Thesis--Copenhagen. / General summary in English and Danish. "Reprints of author's previous investigations (Papers I-VI)": [66] p. at end. Includes bibliographical references.

Thesis--Copenhagen. / General summary in English and Danish. "Reprints of author's previous investigations (Papers I-VI)": [66] p. at end. Includes bibliographical references.

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

The research presented herein explores three aspects of asymmetric catalysis: (1) the development of new catalytic enantioselective reactions, (2) the application of stereoselective catalysis to natural product total synthesis, and (3) the design and synthesis of new chiral catalysts. / Chemistry and Chemical Biology

To prove the post-natal depression model, the antidepressant sertraline, was assessed in rat mothers (n=14) divided into Prenatally Stressed (PS) and Non-Stressed (NS) groups. The data failed to support the hypothesis that ‘the progeny of 10mg of sertraline-treated PS mothers displayed less anxiety than the progeny of vehicle-treated PS mothers’. The forced swim test (FST) was used to examine depressive-like behaviour in mice. Barley successfully increased mobility in mice exposed to the FST. Barley was antidepressant at low doses (0.8g/kg and upwards) if used subchronic; and at high doses(6.4g/kg and 12.8g/kg) if used acutely;(n=113,56acute,57 subchronic- treated). Barley (6.4g/kg) was also able to alleviate the depressive-behaviour in mice induced by the Reserpine Test (n=114, 58 reserpinised, 56 non-reserpinised) and Social ‘Defeat’ Test (n=24, 8 vehicle undefeated, 8 barley defeated, 8 vehicle defeated mice). To confirm that the anti-depressant effects of barley(6.4g/kg) were not simply due to increased locomotor activity in the FST, an Open Field Test(OFT) was undertaken (n=14,7 vehicle, 7 barley). Barley had no effect on locomotor activity and also caused no significant changes in weight (n=16, 8vehicle, 8 barley). In mice,Barley(6.4g/kg) significantly delayed the tremorogenic effects of Physostigmine (n=18, 6 control,6 Physostigmine, 6 Physostigmine with barley); reduced bradykinesia induced by reserpine (n=18,6 control, 6 vehicle, 6 barley treated);and was analgesic in nociception tests (n =20, 5 control, 5 barley, 5 pain, 5 pain with barley). Overall, barley was seen to have many useful properties, though its effect in PND remains to be assessed. / Saudi Cultural Bureau in London; Medical Services Department of the Ministry of Interior in Riyadh, Saudi Arabia. / The full text of this thesis is embargoed indefinitely.

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To prove the post-natal depression model, the antidepressant sertraline, was assessed in rat mothers (n=14) divided into Prenatally Stressed (PS) and Non-Stressed (NS) groups. The data failed to support the hypothesis that ‘the progeny of 10mg of sertraline-treated PS mothers displayed less anxiety than the progeny of vehicle-treated PS mothers’. The forced swim test (FST) was used to examine depressive-like behaviour in mice. Barley successfully increased mobility in mice exposed to the FST. Barley was antidepressant at low doses (0.8g/kg and upwards) if used subchronic; and at high doses(6.4g/kg and 12.8g/kg) if used acutely;(n=113,56acute,57 subchronic- treated). Barley (6.4g/kg) was also able to alleviate the depressive-behaviour in mice induced by the Reserpine Test (n=114, 58 reserpinised, 56 non-reserpinised) and Social ‘Defeat’ Test (n=24, 8 vehicle undefeated, 8 barley defeated, 8 vehicle defeated mice). To confirm that the anti-depressant effects of barley(6.4g/kg) were not simply due to increased locomotor activity in the FST, an Open Field Test(OFT) was undertaken (n=14,7 vehicle, 7 barley). Barley had no effect on locomotor activity and also caused no significant changes in weight (n=16, 8vehicle, 8 barley). In mice,Barley(6.4g/kg) significantly delayed the tremorogenic effects of Physostigmine (n=18, 6 control,6 Physostigmine, 6 Physostigmine with barley); reduced bradykinesia induced by reserpine (n=18,6 control, 6 vehicle, 6 barley treated);and was analgesic in nociception tests (n =20, 5 control, 5 barley, 5 pain, 5 pain with barley). Overall, barley was seen to have many useful properties, though its effect in PND remains to be assessed.

