Solid Lipid Curcumin Particles Protect Medium Spiny Neuronal Morphology, and Reduce Learning and Memory Deficits in the YAC128 Mouse Model of Huntington’s Disease

Huntington’s disease (HD) is a genetic neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms, accompanied by massive neuronal degeneration in the striatum. In this study, we utilized solid lipid curcumin particles (SLCPs) and solid lipid particles (SLPs) to test their efficacy in reducing deficits in YAC128 HD mice. Eleven-month-old YAC128 male and female mice were treated orally with SLCPs (100 mg/kg) or equivalent volumes of SLPs or vehicle (phosphate-buffered saline) every other day for eight weeks. Learning and memory performance was assessed using an active-avoidance task on week eight. The mice were euthanized, and their brains were processed using Golgi-Cox staining to study the morphology of medium spiny neurons (MSNs) and Western blots to quantify amounts of DARPP-32, brain-derived neurotrophic factor (BDNF), TrkB, synaptophysin, and PSD-95. We found that both SLCPs and SLPs improved learning and memory in HD mice, as measured by the active avoidance task. We also found that SLCP and SLP treatments preserved MSNs arborization and spinal density and modulated synaptic proteins. Our study shows that SLCPs, as well as the lipid particles, can have therapeutic effects in old YAC128 HD mice in terms of recovering from HD brain pathology and cognitive deficits.

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Effect of Aronia Melanocarpa Fruit Juice on Fearning and Memory in the Two-Way Active Avoidance Task in Rats

Journal of Biomedical and Clinical Research ◽

10.1515/jbcr-2015-0098 ◽

2013 ◽

Vol 6 (1) ◽

pp. 18-23 ◽

Cited By ~ 2

Author(s):

Stefka Valcheva-Kuzmanova ◽

Miroslav Eftimov ◽

Iren Beleheva ◽

Roman Tashev ◽

Stiliana Beleheva

Keyword(s):

Learning And Memory ◽

Active Avoidance ◽

Fruit Juice ◽

Training Session ◽

Brain Regions ◽

Memory Effects ◽

Avoidance Task ◽

Active Avoidance Task ◽

Aronia Melanocarpa ◽

Improved Learning

Summary Amnia melanocarpa fruits are one of the richest natural sources of phenolic substances, among them flavonoids, mainly from the subclass of anthocyanins. Flavonoids, which are constituents of Amnia melanocarpa fruit juice, have been found to localize in various brain regions that are important for memory. The aim of the present study was to investigate the learning and memory effects of Amnia melanocarpa fruit juice (AMFJ) in young/healthy male Wistarrats. AMFJ was applied orally for 21 and 30 days at a dose of 10 ml/kg b.w., and comparisons were made with saline-treated (10 ml/kg b.w.) controls. Learning and memory functions were evaluated, using the two-way active avoidance task (shuttle box). Administered for the two treatment periods, the juice significantly increased the number of avoidances on training days 1 and 2, as well as at the retention test (24 h after the 2nd training session). These effects were more pronounced in rats treated with AMFJ for 30 days. The learning and memory effects of AMFJ are probably due to its polyphenolic constituents. The findings from the present study suggest that AMFJ applied subchronically improved learning and memory in young/healthy rats.

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Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington’s Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31

Neurotherapeutics ◽

10.1007/s13311-021-01023-8 ◽

2021 ◽

Author(s):

Danielle A. Simmons ◽

Brian D. Mills ◽

Robert R. Butler III ◽

Jason Kuan ◽

Tyne L. M. McHugh ◽

...

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Treatment Response ◽

Diffusion Tensor ◽

Disease Onset ◽

Therapeutic Effects ◽

Plasma Cytokine ◽

Cytokine Levels ◽

Pharmacodynamic Biomarkers

AbstractHuntington’s disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.

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Altered activity of the medial prefrontal cortex and amygdala during acquisition and extinction of an active avoidance task

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2015.00249 ◽

2015 ◽

Vol 9 ◽

Cited By ~ 12

Author(s):

Xilu Jiao ◽

Kevin D. Beck ◽

Catherine E. Myers ◽

Richard J. Servatius ◽

Kevin C. H. Pang

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Active Avoidance ◽

Avoidance Task ◽

Active Avoidance Task

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The Effects of Selective Inhibition of Histone Deacetylase 1 and 3 in Huntington’s Disease Mice

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.616886 ◽

2021 ◽

Vol 14 ◽

Author(s):

Katharina Hecklau ◽

Susanne Mueller ◽

Stefan Paul Koch ◽

Mustafa Hussain Mehkary ◽

Busra Kilic ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Selective Inhibition ◽

Skill Learning ◽

Disease Stage ◽

Therapeutic Effects ◽

Modest Improvement ◽

Symptomatic Disease ◽

Histone Deacetylase 1 ◽

Transcriptional Dysregulation

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 alleviated transcriptional dysregulation of a number of genes, including the transcription factor genes Neurod2 and Nr4a2, and gene sets and programs, especially those that are associated to insulin-like growth factor pathway, in the striatum of R6/1 mice. RGFP109 treatment led to a modest improvement of the motor skill learning and coordination deficit on the RotaRod test, while it did not alter the locomotor and anxiety-like phenotypes in R6/1 animals. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed no significant effects. Collectively, our combined work suggests that specific HDAC1 and HDAC3 inhibition may offer benefits for alleviating the motor phenotypic deficits and transcriptional dysregulation in HD.

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