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Schizophrenia is a debilitating neuropsychiatric disorder that affects approximately one percent of the global population. Aberrant N-methyl-D-aspartate receptors and endoplasmic reticulum stress have been implicated in the pathogenesis of schizophrenia. Despite a century of extensive research, outcomes from best-practice treatments remain dismal. Lurasidone hydrochloride is a novel atypical antipsychotic drug with a unique receptor binding profile that can potentially treat the heterogeneous symptomology of schizophrenia. However, discrepancies in experimental design (i.e. animal models used, symptoms assessed etc.) have yielded conflicting results surrounding the procognitive and antidepressant properties of lurasidone. Furthermore, the limited aqueous solubility of lurasidone poses a considerable challenge for improving antipsychotic drug delivery to the brain and limiting the prevalence of adverse side effects. These obstacles coupled with the elusive pathophysiology of schizophrenia and its incurable nature, highlight the importance of investigating novel therapeutic targets and their underlying mechanisms to improve treatment and enhance the quality of life of patients with schizophrenia. This thesis sought to accomplish three primary objectives: (1) validate the behavioural efficacy of lurasidone hydrochloride; (2) investigate the role of mesencephalic astrocyte-derived neurotrophic factor as a potential therapeutic target of lurasidone; and (3) evaluate the therapeutic potential of intranasal lurasidone administration as a novel method for antipsychotic drug delivery. The data presented within this thesis suggest that repeated lurasidone treatment may be effective at treating the positive, negative, and cognitive symptoms of schizophrenia, but not sensorimotor gating deficits. Furthermore, sub-chronic lurasidone treatment in rats significantly increased the relative expression of mesencephalic astrocyte-derived neurotrophic factor in the rat prefrontal cortex, a primary site of impairment observed in schizophrenia. Lastly, we conclude that lurasidone administered via the nasal route using a novel poly(oligo ethylene glycol methacrylate)-based nanogel formulation required four times less drug to achieve a therapeutic response comparable to traditional intraperitoneal routes. The findings presented within this thesis suggest that lurasidone might be a favourable atypical antipsychotic drug that exerts its therapeutic effects through the modulation of neurotrophic factor expression in the brain regions affected by schizophrenia. This thesis offers new insight that can help guide future studies toward improving the prognosis of patients suffering from schizophrenia. / Thesis / Master of Science (MSc)

Brucella are Gram-negative intracellular bacteria that cause abortion and infertility in livestock and chronic disease in humans. The Centers for Disease Control and Prevention (CDC) categorizes them as class B pathogens due to their zoonotic potential. Currently, there are no efficacious Brucella vaccines for humans available. Very few studies have focused on identifying protective vaccines against respiratory exposure. Protection by B. abortus rough vaccine strains RB51 and RB51SOD is through strong CD4⁺ Th₁ and CD8⁺ Tc₁ adaptive immunity. However, limited information is available on how they stimulate innate immunity. This knowledge is critical for improving these vaccines for their potential use in humans. Dendritic cells (DCs) play a crucial role bridging innate and adaptive immunity. Therefore, enhancing the ability of rough vaccine strains to induce DC maturation and function could be critical for upregulating protective T-cell responses. Herein, we demonstrated that live vaccine strain RB51 induced significantly better (p≤0.05) DC maturation and function in vitro and upon intranasal inoculation in vivo compared to strain RB51SOD or strain 2308. Due to safety concerns of live vaccines, irradiated and heat killed vaccines were also tested; only live strain RB51 infected DCs induced significant (p≤0.05) DC function based on TNF-α and IL-12 secretion. DC activation occurs through Toll-like receptors (TLRs) 2, 4 and 9. Our study reported that strain RB51 induced significant (p≤0.05) DC activation compared to strain 2308, which was not dependent on a specific TLR. However, strain RB51 induced TNF – α production was TLR2 and TLR9 dependent and IL-12 production was TLR2 and TLR4 dependent. TLR4 KO mice had significantly (p≤0.05) higher number of strain RB51 colonies present at day 14 post infection. By unraveling the innate immune responses to Brucella, the ultimate goal of these studies is to develop a protective vaccine for animals and people against respiratory challenge. As such, we tested several vaccination strategies. Despite enhanced DC activation and function achieved by vaccine strains, they failed to protect mice against intranasal challenge with strain 2308. Future experiments will address host-pathogen interaction at the lung microenvironment and elucidate immune mechanisms that will enhance protection against aerosol exposure. / Ph. D.

