Methylene Blue Ameliorates Olfactory Dysfunction and Motor Deficits in a Chronic MPTP/Probenecid Mouse Model of Parkinson’s Disease

Biju, K.C.; Evans, Robert C.; Shrestha, Kripa; Carlisle, Daniel C.B.; Gelfond, Jonathan; Clark, Robert A.

doi:10.1016/j.neuroscience.2018.04.008

Cited by 26 publications

(18 citation statements)

References 38 publications

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“…Since these LMTM effects are not seen in wild-type mice, they are likely to represent secondary consequences of the primary action of LMTM on tau oligomers in synaptic terminals and in mitochondria. The MT moiety (given as MTC) has been reported to affect dopaminergic function in mouse models of Parkinson's disease [43][44][45]. We have found that LMTM increases hippocampal acetylcholine levels in both tau transgenic and wild-type mice, and that this effect is also eliminated by pretreatment with a cholinesterase inhibitor [32].…”

Section: Discussionmentioning

confidence: 79%

Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease

Schelter

Shiells

Baddeley

et al. 2019

JAD

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Background: Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer's disease (AD) comparing doses in the range 150-250 mg/day with 8 mg/day intended as a control. Objective: To determine how drug exposure is related to treatment response. Methods: A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data. Results: There are steep concentration-response relationships for steady state plasma levels in the range 0.3-0.8 ng/ml at the 8 mg/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4-21 ng/ml produced by the high doses are not associated with any additional benefit.

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Section: Discussionmentioning

confidence: 79%

Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease

Schelter

Shiells

Baddeley

et al. 2019

JAD

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“…Biju et al (2018) administered 125 mg/kg of MPTP (25 mg/kg each dose at 3.5-day intervals for five weeks) subcutaneous injections in male C57BL/6J mice models and evaluated the methylene blue (1 mg/kg/day from 11th–100th day with drinking water) against MPTP-induced neurotoxicity. The methylene blue treatment ameliorated MPTP-induced motor dysfunction assessed for the open-field test, static bar test, horizontal bar test, olfactory discrimination, and nesting behavior test [ 137 ]. Datta et al (2020) administered MPTP at the dose of 0.1 mg/nostril at a seven-day interval (Baseline, 7th and 14th day) in male albino Wistar rats and evaluated against MPTP-intranasal administration on liver functions and transition from non-motor to motor impairments.…”

Section: Neurotoxins Used To Induce Pd In Vivo Modelsmentioning

confidence: 99%

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Prasad

Hung

2020

Antioxidants

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Currently, neurodegenerative diseases are a major cause of disability around the world. Parkinson’s disease (PD) is the second-leading cause of neurodegenerative disorder after Alzheimer’s disease. In PD, continuous loss of dopaminergic neurons in the substantia nigra causes dopamine depletion in the striatum, promotes the primary motor symptoms of resting tremor, bradykinesia, muscle rigidity, and postural instability. The risk factors of PD comprise environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular injury, aging, and hereditary defects. The pathologic features of PD include impaired protein homeostasis, mitochondrial dysfunction, nitric oxide, and neuroinflammation, but the interaction of these factors contributing to PD is not fully understood. In neurotoxin-induced PD models, neurotoxins, for instance, 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-Methyl-4-phenylpyridinium (MPP+), paraquat, rotenone, and permethrin mainly impair the mitochondrial respiratory chain, activate microglia, and generate reactive oxygen species to induce autooxidation and dopaminergic neuronal apoptosis. Since no current treatment can cure PD, using a suitable PD animal model to evaluate PD motor symptoms’ treatment efficacy and identify therapeutic targets and drugs are still needed. Hence, the present review focuses on the latest scientific developments in different neurotoxin-induced PD animal models with their mechanisms of pathogenesis and evaluation methods of PD motor symptoms.

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“…Sample size was calculated by power analysis using GPower 3.1.7 software (Universität Düsseldorf, Germany). Existing literature and our own published work 20,27 served as the basis for calculating effect size. Assuming an effect size of 1.9 (power 90% and alpha 0.05), the sample size for behavioral tests was estimated to be 7, whereas with an effect size of 2.1, the sample size for MRI was estimated to be 6.…”

Section: Methodsmentioning

confidence: 99%

Reduced cerebral blood flow in an α-synuclein transgenic mouse model of Parkinson’s disease

Biju

Shen

Hernandez

et al. 2019

J Cereb Blood Flow Metab

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There is increasing evidence that widespread cortical cerebral blood flow deficits occur early in the course of Parkinson’s disease. Although cerebral blood flow measurement has been suggested as a potential biomarker for early diagnosis of Parkinson’s disease, as well as a means for tracking response to treatment, the relationship of cerebral blood flow to α-synucleinopathy, a major pathological hallmark of Parkinson’s disease, remains unclear. Therefore, we performed arterial spin-labeling magnetic resonance imaging and diffusion tensor imaging on transgenic mice overexpressing human wild-type α-synuclein and age-matched controls to measure cerebral blood flow and degenerative changes. As reported for early-stage Parkinson’s disease, α-synuclein mice exhibited a significant reduction in cortical cerebral blood flow, which was accompanied by motor coordination deficits and olfactory dysfunction. Although no overt degenerative changes were apparent in diffusion tensor imaging images, magnetic resonance imaging volumetric analysis revealed a significant reduction in olfactory bulb volume, similar to that seen in Parkinson’s disease patients. Our data, representing the first report of cerebral blood flow deficit in an animal model of Parkinson’s disease, suggest a causative role for α-synucleinopathy in cerebral blood flow deficits in Parkinson’s disease. Thus, α-synuclein transgenic mice comprise a promising model to study Parkinson’s disease-related mechanisms of cerebral blood flow deficits and to investigate further its utility as a potential biomarker for Parkinson’s disease.

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Methylene Blue Ameliorates Olfactory Dysfunction and Motor Deficits in a Chronic MPTP/Probenecid Mouse Model of Parkinson’s Disease

Cited by 26 publications

References 38 publications

Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease

Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Reduced cerebral blood flow in an α-synuclein transgenic mouse model of Parkinson’s disease

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