A single intramuscular injection of rAAV-mediated mutant erythropoietin protects against MPTP-induced parkinsonism

Dhanushkodi, Anandh; Akano, Emmanuel; Roguski, Emily E.; Dantzler, Latasha; Xue, Yi; Rao, Shailaja Kishan; Matta, Shannon G.; Rex, Tonia S.; McDonald, Michael P.

doi:10.1111/j.1601-183x.2012.12001.x

Cited by 6 publications

(14 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, we observed smaller SNc lesions and virtually no MPTP effects on the standard assessment of Parkinsonism. In our hands, a 5-day regimen of 18 mg/kg of the same lot of MPTP destroyed 41% and 45% of the TH+ SNc neurons in control animals, and 25 mg/kg produced a lesion sizes of 75% and 79% (Dhanushkodi et al , 2013; Maiti et al , 2016; and unpublished data). The regimen in the present study produced a smaller lesion (53%) than the 25 mg/kg dose.…”

Section: Discussionmentioning

confidence: 52%

“…Mice were placed in commercially-available activity monitors (MED Associates, Inc., Georgia, VT, USA) for a 30-min session as previously described (Dhanushkodi et al , 2013; Harrison et al , 2010; Harrison et al , 2008; Siesser et al , 2006). The activity monitors measured 27 × 27 cm, with 16 infrared photocell beams equally spaced in the x and y axes of the horizontal plane, 1 cm from the floor of the monitor.…”

Section: Methodsmentioning

confidence: 99%

“…The latency to put its forepaws and then all four paws on the table were recorded. The sticker test is the standard test of MPTP-induced loss of fine motor skills (Dhanushkodi et al , 2013). In this test, mice were gently restrained by the scruff and a 0.64-cm diameter sticker placed on the mouse’s nose.…”

Section: Methodsmentioning

confidence: 99%

“…For unbiased stereological quantification of TH-positive cells, neurons in every fourth section through the rostro-caudal extent of the substantia nigra pars compacta (SNc) were counted in 6–12 sections (mean 8.5) from four mice per group using the optical fractionator method and Stereo Investigator software (MBF Bioscience, Williston, VT) as previously described (Dhanushkodi et al , 2013; Flanigan et al , 2014; Maiti et al , 2016). After delineation of the SNc at low magnification (4x objective), a point grid was overlaid onto each section.…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Targeted deletion of GD3 synthase protects against MPTP‐induced neurodegeneration

Akkhawattanangkul

Maiti

Xue

et al. 2017

Genes Brain and Behavior

View full text Add to dashboard Cite

Parkinson’s disease is a debilitating neurodegenerative condition for which there is no cure. Converging evidence implicates gangliosides in the pathogenesis of several neurodegenerative diseases, suggesting a potential new class of therapeutic targets. We have shown that interventions that simultaneously increase the neuroprotective GM1 ganglioside and decrease the pro-apoptotic GD3 ganglioside—such as inhibition of GD3 synthase (GD3S) or administration of sialidase—are neuroprotective in vitro and in a number of preclinical models. In the present study we investigated the effects of GD3S deletion on parkinsonism induced by 1-Methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP was administered to GD3S−/− mice or controls using a subchronic regimen consisting of three series of low-dose injections (11 mg/kg/day x 5 days each, 3 weeks apart), and motor function was assessed after each. The typical battery of tests used to assess parkinsonism failed to detect deficits in MPTP-treated mice. More sensitive measures—such as the force-plate actimeter and treadmill gait parameters—detected subtle effects of MPTP, some of which were absent in mice lacking GD3S. In wild-type mice MPTP destroyed 53% of the tyrosine-hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc) and reduced striatal dopamine 60.7%. In contrast, lesion size was only 22.5% in GD3S−/− mice and striatal dopamine was reduced by 37.2%. Stereological counts of Nissl-positive SNc neurons that did not express TH suggest that neuroprotection was complete but TH expression was suppressed in some cells. These results demonstrate that inhibition of GD3S has neuroprotective properties in the MPTP model may warrant further investigation as a therapeutic target.

show abstract

Section: Discussionmentioning

confidence: 52%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Targeted deletion of GD3 synthase protects against MPTP‐induced neurodegeneration

