Investigating the Anti-dyskinetic Effects of Serotonin- and Glutamate-acting Compounds, Vilazodone and Amantadine, in Hemiparkinsonian Rats

Parkinson’s disease is a progressive, neurodegenerative movement disorder caused by loss of nigrostriatal dopamine (DA) neurons. DA replacement therapy using L-3,4-dihydroxyphenylalanine (L-DOPA) improves motor functioning but often results in L-DOPA-induced dyskinesia (LID) typified by abnormal involuntary movements (AIMs). In this state of DA depletion, serotonin (5-HT) neuron hyperinnervation and glutamate overactivity are heavily implicated in LID. This study investigated the anti-dyskinetic effects of Vilazodone (VZD), a 5-HT transport blocker and partial 5-HT1a agonist, and/or Amantadine (AMAT), an NMDA glutamate antagonist. It was hypothesized that alone each would reduce LID, while co-administration at low doses would synergistically reduce LID without compromising L-DOPA efficacy. Hemiparkinsonian Sprague-Dawley rats were given L-DOPA (6mg/kg, s.c.) for 14 days to establish LID. VZD (0, 1, 2.5, 5mg/kg) and AMAT (0, 20, 40, 60mg/kg) were administered in a within-subjects counterbalanced design with L-DOPA to ascertain effective anti-LID doses (n=9). AIMs were monitored for 3 hours following injections to measure LID expression. Before examining potential treatment synergy, doses exhibiting minimal effect on AIMs scores were selected (VZD 1.0, 2.5mg/kg; AMAT 40mg/kg). The following cohort (n=8) received 6 counterbalanced treatments consisting of L-DOPA (6mg/kg) and either VZD (1, 2.5mg/kg), AMAT (40mg/kg), or both. Results revealed a significant decrease in AIMs and maintained motor performance with VZD (2.5mg/kg) compared to those receiving only L-DOPA. AMAT prolonged peak AIMs without maintaining L-DOPA motor efficacy when co-administered with VZD or L-DOPA alone. These results suggest co-administration of VZD and AMAT with L-DOPA does not synergistically reduce LID in hemiparkinsonian rats. Rather, our results suggest that AMAT may reduce the efficacy of VZD. However, our results suggest very low doses of VZD (2.5mg/kg) reduce LID severity and duration while maintaining L-DOPA efficacy.https://orb.binghamton.edu/research_days_posters_2021/1099/thumbnail.jp

Evaluation of Dopamine D3 Receptor Antagonists PG01037, PG01042, and VK4-116 Against D1R-induced Dyskinesia

Parkinson’s Disease (PD) results in motor deficits that can be relieved with L-DOPA, a dopamine (DA) replacement therapy. Unfortunately, chronic treatment often leads to L-DOPA-induced dyskinesia (LID), a debilitating side effect characterized by abnormal involuntary movements (AIMs). Overactivity of the direct striatonigral pathway is seen in LID and is characterized by potent changes in D1 and D3 receptors (D1R, D3R). Further, D1R and D3R may physically and functionally interact to form D1R-D3R heteromer thereby potentiating LID. This D1R-D3R heteromer uniquely switches from G-protein dependent to G-protein independent signaling, allowing for an avenue to manage LID. To uncover the role of these pathways in LID, Sprague-Dawley rats were rendered hemi-parkinsonian and treated daily for 2 weeks with L-DOPA (6 mg/kg; s.c.) to induce stable LID. In a within subjects, counterbalanced design, they were then split into treatment groups that received D3R antagonists: PG01037 (10, 30 mg/kg; i.p.), PG01042 (5, 10 mg/kg; i.p.), or VK4-116 (10, 20 mg/kg; i.p.). PG01037 (PG1) is a mixed D3R antagonist, acting at both the G-protein dependent and independent pathways. PG01042 (PG2) acts as an antagonist on G-protein independent signaling and VK4-116 acts as a G-protein dependent antagonist. All drugs were tested against D1R agonist-induced dyskinesia with SKF38393 (2mg/kg; s.c.). The only effects found were with PG2 which implicates promotion of the D1R G-protein dependent pathway as contributing to D1R-induced dyskinesia. Future studies with these drugs and L-DOPA treatment should unveil the importance of D1R, D3R, and D1R-D3R influences in the presence of the natural ligand DA.https://orb.binghamton.edu/research_days_posters_2021/1038/thumbnail.jp

Russia’s Legal Transitions: Marxist Theory, Neoclassical Economics and the Rule of Law

