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Levodopa (L-dopa) and catechol-O-methyltransferase (COMT) inhibition are widely used therapeutics in Parkinson's disease (PD). Despite their therapeutic effects, it was raised that nutrients involved in one-carbon metabolism can be deteriorated by PD therapies. The aim of this meta-analysis was to investigate the impact of L-dopa and COMT inhibitors on levels of homocysteine (Hcy), vitamin B 12 and folate in patients with PD. A total of 35 case-control studies from 14 different countries were selected through PubMed, MEDLINE and Google Scholar and were meta-analyzed. In the L-dopa group, the Hcy level was higher compared to the PD without L-dopa group (SMD: 5.11 μmol/L, 95% CI: 3.56 to 6.66). Moreover, vitamin B 12 and folate levels in the L-dopa group were lower compared to the healthy control (SMD: -62.67 pg/mL, 95% CI: -86.53 to -38.81; SMD: -0.89 ng/mL, 95% CI: -1.44 to -0.33, respectively). The COMT inhibitor group showed lower levels of Hcy (SMD: -3.78 μmol/L, 95% CI: -5.27 to -2.29) and vitamin B 12 (SMD: -51.01 pg/mL, 95% CI: -91.45 to -10.57), but higher folate levels (SMD: 1.78 ng/mL, 95% CI: -0.59 to 4.15) compared to the L-dopa group. COMT inhibitors may ameliorate L-dopa-induced hyper-homocysteine and folate deficiency but exacerbate vitamin B 12 deficiency.

mPGES-1 is found to be up-regulated in the dopaminergic neurons of the substantia nigra pars compacta (SNpc) of postmortem brain tissue from Parkinson's disease (PD) patients and neurotoxin 6-hydroxydopamine (6-OHDA)-induced PD mice. Since the genetic deletion of mPGES-1 abolished 6-OHDA-induced PGE 2 production and 6-OHDA-induced dopaminergic neurodegeneration in vitro and in vivo models, mPGES-1 enzyme has the potential to be an important target for PD therapy. In the present work, we investigated whether a small organic molecule as mPGES-1 inhibitor could exhibit the neuroprotective effects against 6-OHDA-induced neurotoxicity in in vitro and in vivo models. For this research goal, a new series of arylsulfonyl hydrazide derivatives was prepared and investigated whether these compounds may protect neurons against 6-OHDA-induced neurotoxicity in both in vitro and in vivo studies. Among them, compound 7s (MPO-0144) as a mPGES-1 inhibitor (PGE 2 IC 50  = 41.77 nM; mPGES-1 IC 50  = 1.16 nM) exhibited a potent neuroprotection (ED 50  = 3.0 nM) against 6-OHDA-induced in PC12 cells without its own neurotoxicity (IC 50  = >10 μM). In a 6-OHDA-induced mouse model of PD, administration of compound 7s (1 mg/kg/day, for 7 days, i.p.) ameliorated motor impairments and dopaminergic neuronal damage. These significant biological effects of compound 7s provided the first pharmacological evidence that mPGES-1 inhibitor could be a promising therapeutic agent for PD patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

With the elderly population rapidly growing, the prevalence of Parkinson's disease (PD) is quickly increasing because neurodegenerative disorders are usually late-onset. Herbal medicines and formula are adjuvant therapies of conventional PD agents, which result in serious side effects with long-term use. This study evaluated the neuroprotective effects of DA-9805, a standardized herbal formula that consists of an ethanolic extract of Moutan Cortex Radix, Angelica Dahuricae Radix, and Bupleuri Radix against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in vitro and in vivo. In PC12 cells, DA-9805 at concentrations of 1 and 10 μg/mL ameliorated cell viability, which was reduced by 6-OHDA. In addition, DA-9805 activated the extracellular-regulated kinase-nuclear transcription factor-erythroid 2-related factor 2 pathway, subsequently stimulating antioxidative enzymes such as NAD(P)H:quinone oxidoreductase 1 and catalase and suppressing apoptosis. Furthermore, DA-9805 prevented 6-OHDA-induced movement impairment, as well as a decrease of dopaminergic neurons and dopamine transmission in rodents. Taken together, these results suggest that the mixed herbal formula DA-9805 may be a pharmaceutical agent for preventing or improving PD., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

