Unilateral Dopamine Denervation Blocks Corticostriatal LTP

The nigrostriatal dopaminergic projection is crucial for the striatal processing of motor information received from the cortex. Lesion of this pathway in rats causes locomotor alterations that resemble some of the symptoms of Parkinson's disease and significantly alters the excitatory transmission in the striatum. We performed in vitro electrophysiological recordings to study the effects of unilateral striatal dopamine (DA) denervation obtained by omolateral nigral injection of 6-hydroxydopamine (6-OHDA) in the formation of corticostriatal long-term potentiation (LTP). Unilateral nigral lesion did not affect the intrinsic membrane properties of striatal spiny neurons. In fact, these cells showed similar pattern of firing discharge and current-voltage relationship in denervated striata and in naive controlateral striata. Moreover, excitatory postsynaptic potentials (EPSPs) evoked by stimulating corticostriatal fibers and recorded from DA-denervated slices showed a pharmacology similar to that observed in slices obtained from controlateral intact striata. Conversely, in magnesium-free medium, high-frequency stimulation (HFS) of corticostriatal fibers produced LTP in slices from nondenervated striata but not in slices from 6-OHDA–denervated rats. After denervation, in fact, no significant changes in the amplitude of extra- and intracellular synaptic potentials were recorded after the conditioning HFS. The absence of corticostriatal LTP in DA-denervated striata might represent the cellular substrate for some of the movement disorders observed in Parkinson's disease.

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Maackiain Ameliorates 6-Hydroxydopamine and SNCA Pathologies by Modulating the PINK1/Parkin Pathway in Models of Parkinson’s Disease in Caenorhabditis elegans and the SH-SY5Y Cell Line

International Journal of Molecular Sciences ◽

10.3390/ijms21124455 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4455

Author(s):

Rong-Tzong Tsai ◽

Chia-Wen Tsai ◽

Shih-Ping Liu ◽

Jia-Xin Gao ◽

Yun-Hua Kuo ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Caenorhabditis Elegans ◽

Cell Line ◽

Ubiquitin Proteasome System ◽

Substantia Nigra Pars Compacta ◽

Neuron Damage ◽

6 Hydroxydopamine

The movement disorder Parkinson’s disease (PD) is the second most frequently diagnosed neurodegenerative disease, and is associated with aging, the environment, and genetic factors. The intracellular aggregation of α-synuclein and the loss of dopaminergic neurons in the substantia nigra pars compacta are the pathological hallmark of PD. At present, there is no successful treatment for PD. Maackiain (MK) is a flavonoid extracted from dried roots of Sophora flavescens Aiton. MK has emerged as a novel agent for PD treatment that acts by inhibiting monoamine oxidase B. In this study, we assessed the neuroprotective potential of MK in Caenorhabditis elegans and investigated possible mechanism of this neuroprotection in the human SH-SY5Y cell line. We found that MK significantly reduced dopaminergic neuron damage in 6-hydroxydopamine (6-OHDA)-exposed worms of the BZ555 strain, with corresponding improvements in food-sensing behavior and life-span. In transgenic worms of strain NL5901 treated with 0.25 mM MK, the accumulation of α-synuclein was diminished by 27% (p < 0.01) compared with that in untreated worms. Moreover, in worms and the SH-SY5Y cell line, we confirmed that the mechanism of MK-mediated protection against PD pathology may include blocking apoptosis, enhancing the ubiquitin-proteasome system, and augmenting autophagy by increasing PINK1/parkin expression. The use of small interfering RNA to downregulate parkin expression in vivo and in vitro could reverse the benefits of MK in PD models. MK may have considerable therapeutic applications in PD.

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Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: Relevance to Parkinson's disease

Neurobiology of Disease ◽

10.1016/j.nbd.2004.11.009 ◽

2005 ◽

Vol 19 (1-2) ◽

pp. 96-107 ◽

Cited By ~ 213

Author(s):

Isabel Lastres-Becker ◽

Francisco Molina-Holgado ◽

José A. Ramos ◽

Raphael Mechoulam ◽

Javier Fernández-Ruiz

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

6 Hydroxydopamine

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Disruption of the Circadian Clock Alters Antioxidative Defense via the SIRT1-BMAL1 Pathway in 6-OHDA-Induced Models of Parkinson’s Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4854732 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 14

Author(s):

