor Function ◽

Primary Motor Cortex ◽

Treadmill Exercise ◽

Motor Dysfunction ◽

Firing Activity ◽

Cylinder Test ◽

6 Hydroxydopamine ◽

The Right

Hyperactivity in the corticostriatal glutamatergic pathway (CGP) induces basal ganglia dysfunction, contributing to parkinsonian syndrome (PS). Physical exercise can improve PS. However, the effect of exercise on the CGP, and whether this pathway is involved in the improvement of PS, remains unclear. Parkinson’s disease (PD) was induced in rats by 6-hydroxydopamine injection into the right medial forebrain bundle. Motor function was assessed using the cylinder test. Striatal neuron (SN) spontaneous and evoked firing activity was recorded, and the expression levels of Cav1.3 and CaMKII in the striatum were measured after 4 weeks of treadmill exercise. The motor function in PD rats was improved by treadmill exercise. SN showed significantly enhanced excitability, and treadmill exercise reduced SN excitability in PD rats. In addition, firing activity was evoked in SNs by stimulation of the primary motor cortex, and SNs exhibited significantly decreased stimulus threshold, increased firing rates, and reduced latency. The expression of Cav1.3 and p-CaMKII (Thr286) in the striatum were enhanced in PD rats. However, these effects were reversed by treadmill exercise. These findings suggest that treadmill exercise inhibits CGP hyperactivity in PD rats, which may be related to improvement of PS.

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Protective effects of ethanolic extract of Delphinium denudatum in a rat model of Parkinson's disease

Human & Experimental Toxicology ◽

10.1191/0960327106ht635oa ◽

2006 ◽

Vol 25 (7) ◽

pp. 361-368 ◽

Cited By ~ 16

Author(s):

Muzamil Ahmad ◽

Seema Yousuf ◽

M Badruzzaman Khan ◽

Abdullah Shafique Ahmad ◽

Sofiyan Saleem ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rat Model ◽

Ethanolic Extract ◽

Neuronal Injury ◽

Protective Effects ◽

Ipsilateral Striatum ◽

6 Hydroxydopamine ◽

The Right ◽

And Oxidative Stress

Parkinson's disease (PD) is one of the major neurodegenerative disorders, and oxidative stress has been implicated in playing an important role in the pathogenesis of the disease. In the present study, we investigated if Delphinium denudatum extract can slow down the neuronal injury in 6-hydroxydopamine (6-OHDA) rat model of Parkinsonism. Rats were treated with 200, 400 and 600 mg/kg body weight (b.w.) of D. denudatum extract for 3 weeks. On day 22, 2 mL of 6-OHDA (10 mgin 0.1% ascorbic acid-saline) or vehicle was infused into the right striatum of the animals. Three weeks after the 6-OHDA injections, the rats were killed for estimation of lipid peroxidation (LPO), reduced glutathione (GSH) content, superoxide dismutase (SOD) and catalase (CAT) activities, catecholamines, dopaminergic D2 receptor binding and tyrosine hydroxylase (TH) expression. Increased LPO and significant depletion of reduced GSH content in the substantia nigra resulting from the lesion were appreciably prevented with Delphinium treatment. Delphinium extract also dose-dependently attenuated the activities of SOD and CAT in striatum, which had been reduced significantly by lesioning. A significant decrease in the level of dopamine (DA) and its metabolites and an increase in the number of dopaminergic D2 receptors in striatum were observed after 6-OHDA injection, both parameters were significantly recovered with treatment of the extract. Finally, all these results were confirmed by an increase in expression of TH in the ipsilateral striatum of the lesioned groups following treatment with Delphinium extract. Thus, the study indicates that D. denudatum extract may be helpful in checking neuronal injury in Parkinsonism.

