Methyl Yellow: A Potential Drug Scaffold for Parkinson's Disease

Geldenhuys, Werner J.; Kochi, Akiko; Li, Lin; Sutariya, Vijaykumar; Dluzen, Dean E.; Schyf, Cornelis J. Van der; Lim, Mi Hee

doi:10.1002/cbic.201300770

Cited by 7 publications

(3 citation statements)

References 56 publications

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“…Despite many advantages in the application of MSCs, stem cell-based therapies for PD face serious challenges such as low cell survival, uncontrollable differentiation, and unsuccessful engraftment due to lack of physical support of the cells [1,27]. In recent years, scientists have used tissue engineering as promising strategy for cell based therapies [12,28,29]. Using this approach, it is possible to improve cell engraftment to the host tissue after transplantation by providing 3D supportive structure.…”

Section: Introductionmentioning

confidence: 99%

Combining NT3-overexpressing MSCs and PLGA microcarriers for brain tissue engineering: A potential tool for treatment of Parkinson's disease

Moradian

Keshvari

Fasehee

et al. 2017

Materials Science and Engineering: C

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Parkinson's disease (PD) is a progressive neurodegenerative disorder that characterized by destruction of substantia nigrostriatal pathway due to the loss of dopaminergic (DA) neurons. Regardless of substantial efforts for treatment of PD in recent years, an effective therapeutic strategy is still missing. In a multidisciplinary approach, bone marrow derived mesenchymal stem cells (BMSCs) are genetically engineered to overexpress neurotrophin-3 (nt-3 gene) that protect central nervous system tissues and stimulates neuronal-like differentiation of BMSCs. Poly(lactic-co-glycolic acid) (PLGA) microcarriers are designed as an injectable scaffold and synthesized via double emulsion method. The surface of PLGA microcarriers are functionalized by collagen as a bioadhesive agent for improved cell attachment. The results demonstrate effective overexpression of NT-3. The expression of tyrosine hydroxylase (TH) in transfected BMSCs reveal that NT-3 promotes the intracellular signaling pathway of DA neuron differentiation. It is also shown that transfected BMSCs are successfully attached to the surface of microcarriers. The presence of dopamine in peripheral media of cell/microcarrier complex reveals that BMSCs are successfully differentiated into dopaminergic neuron. Our approach that sustains presence of growth factor can be suggested as a novel complementary therapeutic strategy for treatment of Parkinson disease.

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Section: Introductionmentioning

confidence: 99%

Combining NT3-overexpressing MSCs and PLGA microcarriers for brain tissue engineering: A potential tool for treatment of Parkinson's disease

Moradian

Keshvari

Fasehee

et al. 2017

Materials Science and Engineering: C

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“…We measured remaining levels of DA following systemic MPTP treatment, as previously described ( Geldenhuys et al, 2014 ). In brief, mice were euthanized via cervical dislocation, the brain was removed from the skull, and striatal tissue was dissected out then snap frozen in liquid nitrogen.…”

Section: Methodsmentioning

confidence: 99%

A novel biomechanical analysis of gait changes in the MPTP mouse model of Parkinson’s disease

Geldenhuys

Guseman

Pienaar

et al. 2015

PeerJ

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Parkinson’s disease (PD) is an age-associated neurodegenerative disorder hallmarked by a loss of mesencephalic dopaminergic neurons. Accurate recapitulation of the PD movement phenotype in animal models of the disease is critical for understanding disease etiology and developing novel therapeutic treatments. However, most existing behavioral assays currently applied to such animal models fail to adequately detect and subsequently quantify the subtle changes associated with the progressive stages of PD. In this study, we used a video-based analysis system to develop and validate a novel protocol for tracking locomotor performance in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We anticipated that (1) treated mice should use slower, shorter, and less frequent strides and (2) that gait deficits should monotonically increase following MPTP administration, as the effects of neurodegeneration become manifest. Video-based biomechanical analyses, utilizing behavioral measures motivated by the comparative biomechanics literature, were used to quantify gait dynamics over a seven-day period following MPTP treatment. Analyses revealed shuffling behaviors consistent with the gait symptoms of advanced PD in humans. Here we also document dramatic gender-based differences in locomotor performance during the progression of the MPTP-induced lesion, despite male and female mice showing similar losses of striatal dopaminergic cells following MPTP administration. Whereas female mice appeared to be protected against gait deficits, males showed multiple changes in gait kinematics, consistent with the loss of locomotor agility and stability. Overall, these data show that the novel video analysis protocol presented here is a robust method capable of detecting subtle changes in gait biomechanics in a mouse model of PD. Our findings indicate that this method is a useful means by which to easily and economically screen preclinical therapeutic compounds for protecting against or reversing neuropathology associated with PD neurodegeneration.

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“…The parallel artificial membrane permeability assay ( PAMPA) is used in HTS screening which correlates to the permeability across the blood-brain barrier (BBB). 22 In this 96 well micotiter plate assay compound 1 was added at 200 μM to the donor compartment containing phosphate buffered saline (PBS pH 7. 4)/5% v/v DMSO and allowed to distribute across the hexadecane in hexane (5% v/v) organic layer on a filter plate to the acceptor compartment for 5 hours.…”

mentioning

confidence: 99%

High-content screen using zebrafish (Danio rerio) embryos identifies a novel kinase activator and inhibitor

Geldenhuys

Bergeron

Mullins

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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In this report we utilized zebrafish (Danio rerio) embryos in a phenotypical high-content screen (HCS) to identify novel leads in a cancer drug discovery program. We initially validated our HCS model using the flavin adenosine dinucleotide (FAD) containing endoplasmic reticulum (ER) enzyme, endoplasmic reticulum oxidoreductase (ERO1) inhibitor EN460. EN460 showed a dose response effect on the embryos with a dose of 10 μM being significantly lethal during early embryonic development. The HCS campaign which employed a small library identified a promising lead compound, a naphthyl-benzoic acid derivative coined compound 1 which had significant dosage and temporally dependent effects on notochord and muscle development in zebrafish embryos. Screening a 369 kinase member panel we show that compound 1 is a PIM3 kinase inhibitor (IC50 = 4.078 μM) and surprisingly a DAPK1 kinase agonist/activator (EC50 = 39.525 μM). To our knowledge this is the first example of a small molecule activating DAPK1 kinase. We provide a putative model for increased phosphate transfer in the ATP binding domain when compound 1 is virtually docked with DAPK1. Our data indicate that observable phenotypical changes can be used in future zebrafish screens to identify compounds acting via similar molecular signaling pathways.

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Methyl Yellow: A Potential Drug Scaffold for Parkinson's Disease

Cited by 7 publications

References 56 publications

Combining NT3-overexpressing MSCs and PLGA microcarriers for brain tissue engineering: A potential tool for treatment of Parkinson's disease

Combining NT3-overexpressing MSCs and PLGA microcarriers for brain tissue engineering: A potential tool for treatment of Parkinson's disease

A novel biomechanical analysis of gait changes in the MPTP mouse model of Parkinson’s disease

High-content screen using zebrafish (Danio rerio) embryos identifies a novel kinase activator and inhibitor

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