We review the role of economic theory in shaping the process of legal change in Russia during the two transitions it experienced during the course of the twentieth century: the transition to a socialist economy organised along the lines of state ownership of the means of production in the 1920s, and the transition to a market economy which occurred after the fall of the Soviet Union in the 1990s. Despite differences in methodology and in policy implications, Marxist theory, dominant in the 1920s, and neoclassical economics, dominant in the 1990s, offered a similarly reductive account of law as subservient to wider economic forces. In both cases, the subordinate place accorded to law undermined the transition process. Although path dependence and history are frequently invoked to explain the limited development of the rule of law in Russia during the 1990s, policy choices driven by a deterministic conception of law and economics also played a role.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s40803-015-0012-

CHEMILUMINESCENT REACTIONS OF OZONE WITH METHYL MERCAPTAN AND HYDROGEN SULFIDE

Author Institution:The chemiluminescence resulting from the reaction of $O_{3}$ with the simple sulfides, $CH_{3}SH$ and $H_{2}S$, has been studied at low pressures in a beam-gas apparatus. The fluorescence and vibrationally resolved phosphorescence from $SO{^{*}}{_{2}}$ produced in the reaction were monitored as a function of the pressure of the oxidizer, fuel and bath gas over a total pressure range from $5\times10^{-3}$ to $> 10^{-1}$ torr. The observed pressure dependencies provide estimates of the relative contributions of the long-lived $^{1}B_{1}$ and short-lived $^{1}A_{2}$ states to the total fluorescence band from $2800 - 5200$ \AA. The data also demonstrate that the $^{1}A_{2}$ state is quenched to the triplet manifold and help to elucidate the mechanism for intersystem crossing in $SO_{2}$. At longer wave lengths, structured emission for the reaction of $H_{2}S$ is observed and is tentatively identified as HSO. For $CH_{3}SH$ as the reactant, the meinel bands of DH are observed in the wave length region. These data are employed in developing a mechanism for the ozonolysis of these simple sulfides

Characterizing the relationship between L-DOPA-induced-dyskinesia and psychosis-like behaviors in a bilateral rat model of Parkinson\u27s disease

Parkinson\u27s disease associated psychosis (PDAP) is a prevalent non-motor symptom (NMS) that significantly erodes patients\u27 and caregivers\u27 quality of life yet remains vastly understudied. One potential source of PDAP in late-stage Parkinson\u27s disease (PD) is the common dopamine (DA) replacement therapy for motor symptoms, Levodopa (L-DOPA). Given the high incidence of L-DOPA-induced dyskinesia (LID) in later phases of PD, this study sought to characterize the relationship between PDAP and LID in a bilateral medial forebrain bundle 6-hydroxydopamine hydrobromide (6-OHDA) lesion rat model. To assess PDAP in this model, prepulse inhibition (PPI), a well-validated assay of sensorimotor gating, was employed. First, we tested whether a bilateral lesion alone or after chronic L-DOPA treatment was sufficient to induce PPI dysfunction. Rats were also monitored for LID development, using the abnormal involuntary movements (AIMs) test, to examine PPI and LID associations. In experiment 2, Vilazodone (VZD), a serotonin transporter (SERT) blocker and 1A receptor (5-HT) partial agonist was administered to test its potential efficacy in reducing LID and PPI dysfunction. Once testing was complete, tissue was collected for high performance liquid chromatography (HPLC) to examine the monoamine levels in motor and non-motor circuits. Results indicate that bilateral DA lesions produced motor deficits and that chronic L-DOPA induced moderate AIMs; importantly, rats that developed more severe AIMs were more likely to display sensorimotor gating dysfunction. In addition, VZD treatment dose-dependently reduced L-DOPA-induced AIMs without impairing L-DOPA efficacy, although VZD\u27s effects on PPI were limited. Altogether, this project established the bilateral 6-OHDA lesion model accurately portrayed LID and PDAP-like behaviors, uncovered their potential relationship, and finally, demonstrated the utility of VZD for reducing LID

Ab initio calculations and spectral simulation of the A?²A´ ? X? A? emission of the HPCl radical

Geometry optimization and harmonic vibrational frequency calculations were carried out at the B3LYP, MP2 and QCISD levels on some low-lying electronic states of HPCl. Relative energies were calculated up to RCCSD(T)/cc-pV5Z(no h)//RCCSD(T)/cc-pVQZ(no g) level. Franck-Condon factors (FCFs) were computed to simulate the recently, first observed A?²A´ ? X? A? emission of the HPCl radical [Whitehead et al., Chem. Phys. Lett. 331 (2000) 483]. Ab initio results and spectral simulations from the present study confirm the assignment of the observed spectrum to the A?²A´ ? X? A? emission of the HPCl radical, but some of the previous assignments of the observed vibrational structure have been revised

90-Day Readmission Rates for Single Level Anterior Lumbosacral Interbody Fusion: A Nationwide Readmissions Database Analysis.

