The relationship between the distinct ratios of benserazide and carbidopa to levodopa and motor complications in Parkinson's disease: A retrospective cohort study.

BACKGROUND: In Japan, only two medications of immediate-release levodopa with distinct ratios of decarboxylase inhibitor (DCI), namely levodopa/benserazide 100/25 mg and levodopa/carbidopa 100/10 mg, are available for the treatment of Parkinson's disease (PD). The relationship between the difference in the DCI to levodopa ratio and the development of motor complications in long-term administration of levodopa is unknown. PURPOSE: We assessed the duration from initiation of levodopa/DCI to the emergence of motor fluctuations in patients with PD treated with levodopa/benserazide and levodopa/carbidopa. METHODS: We retrospectively assessed the disease course, especially the period from the onset of motor symptoms or initiation of levodopa/DCI to the emergence of motor fluctuations, in patients with PD who were initially treated with either levodopa/benserazide (300/75 mg/day) or levodopa/carbidopa (300/30 mg/day). RESULTS: Of the 186 candidates, 52 patients were enrolled. The mean duration to the emergence of motor fluctuations in the levodopa/carbidopa group was significantly longer than that in the levodopa/benserazide group (5.0 ± 1.4 vs 3.1 ± 1.2 years, p < 0.01). The mean duration from onset of motor symptoms to the emergence of motor fluctuations in the levodopa/carbidopa group was also significantly longer than that in the levodopa/benserazide group (6.6 ± 1.6 vs 4.7 ± 1.3 years, p < 0.01). CONCLUSION: Our study suggests that levodopa/carbidopa therapy with a DCI to levodopa ratio of 1:10 may delay the occurrence of motor fluctuations when compared to levodopa/benserazide therapy with that of 1:4. The difference in the blending ratio of levodopa/DCI may influence the disease progression in PD.

Myricetin prevents high molecular weight Aß1-42 oligomer-induced neurotoxicity through antioxidant effects in cell membranes and mitochondria.

Excessive accumulation of amyloid ß-protein (Aß) is one of the primary mechanisms that leads to neuronal death with phosphorylated tau in the pathogenesis of Alzheimer's disease (AD). Protofibrils, one of the high-molecular-weight Aß oligomers (HMW-Aßo), are implicated to be important targets of disease modifying therapy of AD. We previously reported that phenolic compounds such as myricetin inhibit Aß1-40, Aß1-42, and α-synuclein aggregations, including their oligomerizations, which may exert protective effects against AD and Parkinson's disease. The purpose of this study was to clarify the detailed mechanism of the protective effect of myricetin against the neurotoxicity of HMW-Aßo in SH-SY5Y cells. To assess the effect of myricetin on HMW-Aßo-induced oxidative stress, we systematically examined the level of membrane oxidative damage by measuring cell membrane lipid peroxidation, membrane fluidity, and cell membrane potential, and the mitochondrial oxidative damage was evaluated by mitochondrial permeability transition (MPT), mitochondrial reactive oxygen species (ROS), and manganese-superoxide dismutase (Mn-SOD), and adenosine triphosphate (ATP) assay in SH-SY5Y cells. Myricetin has been found to increased cell viability by suppression of HMW-Aßo-induced membrane disruption in SH-SY5Y cells, as shown in reducing membrane phospholipid peroxidation and increasing membrane fluidity and membrane resistance. Myricetin has also been found to suppress HMW-Aßo-induced mitochondria dysfunction, as demonstrated in decreasing MPT, Mn-SOD, and ATP generation, raising mitochondrial membrane potential, and increasing mitochondrial-ROS generation. These results suggest that myricetin preventing HMW-Aßo-induced neurotoxicity through multiple antioxidant functions may be developed as a disease-modifying agent against AD.

High molecular weight amyloid ß1-42 oligomers induce neurotoxicity via plasma membrane damage.

Amyloid ß-protein (Aß) molecules tend to aggregate and subsequently form low MW (LMW) oligomers, high MW (HMW) aggregates such as protofibrils, and ultimately fibrils. These Aß species can generally form amyloid plaques implicated in the neurodegeneration of Alzheimer disease (AD), but therapies designed to reduce plaque load have not demonstrated clinical efficacy. Recent evidence implicates amyloid oligomers in AD neuropathology, but the precise mechanisms are uncertain. We examined the mechanisms of neuronal dysfunction from HMW-Aß1-42 exposure by measuring membrane integrity, reactive oxygen species (ROS) generation, membrane lipid peroxidation, membrane fluidity, intracellular calcium regulation, passive membrane electrophysiological properties, and long-term potentiation (LTP). HMW-Aß1-42 disturbed membrane integrity by inducing ROS generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and impaired LTP. The damaging effects of HMW-Aß1-42 were significantly greater than those of LMW-Aß1-42. Therapeutic reduction of HMW-Aß1-42 may prevent AD progression by ameliorating direct neuronal membrane damage.-Yasumoto, T., Takamura, Y., Tsuji, M., Watanabe-Nakayama, T., Imamura, K., Inoue, H., Nakamura, S., Inoue, T., Kimura, A., Yano, S., Nishijo, H., Kiuchi, Y., Teplow, D. B., Ono, K. High molecular weight amyloid ß1-42 oligomers induce neurotoxicity via plasma membrane damage.

