• Title/Summary/Keyword: L-DOPA therapy

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Neuroprotective Effects of Herbal Ethanol Extracts from Gynostemma pentaphyllum on L-DOPA Therapy in 6-hydroxydopamine-lesioned Rat Model of Parkinson's Disease (돌외 에탄올 추출물 엑스가 6-hydroxydopamine-유도 파킨슨병 백서 모델에서의 L-DOPA 요법에 미치는 영향)

  • Suh, Kwang-Hoon;Choi, Hyun-Sook;Shin, Keon-Seong;Hwang, Bang-Yeon;Lee, Myung-Koo
    • Korean Journal of Pharmacognosy
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    • v.42 no.4
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    • pp.341-347
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    • 2011
  • The neuroprotective effects of herbal ethanol extracts from Gynostemma pentaphyllum (GP-EX) in 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease treated with L-DOPA were investigated. Rats were prepared for the Parkinson's disease model by 6-OHDA-lesioning for 14 days. The rats were then treated with L-DOPA (10 and 20 mg/kg) with or without the oral administration of GP-EX (30 mg/kg, daily) for 28 days. L-DOPA (20 mg/kg) treatment for 28 days enhanced dopaminergic neuronal cell death in 6-OHDA-lesioned rat groups, but L-DOPA (10 mg/kg) did not. However, the oral administration of GP-EX (30 mg/kg) for 28 days ameliorated the enhanced neurotoxic effects induced by chronic L-DOPA treatment in 6-OHDA-lesioned rat groups by increasing tyrosine hydroxylase (TH)-immunohistochemical staining and the number of TH-immunopositive cells surviving in the substantia nigra. In addition, GP-EX administration (30 mg/kg) for 28 days recovered the levels of dopamine and norepinephrine of the striatum in 6-OHDA-lesioned rat groups, which were markedly reduced by L-DOPA treatment (20 mg/kg). GP-EX (30 mg/kg) did not produce any signs of toxicity, such as weight loss, diarrhea, or vomiting in rats during the 28-day treatment period. These results suggest that GP-EX has protective functions against chronic L-DOPA-induced neurotoxic reactions in dopaminergic neurons in the 6-OHDA-lesioned rat model of Parkinson's disease. Therefore, GP-EX may be beneficial in the prevention of adverse symptoms in parkisonian patients.

In silico discovery and evaluation of phytochemicals binding mechanism against human catechol-O-methyltransferase as a putative bioenhancer of L-DOPA therapy in Parkinson disease

  • Rath, Surya Narayan;Jena, Lingaraja;Bhuyan, Rajabrata;Mahanandia, Nimai Charan;Patri, Manorama
    • Genomics & Informatics
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    • v.19 no.1
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    • pp.7.1-7.13
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    • 2021
  • Levodopa (L-DOPA) therapy is normally practised to treat motor pattern associated with Parkinson disease (PD). Additionally, several inhibitory drugs such as Entacapone and Opicapone are also cosupplemented to protect peripheral inactivation of exogenous L-DOPA (~80%) that occurs due to metabolic activity of the enzyme catechol-O-methyltransferase (COMT). Although, both Entacapone and Opicapone have U.S. Food and Drug Administration approval but regular use of these drugs is associated with high risk of side effects. Thus, authors have focused on in silico discovery of phytochemicals and evaluation of their effectiveness against human soluble COMT using virtual screening, molecular docking, drug-like property prediction, generation of pharmacophoric property, and molecular dynamics simulation. Overall, study proposed, nine phytochemicals (withaphysalin D, withaphysalin N, withaferin A, withacnistin, withaphysalin C, withaphysalin O, withanolide B, withasomnine, and withaphysalin F) of plant Withania somnifera have strong binding efficiency against human COMT in comparison to both of the drugs i.e., Opicapone and Entacapone, thus may be used as putative bioenhancer in L-DOPA therapy. The present study needs further experimental validation to be used as an adjuvant in PD treatment.

Effects of Berberine on L-DOPA Therapy in 6-Hydroxydopamine-induced Rat Models of Parkinsonism (Berberine이 백서의 6-Hydroxydopamine-유도 파킨슨병 모델에서의 L-DOPA 요법에 미치는 영향)

  • Shin, Kun-Seong;Kwon, Ik-Hyun;Choi, Hyun-Sook;Lim, Sung-Cil;Hwang, Bang-Yeon;Lee, Myung-Koo
    • YAKHAK HOEJI
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    • v.55 no.6
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    • pp.510-515
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    • 2011
  • Isoquinoline compounds including berberine enhance L-DOPA-induced cytotoxicity in PC12 cells. In this study, the effects of berberine on L-DOPA therapy in unilateral 6-hydroxydopamine (6-OHDA)-induced rat models of parkinsonism were investigated. Rats were prepared for the models of Parkinson's disease by 6-OHDA-lesioning for 14 days and then treated with L-DOPA (10 mg/kg) with or without berberine (5 and 30 mg/kg, i.p.) for 21 days. Treatment with berberine (5 and 30 mg/kg, i.p.) showed a dopaminergic cell loss in substantia nigra of 6-OHDA-lesioned rats treated with L-DOPA: 30 mg/kg berberine was more intensive neurotoxic. The levels of dopamine were also decreased by berberine (5 and 30 mg/ kg) in striatum-substantia nigra of 6-OHDA-lesioned rats treated with L-DOPA. These results suggest that berberine aggravates cell death of dopaminergic neurons in L-DOPA-treated 6-OHDA-lesioned rat models of Parkinson's disease. Therefore, the long-term L-DOPA therapeutic patients with isoquinoline compounds including berberine may need to be checked for the adverse symptoms.

cAMP Response Element-Binding Protein- and Phosphorylation-Dependent Regulation of Tyrosine Hydroxylase by PAK4: Implications for Dopamine Replacement Therapy

  • Won, So-Yoon;You, Soon-Tae;Choi, Seung-Won;McLean, Catriona;Shin, Eun-Young;Kim, Eung-Gook
    • Molecules and Cells
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    • v.44 no.7
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    • pp.493-499
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    • 2021
  • Parkinson's disease (PD) is characterized by a progressive loss of dopamine-producing neurons in the midbrain, which results in decreased dopamine levels accompanied by movement symptoms. Oral administration of l-3,4-dihydroxyphenylalanine (L-dopa), the precursor of dopamine, provides initial symptomatic relief, but abnormal involuntary movements develop later. A deeper understanding of the regulatory mechanisms underlying dopamine homeostasis is thus critically needed for the development of a successful treatment. Here, we show that p21-activated kinase 4 (PAK4) controls dopamine levels. Constitutively active PAK4 (caPAK4) stimulated transcription of tyrosine hydroxylase (TH) via the cAMP response element-binding protein (CREB) transcription factor. Moreover, caPAK4 increased the catalytic activity of TH through its phosphorylation of S40, which is essential for TH activation. Consistent with this result, in human midbrain tissues, we observed a strong correlation between phosphorylated PAK4S474, which represents PAK4 activity, and phosphorylated THS40, which reflects their enzymatic activity. Our findings suggest that targeting the PAK4 signaling pathways to restore dopamine levels may provide a new therapeutic approach in PD.