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Synchrotron FTIR Microspectroscopy Study of the Striatum in 6-Hydroxydopamine Rat Model of Parkinson's Disease

Spectroscopy An International Journal ◽

10.1155/2012/176937 ◽

2012 ◽

Vol 27 ◽

pp. 229-238 ◽

Cited By ~ 3

Author(s):

Zhu Hongyan ◽

Pei Xiao ◽

Wu Lingyan ◽

Liu Bo ◽

Qi Zeming ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rat Model ◽

Protein Secondary Structure ◽

Nigrostriatal Pathway ◽

Spectral Absorption ◽

Striatal Neurons ◽

Ftir Microspectroscopy ◽

6 Hydroxydopamine ◽

High Level

In the present study, synchrotron-based Fourier transform-infrared (FTIR) microspectroscopy is used to analyze the biochemical composition of the striatal neurons in normal and Parkinson's disease (PD) rat brain tissues. The rat model of Parkinson's disease is established by destroying the nigrostriatal pathway with 6-hydroxydopamine (6-OHDA). The detailed spectral analyses show the significant changes of cellular compositions such as lipids, and proteins in the striatal neurons of 6-OHDA-lesioned PD rats with respect to control neurons. As a result, the intensities of spectral absorption assigned to lipid of the striatal neurons in PD rats are higher than in control animals. Furthermore, the unsaturation levels of phospholipids decrease in PD neurons with respect to control neurons, indicating a high level of lipid peroxidation. The analysis of protein secondary structure shows the significantly higher ratio ofβ-sheet in PD neurons compared to that of control neurons, suggesting that the abnormal protein structure occurs before their morphological appearances in the striatal neurons. These findings suggest that the biochemical changes in neurons could be involved in the pathogenesis of Parkinson's disease.

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Step Sequence is a Critical Gait Parameter of Unilateral 6-OHDA Parkinson's Rat Models

Cell Transplantation ◽

10.3727/096368916x693059 ◽

2017 ◽

Vol 26 (4) ◽

pp. 659-667 ◽

Cited By ~ 4

Author(s):

Heather A. Baldwin ◽

Pyry P. Koivula ◽

Julie C. Necarsulmer ◽

Keith W. Whitaker ◽

Brandon K. Harvey

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Individual Variability ◽

Therapeutic Effects ◽

Nigrostriatal Pathway ◽

Step Cycle ◽

Rat Models ◽

Abnormal Gait ◽

Gait Parameters ◽

6 Hydroxydopamine

Parkinson's disease is a progressive neurological disorder, marked by the loss of dopaminergic neurons in the nigrostriatal pathway that leads to abnormal gait, rigidity, slowness of movement, and tremor. The ability to recapitulate and measure the neurological sequelae in rodent models of Parkinson's disease is important for studying and evaluating potential therapeutics. Individual variability in lesion severity and injury progression are key factors in the 6-hydroxydopamine model that require normalization when evaluating therapeutic effects. The gait parameters that were found to be affected by 6-hydroxydopamine lesioning of the nigrostriatal pathway in rats may be used to study novel transgenic models of Parkinson's disease as well as to test novel therapeutics. Previously, studies have used a video-based system to analyze gait abnormalities in the 6-hydroxydopamine model of Parkinson's disease, but these studies did not account for individual variability on reported gait parameters. By analyzing the ratio of parameters from the injured to uninjured sides and correcting for speed in related parameters, hindpaw step cycle parameters, hindpaw print area, and step sequence are significantly altered in different ways for each type of lesion, when compared to saline-injected controls. These findings enable new metrics for evaluating therapeutic efficacy of drug-, gene-, or cell-based therapies in rat models of Parkinson's disease.

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Acetyl- l -carnitine protects dopaminergic nigrostriatal pathway in 6-hydroxydopamine-induced model of Parkinson’s disease in the rat

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2017.02.007 ◽

2017 ◽

Vol 89 ◽

pp. 1-9 ◽

Cited By ~ 16

Author(s):

Siamak Afshin-Majd ◽

Keyhan Bashiri ◽

Zahra Kiasalari ◽

Tourandokht Baluchnejadmojarad ◽

Reza Sedaghat ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nigrostriatal Pathway ◽

6 Hydroxydopamine

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Effects of carnosine and lipoic acid in the late stage of Parkinson’s disease in rats