Akkhawattanangkul

Maiti

Xue

et al. 2017

Genes Brain and Behavior

View full text Add to dashboard Cite

show abstract

“…Locomotor activity was assessed as part of the savings test of contextual memory. Mice were placed in commercially available activity monitors (MED Associates, Inc., Georgia, VT, USA) for a 10-min session, as previously described (Dhanushkodi et al 2013;Harrison et al 2008Harrison et al , 2009aHarrison et al , 2010Siesser et al 2005Siesser et al , 2006. The activity monitors measured 27 × 27 cm, with 16 infrared photocell beams equally spaced in the x and y axes of the horizontal plane, 1 cm from the floor of the monitor.…”

Section: Sensorimotormentioning

confidence: 99%

Abnormal vibrissa‐related behavior and loss of barrel field inhibitory neurons in 5xFAD transgenics

Flanigan¹,

Xue²,

Rao³

et al. 2014

Genes Brain and Behavior

View full text Add to dashboard Cite

A recent study reported lower anxiety in the 5xFAD transgenic mouse model of Alzheimer's disease, as measured by reduced time on the open arms of an elevated plus maze. This is important because all behaviors in experimental animals must be interpreted in light of basal anxiety and response to novel environments. We conducted a comprehensive anxiety battery in the 5xFAD transgenics and replicated the plus-maze phenotype. However, we found that it did not reflect reduced anxiety, but rather abnormal avoidance of the closed arms on the part of transgenics and within-session habituation to the closed arms on the part of wild-type controls. We noticed that the 5xFAD transgenics did not engage in the whisker-barbering behavior typical of mice of this background strain. This is suggestive of abnormal social behavior, and we suspected it might be related to their avoidance of the closed arms on the plus maze. Indeed, transgenic mice exhibited excessive home-cage social behavior and impaired social recognition, and did not permit barbering by wild-type mice when pair-housed. When their whiskers were snipped the 5xFAD transgenics no longer avoided the closed arms on the plus maze. Examination of parvalbumin (PV) staining showed a 28.9% reduction in PV+ inhibitory interneurons in the in barrel fields of 5xFAD mice, and loss of PV+ fibers in layers IV and V. This loss of vibrissal inhibition suggests a putatively aversive overstimulation that may be responsible for the transgenics’ avoidance of the closed arms in the plus maze.

show abstract

Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration

Dhanushkodi

Xue

Roguski

et al. 2019

Neuroscience Letters

Self Cite

View full text Add to dashboard Cite

Converging evidence demonstrates an important role for gangliosides in brain function and neurodegenerative diseases. Exogenous GM1 is broadly neuroprotective, including in rodent, feline, and primate models of Parkinson's disease, and has shown positive effects in clinical trials. We and others have shown that inhibition of the ganglioside biosynthetic enzyme GD3 synthase (GD3S) increases endogenous levels GM1 ganglioside. We recently reported that targeted deletion of St8sia1, the gene that codes for GD3S, prevents motor impairments and significantly attenuates neurodegeneration induced by 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The current study investigated the effects of GD3S inhibition on the neurotoxicity and parkinsonism induced by MPTP. Mice were injected intrastriatally with a lentiviral-vector-mediated shRNA construct targeting GD3S (shGD3S) or a scrambled-sequence control (scrRNA). An MPTP regimen of 18 mg/kg × 5 days reduced tyrosine-hydroxylase-positive neurons in the substantia nigra pars compacta of scrRNA-treated mice by nearly two-thirds. In mice treated with shGD3S the MPTPinduced lesion was approximately half that size. MPTP induced bradykinesia and deficits in fine motor skills in mice treated with scrRNA. These deficits were absent in shGD3S-treated mice. These results suggest that inhibition of GD3S protects against the nigrostriatal damage, bradykinesia, and fine-motor-skill deficits associated with MPTP administration.

show abstract

A single intramuscular injection of rAAV-mediated mutant erythropoietin protects against MPTP-induced parkinsonism

Cited by 6 publications

References 25 publications

Targeted deletion of GD3 synthase protects against MPTP‐induced neurodegeneration

Targeted deletion of GD3 synthase protects against MPTP‐induced neurodegeneration

Abnormal vibrissa‐related behavior and loss of barrel field inhibitory neurons in 5xFAD transgenics

Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration

Contact Info

Product

Resources

About