DOES ABNORMAL SPINAL RECIPROCAL INHIBITION LEAD TO CO-CONTRACTION OF ANTAGONIST MOTOR UNITS? A MODELING STUDY

It is suggested that co-contraction of antagonist motor units perhaps due to abnormal disynaptic I a reciprocal inhibition is responsible for Parkinsonian rigidity. A neural model of Parkinson's disease bradykinesia is extended to incorporate the effects of spindle feedback on key cortical cells and examine the effects of dopamine depletion on spinal activities. Simulation results show that although reciprocal inhibition is reduced in DA depleted case, it doesn't lead to co-contraction of antagonist motor neurons. Implications to Parkinsonian rigidity are discussed.

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Association of the Non-Motor Burden with Patterns of Striatal Dopamine Loss in de novo Parkinson’s Disease

Journal of Parkinson s Disease ◽

10.3233/jpd-202127 ◽

2020 ◽

Vol 10 (4) ◽

pp. 1541-1549

Author(s):

Seok Jong Chung ◽

Sangwon Lee ◽

Han Soo Yoo ◽

Yang Hyun Lee ◽

Hye Sun Lee ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

De Novo ◽

Early Stage ◽

Striatal Dopamine ◽

Motor Deficits ◽

Dopamine Depletion ◽

Severe Motor ◽

Severe Group ◽

Striatal Dopamine Depletion

Background: Striatal dopamine deficits play a key role in the pathogenesis of Parkinson’s disease (PD), and several non-motor symptoms (NMSs) have a dopaminergic component. Objective: To investigate the association between early NMS burden and the patterns of striatal dopamine depletion in patients with de novo PD. Methods: We consecutively recruited 255 patients with drug-naïve early-stage PD who underwent 18F-FP-CIT PET scans. The NMS burden of each patient was assessed using the NMS Questionnaire (NMSQuest), and patients were divided into the mild NMS burden (PDNMS-mild) (NMSQuest score <6; n = 91) and severe NMS burden groups (PDNMS-severe) (NMSQuest score >9; n = 90). We compared the striatal dopamine transporter (DAT) activity between the groups. Results: Patients in the PDNMS-severe group had more severe parkinsonian motor signs than those in the PDNMS-mild group, despite comparable DAT activity in the posterior putamen. DAT activity was more severely depleted in the PDNMS-severe group in the caudate and anterior putamen compared to that in the PDMNS-mild group. The inter-sub-regional ratio of the associative/limbic striatum to the sensorimotor striatum was lower in the PDNMS-severe group, although this value itself lacked fair accuracy for distinguishing between the patients with different NMS burdens. Conclusion: This study demonstrated that PD patients with severe NMS burden exhibited severe motor deficits and relatively diffuse dopamine depletion throughout the striatum. These findings suggest that the level of NMS burden could be associated with distinct patterns of striatal dopamine depletion, which could possibly indicate the overall pathological burden in PD.

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Resveratrol attenuates 6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson's disease

Brain Research ◽

10.1016/j.brainres.2010.02.031 ◽

2010 ◽

Vol 1328 ◽

pp. 139-151 ◽

Cited By ~ 142

Author(s):

Mohd.Moshahid Khan ◽

Ajmal Ahmad ◽

Tauheed Ishrat ◽

M. Badruzzaman Khan ◽

Md. Nasrul Hoda ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Oxidative Damage ◽

Rat Model ◽

Dopamine Depletion ◽

6 Hydroxydopamine

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Changes in excitability properties of ventromedial motor thalamic neurons in 6-OHDA lesioned mice

10.1101/2020.10.05.327379 ◽

2020 ◽

Author(s):