We developed a diagnostic method for Parkinson's disease by simultaneously analyzing biogenic amines and their metabolites using reverse-phase high-performance liquid chromatography coupled with integrated pulsed amperometric detection (RP-HPLC-IPAD) method. Dopamine (DA), 3, 4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), and homovanillic acid (HVA) were used as biomarkers to diagnose Parkinson's disease. All target components were detected with good sensitivity using sodium hydroxide (as a post-column eluent). The limit of detection (S/N = 3) and limit of quantification (S/N = 10) of the target components ranged from 0.020 to 2.400 ng and from 0.080 to 8.000 ng, respectively. The coefficients of linear regression ranged from 0.9996 to 1.0000, all inter-day and intra-day precision values were <3.43%, and the average recovery and RSD ranged from 97.55 to 103.60% and 0.22 to 4.79% for mice striatum samples. This method exhibited good selectivity, sensitivity, and reproducibility and can be used directly without any pretreatment steps. Our method will be useful as a tool to diagnose Parkinson's disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aside from the glucocerebrosidase gene, the genetic risk factors for cognitive decline in Parkinson's disease (PD) are controversial. We investigated whether the G2385R polymorphism in leucine-rich repeat kinase 2 gene (LRRK2), a risk variant for the development of PD in East Asians, is associated with cognitive dysfunction in PD. We recruited 299 PD patients, consisting of 23 carriers and 276 non-carriers of LRRK2 G2385R, from 14 centers. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). PD with cognitive dysfunction was defined as an MMSE Z score that, adjusting for age at study entry and years of education, was below -1.0 standard deviations. In multivariate analysis, PD duration, age at study entry and depression were significant risk factors for cognitive dysfunction as assessed by MMSE performance or the MoCA. In linear regression analysis of the association between MMSE Z scores and PD duration, there was no significant difference associated with the LRRK2 G2385R genotype. The interaction terms between PD duration and the LRRK2 G2385R genotype were not significant for the MMSE Z score but were significant for the MoCA. In conclusion, the LRRK2 G2385R genotype may not be associated with cognitive dysfunction in PD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Mulberry fruit, which has been long used in traditional oriental medicine, was reported to ameliorate motor dysfunction and dopaminergic neuronal degeneration via antioxidant and antiapoptotic effects in an animal model of Parkinson's disease (PD). More than 95% of PD patients exhibit nonmotor problems such as olfactory dysfunction and gastrointestinal constipation, which are generally considered to be early symptoms of PD. However, few studies have actually examined potential drugs to treat early PD symptoms. The present study examined the protective effects of mulberry fruit extract (ME) against neurotoxicity in a 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine/probenecid (MPTP/p) model of early PD. MPTP/p model was developed by systemic administration with MPTP (25 mg/kg) and probenecid (250 mg/kg) over 5 weeks. The behavioral studies showed that treatment of mice with ME significantly improved PD-related nonmotor symptoms as well as motor impairment, demonstrated by utilizing the olfactory, pole, rotarod and open field tests. In addition, immunohistochemical analysis indicated that ME exhibits the protective effects against dopaminergic neuronal damage induced by MPTP/p in the substantia nigra and striatum. Moreover, by using Western blot analysis, we found that treatment with ME inhibited the up-regulation of α-synuclein and ubiquitin, well known as composition of Lewy bodies in the substantia nigra and striatum of the MPTP/p mice. Taken together, these data suggest that ME may have therapeutic potential for preventing PD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: The modified-Chungsimyeolda-tang (DG) is an important traditional Korean herbal formula used in traditional oriental medicine for treatment of cerebrovascular disorders, including stroke. The formula is based on the book "Dongui Sasang Shinpyun"., Aim of the Study: In the previous studies, the neuroprotective effect of DG is demonstrated in an in vitro Parkinson's disease (PD) model, and in this study, the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD is used to evaluate the behavioral effect of DG and possible mechanism through anti-apoptosis of DG. 6-Hydroxydopamine (6-OHDA) also is used to evaluate the anti-apoptosis effect of DG in SH-SY5Y cells., Materials and Methods: MPTP was used to evaluate the behavioral damage and