Yali Wang ◽

Dongjun Lv ◽

Wenwen Liu ◽

Siyue Li ◽

Jing Chen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Circadian Clock ◽

Antioxidative Activity ◽

Expression Patterns ◽

Antioxidative Defense ◽

Real Time Quantitative Pcr ◽

6 Hydroxydopamine

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is known to involve circadian dysfunction and oxidative stress. Although antioxidative defense is regulated by the molecular circadian clock, few studies have examined their function in PD and their regulation by silent information regulator 1 (SIRT1). We hypothesize that reduced antioxidative activity in models of PD results from dysfunction of the molecular circadian clock via the SIRT1 pathway. We treated rats and SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) and measured the expression of core circadian clock and associated nuclear receptor genes using real-time quantitative PCR as well as levels of SIRT1, brain and muscle Arnt-like protein 1 (BMAL1), and acetylated BMAL1 using Western blotting. We found that 6-OHDA treatment altered the expression patterns of clock and antioxidative molecules in vivo and in vitro. We also detected an increased ratio of acetylated BMAL1:BMAL1 and a decreased level of SIRT1. Furthermore, resveratrol, an activator of SIRT1, decreased the acetylation of BMAL1 and inhibited its binding with CRY1, thereby reversing the impaired antioxidative activity induced by 6-OHDA. These results suggest that a dysfunctional circadian clock contributes to an abnormal antioxidative response in PD via a SIRT1-dependent BMAL1 pathway.

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Effect of PAR‐1 Receptor Inhibition in an In Vitro 6‐hydroxydopamine Model of Parkinson’s Disease Using Differentiated PC12 Cell Line and Undifferentiated SH‐SY5Y Cell Line.

The FASEB Journal ◽

10.1096/fasebj.2020.34.s1.00103 ◽

2020 ◽

Vol 34 (S1) ◽

pp. 1-1

Author(s):

Kalyani Narendra Natu ◽

Mattia M. Migliore

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Line ◽

Pc12 Cell ◽

Pc12 Cell Line ◽

Receptor Inhibition ◽

6 Hydroxydopamine

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Hesperetin protects SH-SY5Y cells against 6- hydroxydopamine-induced neurotoxicity via activation of NRF2/ARE signaling pathways

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i6.12 ◽

2020 ◽

Vol 19 (6) ◽

pp. 1197-1201 ◽

Cited By ~ 1

Author(s):

Jing Li ◽

Yue Liu ◽

Li Wang ◽

Zhaowei Gu ◽

Zhigang Huan ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Viability ◽

Heme Oxygenase 1 ◽

Protective Effects ◽

Neuroprotective Effects ◽

Ldh Release ◽

6 Hydroxydopamine

Purpose: To investigation the protective effects of hesperetin against 6-hydroxydopamine (6-OHDA)- induced neurotoxicity. Methods: SH-SY5Y cells were incubated with 6-OHDA to create an in vitro model of neurotoxicity. This model was used to test the neuroprotective effects of hesperetin. Cell viability was assessed by MTT and lactate dehydrogenase (LDH) release assays. Flow cytometry and western blot were used to quantify apoptosis. Oxidative stress was evaluated by determining intracellular glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS). Results: In SH-SY5Y cells, treatment with 6-OHDA decreased cell viability and promoted LDH release. However, exogenous hesperetin protected against 6-OHDA-mediated toxicity. Similarly, although incubation with 6-OHDA induced apoptosis and increased cleaved caspase-3 and -9 levels, treatment with hesperetin protected against these effects. Treatment with 6-OHDA also led to significant oxidative stress, as indicated by reduced GSH and SOD levels and increased MDA and ROS levels in SH-SY5Y cells. However, these changes were reversed by pre-treatment with hesperetin. Of interest, hesperetin led to changes in 6-OHDA-induced expression of NRF2, heme oxygenase-1 (HO-1), glutamate-cysteine ligase (GCL) catalytic subunit (GCLC), and GCL modulatory (GCLM). Conclusion: Hesperetin protects against cell toxicity, apoptosis, and oxidative stress via activation of NRF2 pathway in a 6-OHDA-induced model of neurotoxicity. Future studies should investigate the use of hesperetin as a potential therapeutic approach for prevention or management of Parkinson’s disease. Keywords: Hesperetin, 6-OHDA, Neurotoxicity, NRF2, Parkinson’s disease

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Carvacrol Protects Against 6-Hydroxydopamine-Induced Neurotoxicity in In Vivo and In Vitro Models of Parkinson’s Disease

Neurotoxicity Research ◽

10.1007/s12640-019-00088-w ◽

2019 ◽

Vol 37 (1) ◽

pp. 156-170 ◽

Cited By ~ 4

Author(s):