STUDY DESIGN: Nationwide Readmissions Database Study. OBJECTIVE: To investigate the patterns of readmissions and complications following hospitalization for elective single level anterior lumbobsacral interbody fusion. SUMMARY OF BACKGROUND DATA: Lumbar interbody spine fusions for degenerative disease have increased annually in the United States, including associated hospital costs. Anterior lumbar interbody fusions (ALIFs) have become popularized secondary to higher rates of fusion compared to posterior procedures, and preservation of posterior elements. Prior national databases have sought to study readmission rates with some limitations due to older diagnosis and procedure codes. The newer 2016 International Classification of Diseases Tenth Revision, Clinical Modification (ICD-10 CM) includes more specification of the surgical site. METHODS: We utilized the 2016 United States Nationwide Readmissions Database (NRD), this nationally representative, all-payer database that includes weighted probability sample of inpatient hospitalizations for all ages. We identified all adults (≥ 18 years) using the 2016 ICD-10 coding system who underwent elective primary L5-S1 ALIF and examined rates of readmissions within 90-days of discharge. RESULTS: Between January and September 2016, a total of 7,029 patients underwent elective stand-alone L5-S1 ALIF who were identified from NRD of which 497 (7.07%) were readmitted within 90-days of their procedure. No differences in gender was appreciated. Medicare patients had statistically significant higher readmission rates (47.69%) among all payer types. With respect to intraoperative complications, vascular complications had statistically significant increased odds of readmission (OR, 3.225, 95% CI, 0.59 - 1.75; p = 0.0001). Readmitted patients had higher total healthcare costs. CONCLUSION: An overall 90-day readmission of 7.07% following stand-alone single level lumbosacral (L5-S1) ALIF. ALIF procedures have increased in frequency, and an understanding of the comorbidities, age-related demographics, and costs associated with 90-day readmissions are critical. Surgeons should consider these risk factors in preoperative planning and optimization. LEVEL OF EVIDENCE: 3

The multimodal serotonin compound Vilazodone alone, but not combined with the glutamate antagonist Amantadine, reduces l-DOPA-induced dyskinesia in hemiparkinsonian rats

Parkinson\u27s disease (PD) is a progressive, neurodegenerative movement disorder caused by loss of nigrostriatal dopamine (DA) neurons. DA replacement therapy using L-3,4-dihydroxyphenylalanine (l-DOPA) improves motor function but often results in l-DOPA-induced dyskinesia (LID) typified by abnormal involuntary movements (AIMs). In states of DA depletion, striatal serotonin (5-HT) hyperinnervation and glutamate overactivity are implicated in LID. To target these co-mechanisms, this study investigated the potential anti-dyskinetic effects of FDA-approved Vilazodone (VZD), a 5-HT transport blocker and partial 5-HT agonist, and Amantadine (AMAT), a purported NMDA glutamate antagonist, in 6-hydroxydopamine-lesioned hemiparkinsonian Sprague-Dawley rats. Dose-response curves for each drug against l-DOPA-induced AIMs were determined to identify effective threshold doses. A second cohort of rats was tested using the threshold doses of VZD (1, 2.5 mg/kg, s.c.) and/or AMAT (40 mg/kg, s.c.) to examine their combined, acute effects on LID. In a third cohort, VZD and/or AMAT were administered daily with l-DOPA for 14 days to determine prophylactic effects on LID development. In a final cohort, rats with established LID received VZD and/or AMAT injections for 2 weeks to examine their interventional properties. Throughout experiments, AIMs were rated for dyskinesia severity and forepaw adjusting steps (FAS) were monitored l-DOPA motor efficacy. Results revealed that acute and chronic VZD + l-DOPA treatment significantly decreased AIMs and maintained FAS compared to l-DOPA alone. AMAT + l-DOPA co-administration did not exert any significant effects on AIMs or FAS, while the co-administration of VZD and AMAT with l-DOPA demonstrated intermediate effects. These results suggest that co-administration of low-dose VZD and AMAT with l-DOPA does not synergistically reduce LID in hemiparkinsonian rats. Importantly, low doses of VZD (2.5, 5 mg/kg) did reduce the development and expression of LID while maintaining l-DOPA efficacy, supporting its potential therapeutic utility for PD patients