neurotoxicity in mice. The bradykinesia symptom was measured by a Pole test and a Rota-rod test in mice. Also the loss of tyrosine hydroxylase (TH)-positive neurons induced by MPTP was examined by an immunohistochemical assay. The DG-mediated anti-apoptosis effect was measured using an immunoblotting assay with apoptosis-related markers such as Bax and cleaved caspase-3. DG and 1-methyl-4-phenylpyridinium (MPP(+)) were co-treated with primary dopaminergic neurons to evaluate the protective effect of DG. The expression of caspase-3 and PARP was measured to detect the protective effect of DG from the damage by 6-OHDA., Results and Conclusions: The treatment with DG resulted in prophylactic effects on MPTP-induced Parkinsonian bradykinesia and the immunohistochemical analysis showed that DG provided the neuroprotection against the MPP(+)-induced dopaminergic neurons loss through the anti-apoptosis effect. The present results suggested that it might be possible to use DG for the prevention of substantia nigra pars compacta (SNpc) degeneration induced by exposure to the toxic substances, such as MPTP/MPP(+), in PD mouse model., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Dangguijakyak-san protects dopamine neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity under postmenopausal conditions., Ethnopharmacological Relevance: Dangguijakyak-san (DJS), a famous traditional herbal formula, has long been used to treat gynecological disorders, including postmenopausal symptoms. This study evaluated the effects and mechanism of DJS on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a postmenopausal mouse model induced by ovariectomy., Materials and Methods: Three weeks after ovariectomy, C57bl/6 female mice were divided randomly into (1) control, (2) MPTP (30 mg/kg/day, i.p., 5 days), (3) MPTP+estrogen (50 μg/kg/day, i.p., 5 days), and (4) MPTP+DJS (50 mg/kg/day, p.o., 5 days) groups. We investigated the behavioral recovery and dopamine neuron protection of DJS using the pole test and tyrosine hydroxylase (TH) immunohistochemistry. We also explored the mechanism by assessing the protein expression of Bax, Bcl-2, cytochrome c, and cleaved caspase-3., Results: DJS treatment restored the movement behavior impaired by MPTP, showing a similar or better effect than estrogen. DJS protected TH-immunoreactive cells and fibers in the nigrostriatal region from MPTP toxicity. In addition, DJS inhibited the Bcl-2 decrease and Bax increase in mitochondria, cytochrome c release to the cytosol, and caspase-3 activation induced by MPTP., Conclusions: DJS showed behavior recovery and dopamine neuron protection against MPTP-induced toxicity via anti-apoptotic activities in ovariectomized female mice. These results suggest that DJS treatment is effective for postmenopausal neurodegenerative diseases., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Acacetin (5,7-dihydroxy-4'-methoxyflavone), a constituent of flavone naturally present in plants, has anti-cancer and anti-inflammatory activities. Neuroinflammation is thought to be one of the major pathological mechanisms responsible for Parkinson's disease (PD), and has been a primary target in the development of treatment for PD. In the present study, we evaluated the neuroprotective effect of acacetin in PD induced by 1-methyl-4-phenylpyridine (MPP+)/or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and examined the related pathways in vitro and in vivo. In primary mesencephalic culture, acacetin protected dopaminergic (DA) cells and inhibited production of inflammatory factors such as nitric oxide, prostaglandin E2, and tumor necrosis factor-α against MPP+-induced toxicity in a dose-dependent manner. Then, we confirmed the effect of acacetin (10 mg/kg/d for 3 d, per os (p.o.)) in a mouse model of PD induced by MPTP (30 mg/kg/d for 5 d, intraperitoneally (i.p.)). In the behavioral test (pole test), the acacetin-treated mice showed decreased time of turning and locomotor activity, which were longer in MPTP-only treated mice. In addition, the acacetin-treated group inhibited degeneration of DA neurons and depletion of dopamine level induced by MPTP toxicity in the substantia nigra and striatum of the brain. Moreover, the acacetin-treated group inhibited microglia activation, accompanied by production of inducible nitric oxide synthases and cyclooxygenase-2. These results suggest that acacetin can protect DA neurons against the neurotoxicity involved in PD via its anti-inflammatory action.