Edyta K Bichler ◽

Francesco Cavarretta ◽

Dieter Jaeger

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Basal Ganglia ◽

Potassium Current ◽

Cellular Level ◽

Inhibitory Input ◽

Dopamine Depletion ◽

Thalamic Nuclei ◽

Adult Mice ◽

Motor Thalamus

AbstractThe activity of basal ganglia input receiving motor thalamus (BGMT) makes a critical impact on motor cortical processing, but modification in BGMT processing with Parkinsonian conditions have not be investigated at the cellular level. Such changes may well be expected due to homeostatic regulation of neural excitability in the presence of altered synaptic drive with dopamine depletion. We addressed this question by comparing BGMT properties in brain slice recordings between control and unilaterally 6-OHDA treated adult mice. At a minimum of 1 month post 6-OHDA treatment, BGMT neurons showed a highly significant increase in intrinsic excitability, which was primarily due to a decrease in M-type potassium current. BGMT neurons after 6-OHDA treatment also showed an increase in T-type calcium rebound spikes following hyperpolarizing current steps. Biophysical computer modeling of a thalamic neuron demonstrated that an increase in rebound spiking can also be accounted for by a decrease in the M-type potassium current. Modeling also showed that an increase in sag with hyperpolarizing steps found after 6-OHDA treatment could in part but not fully be accounted for by the decrease in M-type current. These findings support the hypothesis that homeostatic changes in BGMT neural properties following 6-OHDA treatment likely influence the signal processing taking place in basal ganglia thalamocortical processing in Parkinson’s disease.Significance StatementOur investigation of the excitability properties of neurons in the basal ganglia input receiving motor thalamus (BGMT) is significant because they are likely to be different from properties in other thalamic nuclei due to the additional inhibitory input stream these neurons receive. Further, they are important to understand the role of BGMT in the dynamic dysfunction of cortico – basal ganglia circuits in Parkinson’s disease. We provide clear evidence that after 6-OHDA treatment of mice important homeostatic changes occur in the intrinsic properties of BGMT neurons. Specifically we identify the M-type potassium current as an important thalamic excitability regulator in the parkinsonian state.

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Oxidative stress and dopamine depletion in an intrastriatal 6-hydroxydopamine model of Parkinson’s disease

Neuroscience ◽

10.1016/j.neuroscience.2006.10.004 ◽

2007 ◽

Vol 144 (3) ◽

pp. 1057-1066 ◽

Cited By ~ 54

Author(s):

M.P. Smith ◽

W.A. Cass

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopamine Depletion ◽

6 Hydroxydopamine

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Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson’s disease

Molecular Biology of the Cell ◽

10.1091/mbc.e15-06-0415 ◽

2015 ◽

Vol 26 (24) ◽

pp. 4478-4491 ◽

Cited By ~ 19

Author(s):

BK. Binukumar ◽

Varsha Shukla ◽

Niranjana D. Amin ◽

Philip Grant ◽

M. Bhaskar ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Neuroprotective Effect ◽

Selective Inhibition ◽

Motor Dysfunction ◽

Dopamine Neurons ◽

Dopamine Depletion ◽

Neuroprotective Effects

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions, including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer’s disease. Here we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Here we show selective inhibition of Cdk5/p25 hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson’s disease.

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Isolongifolene mitigates rotenone-induced dopamine depletion and motor deficits through anti-oxidative and anti-apoptotic effects in a rat model of Parkinson's disease

Journal of Chemical Neuroanatomy ◽

10.1016/j.jchemneu.2020.101890 ◽

2021 ◽

Vol 112 ◽

pp. 101890

Author(s):

Rengasamy Balakrishnan ◽

Dhanraj Vijayraja ◽

Thangavel Mohankumar ◽

Dharmar Manimaran ◽

Palanivel Ganesan ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rat Model ◽

Motor Deficits ◽

Dopamine Depletion ◽

Apoptotic Effects

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Inflammatory Animal Model for Parkinson's Disease: The Intranigral Injection of LPS Induced the Inflammatory Process along with the Selective Degeneration of Nigrostriatal Dopaminergic Neurons

ISRN Neurology ◽

10.5402/2011/476158 ◽

2011 ◽

Vol 2011 ◽

pp. 1-16 ◽

Cited By ~ 29

Author(s):