Treatment of rats with reserpine, an inhibitor of the vesicular monoamine transporter (VMAT), depletes norepinephrine (NE) and regulates NE transporter (NET) expression. The present study examined the molecular mechanisms involved in regulation of the NET by reserpine using cultured cells. Exposure of rat PC12 cells to reserpine for a period as short as 5min decreased [ H]NE uptake capacity, an effect characterized by a robust decrease in the V of the transport of [ H]NE. As expected, reserpine did not displace the binding of [ H]nisoxetine from the NET in membrane homogenates. The potency of reserpine for reducing [ H]NE uptake was dramatically lower in SK-N-SH cells that have reduced storage capacity for catecholamines. Reserpine had no effect on [ H]NE uptake in HEK-293 cells transfected with the rat NET (293-hNET), cells that lack catecholamine storage vesicles. NET regulation by reserpine was independent of trafficking of the NET from the cell surface. Pre-exposure of cells to inhibitors of several intracellular signaling cascades known to regulate the NET, including Ca /Ca -calmodulin dependent kinase and protein kinases A, C and G, did not affect the ability of reserpine to reduce [ H]NE uptake. Treatment of PC12 cells with the catecholamine depleting agent, α-methyl-p-tyrosine, increased [ H]NE uptake and eliminated the inhibitory effects of reserpine on [ H]NE uptake. Reserpine non-competitively inhibits NET activity through a Ca -independent process that requires catecholamine storage vesicles, revealing a novel pharmacological method to modify NET function. Further characterization of the molecular nature of reserpine's action could lead to the development of alternative therapeutic strategies for treating disorders known to be benefitted by treatment with traditional competitive NET inhibitors.

In the present study, two different drugs were used to induce a Parkinson-like condition. The first drug was the centrally acting cholinergic agonist oxotremorine (OXTM) which readily induces tremor and rigidity in mice (54). This tremor has been reported to be antagonized by dopamine agonists such as L-dopa and apomorphine (50,54,55) as well as by anticholinergic drugs such as scopolamine (46) . The other drug used was reserpine which interferes with the neuronal storage of dopamine and results in its depletion in the brain (56). Reserpine induces tremor, rigidity, blepharoptosis (a drooping of the eyelids), and catalepsy (48,57-59). The catalepsy is readily reversed by the administration of L—dopa (48,60-62). Using these two models of Parkinson's disease, selected narcotic antagonists have been tested to determine if they could potentiate dopaminergic influences and restore the normal balances of acetylcholine and dopamine in the corpus striatum.

<p dir="ltr">Mycobacterium abscessus (Mab) is a type of mycobacterium that is known for its remarkable resistance to a variety of antibiotics. This pathogen poses a significant risk for individuals with weakened immune systems as it can cause skin and soft tissue infections, pulmonary disease and disseminated infections. Mab's ability to expel antibiotics through efflux pumps and form strong biofilms makes it even more challenging to treat infections. Lipids form a major part of the extracellular matrix of Mab biofilms. Efflux pumps have been shown to export lipids to the cell surface. Despite ongoing research into Mab's antibiotic tolerance, there is still much to learn about the impact of efflux pump inhibitors (EPIs) on antibiotic resistance and lipid biosynthesis during biofilm development in Mab. In this study, we investigated the impact of the EPIs; CCCP (carbonyl cyanide m-chlorophenyl hydrazone), piperine (PIP), reserpine (RES), berberine (BER), and verapamil (VER) on efflux activity, biofilm formation, antibiotic resistance, and lipid biosynthesis in Mab during planktonic and biofilm growth conditions. We found that Mab cells had a higher tolerance to EPIs in biofilm-stimulating medium and that the presence of EPIs led to a decrease in minimum inhibitory concentrations of frontline antibiotics, reduced efflux activity within Mab cells, and significantly inhibited biofilm formation. We examined the effects of EPIs that inhibited biofilm formation on lipid metabolism in Mab using radiolabeling with 14C?palmitic acid and 14C-acetic acid which are precursors of lipid biosynthesis. We observed that the EPI berberine inhibited the incorporation of 14C-palmitic acid into glycopeptidolipids in the surface lipids of planktonic cells and increased cellular glycopeptidolipid (GPL) in biofilm cells. Verapamil-treated cells showed a 55 % increase in cellular trehalose monomycolate (TMM) compared to controls. Piperine-treated cells exhibited a 50 % increase in cardiolipin. The incorporation of 14C-acetate into biofilm cells showed that piperine-treated biofilm cells showed a 146 % increase in surface glycopeptidolipids. Overall, our study enhances our understanding of lipid biosynthesis in Mab, the effects of EPIs on Mab biofilms, efflux mechanisms, and antibiotic resistance and offers insights for combating Mab-related infections.</p>