Intensification of cataleptic response in 6-hydroxydopamine-induced neurodegeneration of substantia nigra is not dependent on the degree of dopamine depletion

Synapse ◽  
2003 ◽  
Vol 51 (3) ◽  
pp. 213-218 ◽  
Author(s):  
J. Srinivasan ◽  
Werner J. Schmidt
Keyword(s):  
Substantia Nigra ◽  
Dopamine Depletion ◽  
6 Hydroxydopamine

Upregulation of D2-class signaling in dopamine-denervated striatum is in part mediated by D3 receptors acting on CaV2.1 channels via PIP2 depletion

2011 ◽  
Vol 105 (5) ◽  
pp. 2260-2274 ◽  
Author(s):  
G. Aleph Prieto ◽  
Azucena Perez-Burgos ◽  
Marcela Palomero-Rivero ◽  
Elvira Galarraga ◽  
Rene Drucker-Colin ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Intracellular Signaling ◽  
Cell Voltage ◽  
Gaba Release ◽  
Projection Neurons ◽  
Striatal Neurons ◽  
Dopamine Depletion ◽  
R And D ◽  
Relative Contribution ◽  
6 Hydroxydopamine

The loss of dopaminergic neurons in the substantia nigra compacta followed by striatal dopamine depletion is a hallmark of Parkinson's disease. After dopamine depletion, dopaminergic D2 receptor (D2R)-class supersensitivity develops in striatal neurons. The supersensitivity results in an enhanced modulation of Ca2+ currents by D2R-class receptors. However, the relative contribution of D2R, D3R, and D4R types to the supersensitivity, as well as the mechanisms involved, have not been elucidated. In this study, whole cell voltage-clamp recordings were performed to study Ca2+ current modulation in acutely dissociated striatal neurons obtained from rodents with unilateral 6-hydroxydopamine lesions in the substantia nigra compacta. Selective antagonists for D2R, D3R, and D4R types were used to identify whether the modulation by one of these receptors experiences a selective change after dopaminergic denervation. It was found that D3R-mediated modulation was particularly enhanced. Increased modulation targeted CaV2.1 (P/Q) Ca2+ channels via the depletion of phosphatidylinositol 4,5-bisphosphate, an intracellular signaling cascade hard to detect in control neurons and hypothesized as being amplified by dopamine depletion. An imbalance in the striatal expression of D3R and its splice variant, D3nf, accompanied enhanced D3R activity. Because CaV2.1 Ca2+ channels mediate synaptic GABA release from the terminals of striatal neurons, reinforcement of their inhibition by D3R may explain in part the profound decrease in synaptic strength in the connections among striatal projection neurons observed in the dopamine-depleted striatum.

Substantia nigra hyperechogenicity and CSF dopamine depletion in HIV

2008 ◽  
Vol 35 (S 01) ◽  
Author(s):  
J Thiermann ◽  
M Obermann ◽  
M Küper ◽  
O Kastrup ◽  
Ö Yaldizli ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Dopamine Depletion ◽  
Substantia Nigra Hyperechogenicity

scholarly journals Neuroprotective Potential of a Small Molecule RET Agonist in Cultured Dopamine Neurons and Hemiparkinsonian Rats

2021 ◽  
pp. 1-24
Author(s):  
Juho-Matti Renko ◽  
Arun Kumar Mahato ◽  
Tanel Visnapuu ◽  
Konsta Valkonen ◽  
Mati Karelson ◽  
...  
Keyword(s):  
Mapk Signaling ◽  
Dopamine Neurons ◽  
Dopamine Depletion ◽  
Wild Type ◽  
Disease Modifying Therapy ◽  
Immortalized Cells ◽  
Midbrain Dopamine ◽  
6 Hydroxydopamine

Background: Parkinson’s disease (PD) is a progressive neurological disorder where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor symptoms. Currently, no treatment is able to halt the progression of PD. Glial cell line-derived neurotrophic factor (GDNF) rescues degenerating dopamine neurons both in vitro and in animal models of PD. When tested in PD patients, however, the outcomes from intracranial GDNF infusion paradigms have been inconclusive, mainly due to poor pharmacokinetic properties. Objective: We have developed drug-like small molecules, named BT compounds that activate signaling through GDNF’s receptor, the transmembrane receptor tyrosine kinase RET, both in vitro and in vivo and are able to penetrate through the blood-brain barrier. Here we evaluated the properties of BT44, a second generation RET agonist, in immortalized cells, dopamine neurons and rat 6-hydroxydopamine model of PD. Methods: We used biochemical, immunohistochemical and behavioral methods to evaluate the effects of BT44 on dopamine system in vitro and in vivo. Results: BT44 selectively activated RET and intracellular pro-survival AKT and MAPK signaling pathways in immortalized cells. In primary midbrain dopamine neurons cultured in serum-deprived conditions, BT44 promoted the survival of the neurons derived from wild-type, but not from RET knockout mice. BT44 also protected cultured wild-type dopamine neurons from MPP +-induced toxicity. In a rat 6-hydroxydopamine model of PD, BT44 reduced motor imbalance and could have protected dopaminergic fibers in the striatum. Conclusion: BT44 holds potential for further development into a novel, possibly disease-modifying therapy for PD.

scholarly journals In vivo electrophysiology of nigral and thalamic neurons in alpha-synuclein-overexpressing mice highlights differences from toxin-based models of parkinsonism

2013 ◽  
Vol 110 (12) ◽  
pp. 2792-2805 ◽  
Author(s):  
C. J. Lobb ◽  
A. K. Zaheer ◽  
Y. Smith ◽  
D. Jaeger
Keyword(s):  
Primary Motor Cortex ◽  
Alpha Synuclein ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Dopamine Depletion ◽  
Wild Type ◽  
Beta Oscillations ◽  
Nigrostriatal Dopamine ◽  
6 Hydroxydopamine

Numerous studies have suggested that alpha-synuclein plays a prominent role in both familial and idiopathic Parkinson's disease (PD). Mice in which human alpha-synuclein is overexpressed (ASO) display progressive motor deficits and many nonmotor features of PD. However, it is unclear what in vivo pathophysiological mechanisms drive these motor deficits. It is also unknown whether previously proposed pathophysiological features (i.e., increased beta oscillations, bursting, and synchronization) described in toxin-based, nigrostriatal dopamine-depletion models are also present in ASO mice. To address these issues, we first confirmed that 5- to 6-mo-old ASO mice have robust motor dysfunction, despite the absence of significant nigrostriatal dopamine degeneration. In the same animals, we then recorded simultaneous single units and local field potentials (LFPs) in the substantia nigra pars reticulata (SNpr), the main basal ganglia output nucleus, and one of its main thalamic targets, the ventromedial nucleus, as well as LFPs in the primary motor cortex in anesthetized ASO mice and their age-matched, wild-type littermates. Neural activity was examined during slow wave activity and desynchronized cortical states, as previously described in 6-hydroxydopamine-lesioned rats. In contrast to toxin-based models, we found a small decrease, rather than an increase, in beta oscillations in the desynchronized state. Similarly, synchronized burst firing of nigral neurons observed in toxin-based models was not observed in ASO mice. Instead, we found more subtle changes in pauses of SNpr firing compared with wild-type control mice. Our results suggest that the pathophysiology underlying motor dysfunction in ASO mice is distinctly different from striatal dopamine-depletion models of parkinsonism.

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

2010 ◽  
Vol 1328 ◽  
pp. 139-151 ◽  
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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