A. Machado ◽

A. J. Herrera ◽

J. L. Venero ◽

M. Santiago ◽

R. M. de Pablos ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Animal Model ◽

Dopaminergic Neurons ◽

Inflammatory Process ◽

Dopaminergic System ◽

Neuronal System ◽

Dopamine Depletion ◽

Anti Inflammatory ◽

Dopaminergic Degeneration

We have developed an animal model of degeneration of the nigrostriatal dopaminergic neurons, the neuronal system involved in Parkinson's disease (PD). The implication of neuroinflammation on this disease was originally established in 1988, when the presence of activated microglia in the substantia nigra (SN) of parkinsonians was reported by McGeer et al. Neuroinflammation could be involved in the progression of the disease or even has more direct implications. We injected 2 μg of the potent proinflammatory compound lipopolysaccharide (LPS) in different areas of the CNS, finding that SN displayed the highest inflammatory response and that dopaminergic (body) neurons showed a special and specific sensitivity to this process with the induction of selective dopaminergic degeneration. Neurodegeneration is induced by inflammation since it is prevented by anti-inflammatory compounds. The special sensitivity of dopaminergic neurons seems to be related to the endogenous dopaminergic content, since it is overcome by dopamine depletion. Compounds that activate microglia or induce inflammation have similar effects to LPS. This model suggest that inflammation is an important component of the degeneration of the nigrostriatal dopaminergic system, probably also in PD. Anti-inflammatory treatments could be useful to prevent or slow down the rate of dopaminergic degeneration in this disease.

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Phytochemicals as future drugs for Parkinson’s disease: a comprehensive review

Reviews in the Neurosciences ◽

10.1515/revneuro-2016-0004 ◽

2016 ◽

Vol 27 (6) ◽

pp. 651-668 ◽

Cited By ~ 27

Author(s):

Zahra Shahpiri ◽

Roodabeh Bahramsoltani ◽

Mohammad Hosein Farzaei ◽

Fatemeh Farzaei ◽

Roja Rahimi

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Prostaglandin E ◽

Pharmaceutical Drugs ◽

Dopamine Depletion ◽

Therapeutic Approaches ◽

Positive Effects ◽

Fatty Acid Amides ◽

Therapeutic Benefits ◽

Wide Range

AbstractParkinson’s disease (PD) is the second most common chronic neurodegenerative disease that affects motor skills and cognitive performance. The conventional therapeutic approaches for the management of PD are just able to alleviate symptoms. Exploring for achieving novel substances with therapeutic benefits in PD patients is the focus of a wide range of current investigations. The aim of the present study is to comprehensively review phytochemicals with protective or therapeutic activities in PD and focus on their neuropsychopharmacological mechanisms. Various subgroups of polyphenols (flavonoids, phenolic acids, stilbenes, and lignanes) and terpenes are the most abundant groups of phytochemicals with well-established antiparkinsonian effects. Other phytochemical categories, such as alkaloids, cinnamates, carbohydrates, amino acids, and fatty acid amides, also have some representatives with positive effects in PD. Phytochemicals perform their antiparkinsonian effect through several mechanisms of action, including suppressing apoptosis (via the reduction of Bax/Bcl-2, caspase-3, -8, and -9, and α-synuclein accumulation), decreasing dopaminergic neuronal loss and dopamine depletion, reducing the expression of proinflammatory cytokines (such as prostaglandin E2, interleukin-6, interleukin-1β, and nuclear factor-κB), and modulating nuclear and cellular inflammatory signaling, elevation of neurotrophic factors, and improvement of antioxidant status. Plant-derived natural products can be considered as future pharmaceutical drugs or adjuvant treatment with conventional therapeutic approaches to improve their efficacy and alleviate their psychological adverse effects in the management of PD. Well-designed clinical trials are mandatory to evaluate the protective and healing benefits of phytochemicals as promising future drugs in the management of neurodegenerative diseases.

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