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

No description available.

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.

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.

Autonomic nervous system activity is related to body weight regulation. Based on the MONA LISA hypothesis it has been suggested that most obese subjects and animals have low sympathetic nervous system activity. The aim of this study was to investigate whether there are differences in autonomic nervous system activity between lines of chickens selected for either high (HWS) or low body weight (LWS). In Exp. 1, various pharmacological agents were injected intravenously, and the changes in blood pressure (BP) and heart rate (HR) of both HWS and LWS chickens were compared. The results showed that the HWS birds had a greater increase in BP and HR than the LWS following injection of atropine, a muscarinic receptor blocker, and LWS birds had a greater decrease in BP and HR to propranolol, a beta- adrenergic receptor blocker than the HWS birds. These results suggested that HWS chickens have higher parasympathetic tone, whereas LWS chickens have a higher sympathetic nervous system tone regulating the cardiovascular system. HWS and LWS chickens displayed a similar response in BP and HR following injection of the ganglion blocker tetraethylammonium chloride. These results suggest that there is no significant difference in the central autonomic nervous system in the cardiovascular regulation between HWS and LWS together. Since there does not appear to be any differences in the activity of the autonomic nervous system activity at the level of the central nervous system, these findings imply that the difference in response to atropine and propranolol could be caused by differences in adrenal activity. The ratio of heart rate and blood pressure after the injection of phenylephrine showed significant difference between these two lines of birds, but not when phenylephrine was injected following atropine. This result indicated that HWS are more dependent on the parasympathetic nervous system to regulate the baroreceptor reflex. The percentage of adrenal and sympathetic impact on the regulation of heart rate showed that LWS females required greater adrenal activity than the other birds. In Exp. 2, the body weight and food intake responses of HWS and LWS chickens to ip injections of reserpine were compared. Reserpine caused a transitory decrease in food intake and body weight in both lines of birds. However HWS chickens recovered more slowly from the depression caused by reserpine than the LWS chickens. This could be due to lower sympathetic nervous system activity. In conclusion, it appears that HWS may have lower sympathetic activity than LWS. Combining the results of both experiments, it appears that the HWS birds have lower sympathetic and higher parasympathetic activity. Furthermore central nervous system autonomic activity in BP and HR regulation is not different between HWS and LWS, but the activity of the adrenal gland may be different between these two lines of birds. / Master of Science

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.