568 research outputs found

    The Effects of Vilazodone, YL-0919, and Vortioxetine in L-DOPA Treated Hemiparkinsonian Rats

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    Parkinson\u27s Disease (PD) is a debilitating, neurodegenerative disorder characterized by motor symptoms, including bradykinesia, tremor, stiffness, and postural instability, that result from significant nigrostriatal dopamine (DA) loss. The current gold standard treatment for PD involves replacement therapy via the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA); however, 90% of patients eventually experience choreic and dystonic side effects termed L-DOPA induced dyskinesia (LID). A key driver of LID is neuroplasticity within the serotonin (5-HT) system leading to the unregulated release of L-DOPA derived DA from 5-HT terminals into the striatum. Previous work has implicated the dual action of 5-HT1A receptor agonism and 5-HT transporter (SERT) blockade as an effective therapeutic method for attenuating LID. The present study examined 3 purportedly similar pharmacological drugs, Vilazodone, YL-0919, and Vortioxetine, that act as 5-HT1A agonists and SERT blockers. Adult female Sprague-Dawley rats received unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) to deplete DA neurons. Thereafter they received 2 weeks of L-DOPA treatment until they developed stable abnormal involuntary movement (AIMs) akin to LID. Rats were also assessed for motor performance with the forepaw adjusting steps (FAS) test. Results revealed that Vilazodone and Vortioxetine significantly reduced AIMs and maintained L-DOPA beneficial prokinetic effects. In contrast, YL-0919 unexpectedly had no effect on LID though it did maintain L-DOPA motor performance. Overall, these findings support pharmacological targets within the 5-HT system that reduce LID. They also provide evidence for unique features of Vilazodone and Vortioxetine, both FDA approved compounds, as potential adjunct therapeutics for LID management in PD patients.https://orb.binghamton.edu/research_days_posters_2021/1090/thumbnail.jp

    Electrification of wind-blown sand on Mars and its implications for atmospheric chemistry

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    Wind-blown sand, or 'saltation,' creates sand dunes, erodes geological features, and could be a significant source of dust aerosols on Mars. Moreover, the electrification of sand and dust in saltation, dust storms, and dust devils could produce electric discharges and affect atmospheric chemistry. We present the first calculations of electric fields in martian saltation, using a numerical model of saltation that includes sand electrification, plasma physics, and the adsorption of ions and electrons onto particulates. Our results indicate that electric discharges do not occur in martian saltation. Moreover, we find that the production of hydrogen peroxide and the dissociation of methane by electric fields are less significant than previously thought. Both these species are highly relevant to studies of past and present life on Mars.Comment: 5 journal pages, 3 figures, published in Geophysical Research Letter

    Cell Discovery / Cancer cell specific inhibition of Wnt/-catenin signaling by forced intracellular acidification

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    Use of the diabetes type II drug Metformin is associated with a moderately lowered risk of cancer incidence in numerous tumor entities. Studying the molecular changes associated with the tumor-suppressive action of Metformin we found that the oncogene SOX4, which is upregulated in solid tumors and associated with poor prognosis, was induced by Wnt/-catenin signaling and blocked by Metformin. Wnt signaling inhibition by Metformin was surprisingly specific for cancer cells. Unraveling the underlying specificity, we identified Metformin and other Mitochondrial Complex I (MCI) inhibitors as inducers of intracellular acidification in cancer cells. We demonstrated that acidification triggers the unfolded protein response to induce the global transcriptional repressor DDIT3, known to block Wnt signaling. Moreover, our results suggest that intracellular acidification universally inhibits Wnt signaling. Based on these findings, we combined MCI inhibitors with H+ ionophores, to escalate cancer cells into intracellular hyper-acidification and ATP depletion. This treatment lowered intracellular pH both in vitro and in a mouse xenograft tumor model, depleted cellular ATP, blocked Wnt signaling, downregulated SOX4, and strongly decreased stemness and viability of cancer cells. Importantly, the inhibition of Wnt signaling occurred downstream of -catenin, encouraging applications in treatment of cancers caused by APC and -catenin mutations.(VLID)270614
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