Bulletin of Russian State Medical University ◽

10.24075/brsmu.2019.060 ◽

2019 ◽

pp. 45-50

Author(s):

D.S. Berezhnoy ◽

T.N. Fedorova ◽

O.I. Kulikova ◽

A.V. Stavrovskaya ◽

D.A. Abaimov ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lipoic Acid ◽

Late Stage ◽

Right Hemisphere ◽

Neuroprotective Effect ◽

Neuronal Loss ◽

Fold Increase ◽

6 Hydroxydopamine ◽

The Right

The late stage of Parkinson’s disease is characterized by massive neuronal loss in the substantia nigra (SN) and degeneration of the dopaminergic innervation in the striatum. There is a need to assess the neuroprotective effect of antioxidants (AO) at this stage of the disease. The aim of our study was to assess the efficacy of two AO, carnosine and lipoic acid (LA), in the rat model of late-stage parkinsonism. The pathology was induced by a unilateral injection of 6-hydroxydopamine (6-OHDA) into the SN of the right brain hemisphere. AO were administered 4 times, starting on day 14 following the injection of the toxin. We investigated the effect of the injected drugs on the behavior of rats, the loss of neurons in the SN and the metabolism of biogenic neurotransmitter amines. Both AO dampened the development of 6-OHDA-induced neurological and behavioral symptoms. 6-OHDA induced a 90% drop (p = 0.01) in the levels of dopamine (DA) and its metabolites in the right striatum and caused death of over 95% of neurons (p = 0.01) in the SN of the right hemisphere (p = 0.01). AO did not have a significant effect on the number of neurons in the SN but caused an increase in the levels of DA metabolites, as compared to their levels in the animals exposed to 6-OHDA. Elevated DA (a 5.8-fold increase, p = 0.007) was observed only in the animals treated with carnosine. LA stimulated a 23% decline in serotonin levels (p = 0.06) and a 36% increase (p = 0.009) in its metabolite, 5-hydroxyindolacetic acid (5-HIAA). We conclude that although carnosine and LA did not have a direct neuroprotective effect, they could relieve the symptoms. This suggests that these AO could be used as an adjunctive component to antiparkinsonian therapy.

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Neuroprotective effects of Withania somnifera on 6-hydroxydopamine induced Parkinsonism in rats

Human & Experimental Toxicology ◽

10.1191/0960327105ht509oa ◽

2005 ◽

Vol 24 (3) ◽

pp. 137-147 ◽

Cited By ~ 112

Author(s):

Muzamil Ahmad ◽

Sofiyan Saleem ◽

Abdullah Shafique Ahmad ◽

Mubeen Ahmad Ansari ◽

Seema Yousuf ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Withania Somnifera ◽

Oxidant Stress ◽

Dependent Manner ◽

Glutathione S Transferase ◽

Neuroprotective Effects ◽

Ample Evidence ◽

6 Hydroxydopamine ◽

The Right

6-Hydroxydopamine (6-OHDA) is one of the most widely used rat models for Parkinson's disease. There is ample evidence in the literature that 6-OHDA elicits its toxic manifestations through oxidant stress. In the present study, we evaluated the anti-parkinsonian effects of Withania somnifera extract, which has been reported to have potent anti-oxidant, anti-peroxidative and free radical quenching properties in various diseased conditions. Rats were pretreated with 100, 200 and 300 mg/kg b.w. of the W. somnifera extract orally for 3 weeks. On day 21, 2 mL of 6-OHDA (10 mg in 0.1% in ascorbic acidsaline) was infused into the right striatum while sham operated group received 2 mL of the vehicle. Three weeks after 6-OHDA injections, rats were tested for neurobehavioral activity and were killed 5 weeks after lesioning for the estimation of lipidperoxidation, reduced glutathione content, activities of glutathione-S-transferase, glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase, catecholamine content, dopaminergic D2 receptor binding and tyrosine hydroxylase expression. W. somnifera extract was found to reverse all the parameters significantly in a dose-dependent manner. Thus, the study demonstrates that the extract of W. somnifera may be helpful in protecting the neuronal injury in Parkinson's disease.

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