Mahboubeh Manouchehrabadi ◽

Mona Farhadi ◽

Zahra Azizi ◽

Anahita Torkaman-Boutorabi

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

In Vitro Models ◽

6 Hydroxydopamine

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Electroacupuncture Restores Spatial Learning and Downregulates Phosphorylated N-Methyl-D-Aspartate Receptors in a Mouse Model of Parkinson's Disease

Acupuncture in Medicine ◽

10.1136/acupmed-2015-011041 ◽

2017 ◽

Vol 35 (2) ◽

pp. 133-141 ◽

Cited By ~ 15

Author(s):

Kung-Wen Lu ◽

Jun Yang ◽

Ching-Liang Hsieh ◽

Yu-Chan Hsu ◽

Yi-Wen Lin

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nmda Receptor ◽

Protein Kinase ◽

Spatial Learning ◽

Long Term Potentiation ◽

Camp Response Element Binding ◽

Morris Water Maze Task ◽

Element Binding Protein ◽

6 Hydroxydopamine

Objective Parkinson's disease (PD) is a degenerative disorder of the central nervous system. PD can be classified as idiopathic, acquired or hereditary and may be caused by various factors such as oxidative stress, loss of mitochondrial function, neuronal excitotoxicity or calcium imbalance. Methods We hypothesised that electroacupuncture (EA) at KI3 would reduce neuronal excitotoxicity by regulating N-methyl-D-aspartate (NMDA) receptor function and may represent a novel therapeutic approach for PD. Results Our results showed that deficits in spatial learning (reflected by the escape latency time in the Morris water maze task) and long-term potentiation (LTP) caused by systemic 6-hydroxydopamine (6-OHDA) administration (that damages dopaminergic neurons) could be rescued by EA on day 3. In PD mice, phosphorylated NMDA receptor subunits NR1 and NR2B were elevated (134.03±10.17% and 123.46±3.47% of baseline levels, respectively) but total NR1 and NR2B was unaffected (101.37±3.87% and 102.61±4.22% of baseline, respectively). Elevated levels of pNR1 and pNR2B, and phosphorylated forms of protein kinase A, protein kinase C, α Ca2+/calmodulin-dependent protein kinase extracellular signal-regulated kinases (pERK), and cAMP response element-binding protein were also reduced following EA. Conclusions These novel findings suggest that EA can rescue learning and LTP deficits in a rodent model of PD. The results point to a possible role for EA-based approaches in the clinical treatment of learning deficits associated with PD.

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Tetramethylpyrazine Analogue T-006 Exerts Neuroprotective Effects against 6-Hydroxydopamine-Induced Parkinson’s Disease In Vitro and In Vivo

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/8169125 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Hefeng Zhou ◽

Min Shao ◽

Xuanjun Yang ◽

Chuwen Li ◽

Guozhen Cui ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Motor Coordination ◽

Neurodegenerative Disorder ◽

Nerve Fibers ◽

Substantia Nigra Pars Compacta ◽

Neuroprotective Effects ◽

6 Hydroxydopamine

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and there is no cure for it at present. We have previously reported that the tetramethylpyrazine (TMP) derivative T-006 exhibited beneficial effects in Alzheimer’s disease (AD) models. However, its effect on PD remains unclear. In the present study, we investigated the neuroprotective effects and underlying mechanisms of T-006 against 6-hydroxydopamine- (6-OHDA-) induced lesions in in vivo and in vitro PD models. Our results demonstrated that T-006 alleviated mitochondrial membrane potential loss and restored the energy metabolism and mitochondrial biogenesis that were induced by 6-OHDA in PC12 cells. In addition, animal experiments showed that administration of T-006 significantly attenuated the 6-OHDA-induced loss of tyrosine hydroxylase- (TH-) positive neurons in the SNpc, as well as dopaminergic nerve fibers in the striatum, and also increased the concentration of dopamine and its metabolites (DOPAC, HVA) in the striatum. Functional deficits were restored following T-006 treatment in 6-OHDA-lesioned mice, as demonstrated by improved motor coordination and rotational behavior. In addition, we found that the neuroprotective effects of T-006 were mediated, at least in part, by the activation of both the PKA/Akt/GSK-3β and CREB/PGC-1α/NRF-1/TFAM pathways. In summary, our findings demonstrate that T-006 could be developed as a novel neuroprotective agent for PD, and the two pathways might be promising therapeutic targets for PD.

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