Cerebrospinal fluid 5-HIAA concentrations correlate with cardiac uptake of 123I-MIBG during myocardial scintigraphy in drug naïve Parkinson's disease.

We examined the correlations between cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) and imaging assessment scores, using 123I-Ioflupane SPECT and 123I-MIBG myocardial scintigraphy in 23 drug naïve PD patients. The CSF 5-HIAA concentration correlated with the H/M ratio of the delayed image (r = 0.458, p < 0.05) and the washout rate (r = - 0.642, p < 0.01) of 123I-MIBG myocardial scintigraphy. These correlations suggest some unclarified pathophysiological links between the central serotonergic and cardiac sympathetic systems.

Usefulness Differs Between the Visual Assessment and Specific Binding Ratio of 123I-Ioflupane SPECT in Assessing Clinical Symptoms of Drug-Naïve Parkinson's Disease Patients.

Background: In clinical practice, assessment of the striatal accumulation in 123I-ioflupane single photon emission computed tomography (SPECT) is commonly performed calculating the specific binding ratio (SBR) for the whole striatum. On the other hand, visual assessment of striatal accumulation in the SPECT was recently established. However, correlations of visual assessment with motor and cognitive functions in Parkinson's disease (PD) have rarely been examined. Differences in the usefulness of these assessments at clinics are uncertain. Objective: We performed this study to compare correlations of cognitive and motor functions in drug-naive PD between the SBR and visual assessment using 123I-ioflupane SPECT. Methods: Cognitive and motor assessments and 123I-ioflupane SPECT were performed in 47 drug-naïve PD patients with Mini-mental State Examination scores of ≥25. Cognitive function was assessed using the total score and 6 subscores of the Montreal Cognitive Assessment (MoCA) and 10 separate subtests of the Neurobehavioral Cognitive Status Examination (COGNISTAT). Motor function was assessed using the Hoehn and Yahr scale and Unified Parkinson's Disease Rating Scale. Accumulation of 123I-ioflupane was determined by visual assessment based on five grades: 1, burst striatum; 2, egg-shaped; 3, mixed type; 4, eagle wing; 5, normal striatum; and by calculating SBR averaged for the bilateral striatum using the DaTView computer software commonly used in clinical practice. Each SPECT assessment was compared with each subscore for cognitive and motor assessments. Results: Spearman correlation analysis showed SBR was significantly correlated with the MoCA subscores of visuospatial function and attention, and with COGNISTAT subtests of attention. Visual assessment showed significant negative correlation with the Hoehn and Yahr scale. Mean score of postural instability in patients with visual grade of 1 was significantly higher than those in patients with visual grades of 2 and 3. Conclusion: Clinical symptoms reflected by 123I-ioflupane SPECT differ between the SBR and visual assessment. SBR reflects some cognitive functions, whereas a visual assessment grade of 1, which signifies decreased uptake of 123I-Ioflupane in the caudate nucleus, reflects postural instability. Thus, the caudate nucleus may play an important role in posture maintenance. Our results suggest that performing both assessments is of value.

Cilostazol Suppresses Aß-induced Neurotoxicity in SH-SY5Y Cells through Inhibition of Oxidative Stress and MAPK Signaling Pathway.

Alzheimer's disease (AD) is a slowly progressive form of dementia, characterized by memory impairment and cognitive dysfunction. AD is mainly characterized by the deposition of amyloid ß (Aß) plaques and intracellular neurofibrillary tangles in the brain, along with neuronal degeneration and high levels of oxidative stress. Cilostazol (CSZ) was recently found to suppress the progression of cognitive decline in patients with stable AD receiving acetylcholinesterase inhibitors. This present study aimed to clarify the mechanism by which CSZ protects neurons from degeneration associated with Aß(1-42). We used Aß(1-42) to induce neurotoxicity in human neuroblastoma SH-SY5Y cells. Cells were pretreated with CSZ before co-treatment with Aß. To evaluate the effect of CSZ on oxidative stress, we examined levels of reactive oxygen species (ROS), nicotinamide adenine dinucleotide phosphate oxidase (Nox) activity, mRNA expression of NOX4, and Cu/Zn-Superoxide Dismutase (SOD), as well as apoptosis biomarkers [MTT, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), caspase-3 and -9 activities and staining of annexin V]. We also assayed the activity of mitogen-activated protein kinases (MAPK): p38 MAPK and extracellular signal-regulated kinase1/2 (ERK1/2), and biomarkers of mitochondrial function (Bcl-2 and Bax), and cyclic adenosine monophosphate response element-binding protein (CREB). Aß-induced oxidative stress (ROS, NOX4 activity, and expression of NOX mRNA), caspase activation (caspase-3 and -9), and p38 MAPK phosphorylation were suppressed by co-treatment with CSZ, but not by ERK1/2 activation. In addition, pretreatment with CSZ suppressed Aß-induced apoptosis and increased cell viability via suppression of Bax (a proapoptotic protein), upregulation of Bcl-2 (an antiapoptotic protein) and Cu/Zn-SOD (a superoxide scavenging enzyme), and phosphorylation of CREB. These findings suggested that CSZ could counteract neurotoxicity through multiple mechanisms, one mechanism involving the attenuation of oxidative stress by suppressing NOX activity and Nox mRNA expression in Aß-induced neurotoxicity and another involving the anti-neurotoxic effect via the ERK1/2/phosphorylated CREB pathway.