Aim of the Study: Polygalae radix, the root of Polygala tenuifolia Willd, has commonly been used for the treatment of amnesia and anxiety in traditional Korean medicine. The aim of this study was to investigate its neuroprotective effects and possible mechanisms of action in models of Parkinson's disease., Materials and Methods: This study utilized a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, a reactive oxygen species (ROS) assay, a nitric oxide (NO) production assay, and a caspase-3 activity test as measures of cell viability in PC12 cells damaged by 6-hydroxydopamine (6-OHDA). The protective effects of PRE against 1-methyl-4-phenylpyridium (MPP(+))-induced neurotoxicity were assessed in rat primary dopaminergic neurons and in a mouse PD model in which PRE was administered (100mg/kg/day, 3 days, p.o.) before acute 1-mehtyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Finally, TH immunohistochemistry tests were conducted in the substantia nigra pars compacta (SNpc) and striatum (ST)., Results and Conclusions: PRE significantly inhibited 6-OHDA-induced cell damage at doses of 0.05-1μg/ml with a maximal effect at 0.1μg/ml. Caspase-3 activity and the production of ROS and NO were alleviated at 0.1μg/ml. Also at this dose, PRE protected mesencephalic dopaminergic neurons from MPP(+)-induced toxicity. In an in vivo mouse model of PD, PRE protected dopaminergic neurons and fibers from MPTP-induced toxicity in the SNpc and ST. These results demonstrate that PRE has protective effects on dopaminergic neurons via its anti-oxidant and anti-apoptotic activity., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Aim of Study: Modified Yeoldahanso-tang (MYH) is a Korean herbal formula, containing 10 herbs: Pueraria lobata (Willd.) Ohwi, Angelica tenuissima Nakai, Scutellaria baicalensis Georgi, Platycodon grandiflorum (Jacq), Angelicae Dahurica, Cimicifuga heracleifolia Kom, Raphanus sativa L., Polygala tenuifolia (Willd.), Acorus gramineus Soland. and Dimocarpus longan Lour. The constitutive ratio of the ten herbs is at 6:4:2:1:2:2:2:4:6:6 in dry weight. MYH has been used to treat amnesia, hypochondria and dementia in Korea. In this study, we explored the possibility of using MYH in the prevention and treatment of Parkinson's disease (PD). Specifically, we made an effort to demonstrate the neuroprotective effects of MYH using experimental methods similar to those used in a recent study of PD., Materials and Methods: 1-Methyl-4-phenylpyridinium (MPP+) (400μM) was used to induce cytotoxicity in NGF (nerve growth factor)-differentiated PC12 cells. Cell viability was measured using a MTT assay. Induction of autophagy by MYH in NGF-differentiated PC12 cells was measured using an immunoblotting assay with LC3 and beclin 1 antibodies. The proteasomal inhibitor lactacystin (10μM) was used to cause UPS dysfunction in NGF-differentiated PC12 cells. Clearance of aggregated proteins by MYH was measured using an immunoblotting assay with an ubiquitin antibody. 1-Methyl-4-phenyl-1,2,3,6-tetrahydrophenylpyridine (MPTP) (20mg/kg, 4 times i.p.) caused substantia nigra injuries in C57BL/6 mice. Dopamine (DA) neurons were identified using a tyrosine hydroxylase-immunohistochemistry (TH-IHC) assay with a rabbit anti-TH antibody., Results: Our findings indicate that MYH provides protection against MPP+-induced injury in NGF-differentiated PC12 cell. And MYH provides neuroprotection against lactacystin-induced NGF-differentiated PC12 cell death, which effect is partially mediated by autophagy enhancement through enhanced degradation of aggregated proteins. Additionally, in a C57BL/6 mice model with MPTP-induced substantia nigra injuries, MYH inhibits both the loss of TH-positive neurons in the substantia nigra pars compacta (SNpc) and the reduction of the optical density of TH-IR fibers in the striatum (ST)., Conclusions: All of our results indicate that MYH treatment has neuroprotective effects that are partially mediated by autophagy enhancement. MYH may be a promising herbal formula for the prevention and treatment of neurodegenerative diseases, especially PD., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Previous reports have suggested that the herbal medicine Chunghyuldan (CHD, Qingxue-dan in Chinese and Daio-Orengedokuto in Japanese) has wide-ranging biological effects, including anti-hyperlipidaemic, anti-ischaemic, anti-inflammatory and antioxidant activities. Reactive oxygen species (ROS)-mediated mitochondrial dysfunction is thought to be one of the major pathological mechanisms responsible for Parkinson's disease (PD) and may underlie the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) that is a hallmark of this disease. In this study, we examined the neuroprotective effects of CHD in PD models produced by treatment with neurotoxins that act via ROS-mediated mitochondrial dysfunction. In an in vitro PD model using 6-hydroxydopamine, CHD applied at concentrations of 10 and 100 μg/ml exhibited significant protective effects in PC12 cells by inhibiting intracellular ROS generation. CHD applied at 10 and 100 μg/ml also prevented 6-hydroxydopamine-induced mitochondrial depolarization and elevation of caspase-3 activity. At the same doses, CHD showed regulatory effects on the haem oxygenase-1 and gp91 phagocytic oxidase which have critical roles in generating ROS. In addition, CHD protected dopaminergic neurons in a primary mesencephalic culture against MPP+ neurotoxicity. In an in vivo PD model produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment (20 mg/kg, 4 times, i.p.), co-administration of CHD (50 mg/kg, 5 days, p.o.) ameliorated PD-like behavioural symptoms (bradykinesia) and reduced dopaminergic neuronal damage in the SNpc and striatum as measured by immunocytochemistry. These results demonstrate the neuroprotective effects of CHD in PD models that are mediated through inhibition of ROS generation and associated mitochondrial dysfunction., (© 2010 The Authors. Basic & Clinical Pharmacology & Toxicology © 2010 Nordic Pharmacological Society.)

Cyperi rhizoma, the rhizome of Cyperus rotundus L. (Family Cyperaceae), is a well-known functional food and traditional herbal medicine in Korea. It has been reported that Cyperi rhizoma has antioxidant and free radical scavenging activities that play a major role in protection of neurodegenerative disorders, such as Parkinson's disease (PD). In the present study, the neuroprotective effects of a water extract of Cyperi rhizoma (CRE) against 6-hydroxydopamine (6-OHDA)-induced neuronal damage were evaluated in an experimental model of PD. In PC12 cells, CRE showed a significant protective effect on cell viability at 50 and 100 microg/mL. CRE inhibited generation of reactive oxygen species and nitric oxide, reduction of mitochondrial membrane potential, and caspase-3 activity, which were induced by 6-OHDA. CRE also showed a significant protective effect against damage to dopaminergic neurons in primary mesencephalic culture. These results suggest that CRE has neuroprotective effects against 6-OHDA-induced toxicity through antioxidant and anti-apoptotic activities in an in vitro PD model.

Ethnopharmacological Relevance: While the hook of Uncaria rhynchophylla (URH) is a traditional herb used in northeast Asia for the treatment of Parkinson's disease (PD)-like symptoms such as tremor, it has not been experimentally evaluated in a PD model., Aim of the Study: We investigated the effects of URH on 6-hydroxydapamine (6-OHDA)-induced neurotoxicity in in vitro and in vivo models of PD., Materials and Methods: The cell viability, anti-oxidative activity, and anti-apoptotic activity of a water extract of URH (URE) were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide, reactive oxygen species (ROS), total glutathione (GSH), and caspase-3 assays in PC12 cells stressed by 6-OHDA. We also investigated the behavioral recovery and dopaminergic neuron protection of URE using an apomorphine-induced rotation test and tyrosine hydroxylase immunohistochemistry in the hemi-parkinsonian rat model of the unilateral 6-OHDA lesion of the medial forebrain bundle., Results: In PC12 cells, URE significantly reduced cell death and the generation of ROS, increased GSH levels, and inhibited caspase-3 activity induced by 6-OHDA. In 6-OHDA-lesioned rats, posttreatment with URE (5 mg/kg/day for 14 days) significantly reduced apomorphine-induced rotation, and it lowered dopaminergic neuronal loss in substantia nigra pars compacta., Conclusions: URE possesses neuroprotective activity against 6-OHDA-induced toxicity through anti-oxidative and anti-apoptotic activities in PD models.