Brucella abortus is amongst the top 5 zoonotic diseases worldwide. The overall goal of this research is to generate a safe and effective vaccine for humans. Brucella abortus strain RB51, approved for use in cattle, provides protection by initiating a strong T-helper 1 (Th1) type response is a candidate vaccine. Based on a model for aerosol exposure mice were vaccinated intranasally (IN) with strain RB51 and challenged IN with B. abortus strain 2308, strain RB51 did not protect. Protection against Brucella is mediated through TLRs 2, 4 and 9. The addition of TLR 2 or TLR 4 and a trend with TLR9 agonists with intranasal RB51 vaccination significantly increased bacterial clearance in the lung after strain 2308 challenge. Therefore, we hypothesized that combining TLR agonists 2, 4, and 9 with strain RB51 IN would upregulate protection and clearance in the lung against strain 2308 challenge (IN), by upregulating the DC1 and CD4 Th1 and CD8 immune response. This study showed that protection is not upregulated by combining all TLR agonists. Overall the addition of TLR 2 and 4 vs. TLR 2, 4 and 9 agonists affects the immune response and impacts the level of clearance. Our data support the development of a DC1 Th1 CD8 response, based on serology, and both DC and T-cell activation and function by the group which received the TLR 2 and 4 agonists and to a lesser degree the group receiving TLR 2, 4, and 9 agonists. Additional studies are warranted to further define the differential mechanisms and endpoints of protection. / Master of Science

No description available.

Master of Veterinary Biomedical Sciences / Department of Clinical Sciences / Bradley White / Objective- To compare serologic response and viral replication following intranasal administration of a modified-live bovine rhinotracheitis (IBR) parainfluenza-3 (PI-3) vaccine in high (32°C) and moderate (21°C) ambient temperatures. Animals- 28 heifers (mean body weight, 206.8 kg) Procedures- Heifers randomly allocated to treatment groups: High Ambient Temperature (HAT, n=10): received vaccine, housed outdoors, Moderate Ambient Temperature (MAT, n=10): received vaccine, housed indoors, High Ambient Control (HAC, n=4): no vaccine, housed outdoors, Moderate Ambient Control (MAC, n=4): no vaccine, housed indoors. Rectal and nasal mucosal temperatures were recorded every 2 hours from 8am to 8pm on trial days 0 and 1. Nasal swabs were collected on trial days 0 through 7 for virus isolation. Serum samples were collected for serology on trial days 0, 7, 14, and 28. Results- Rectal temperatures did not differ among treatment groups over the study period, but nasal temperatures were higher in the HAT calves compared to MAT group at study hours: 6, 24, 30, 32, and 38. Two weeks post-vaccination, IBR titers were significantly greater in vaccinates (HAT,MAT) relative to non-vaccinates (HAC, LAC), but no differences were identified among HAT and MAT. Viable IBR virus was recovered via virus isolation from all vaccinated calves (HAT,MAT) on trial days 1 through 6. Conclusions and Clinical Relevance- The ability to isolate IBR and stimulate the calf immune response following administration of a modified-live IBR-PI3 intranasal vaccine did not differ in calves housed in temperature-controlled and high ambient temperature environments.

As proteínas de classe 3 são candidatas na preparação de uma vacina contra a doença meningocócica. O objetivo deste estudo é determinar a imunogenicidade da proteína de classe 3 purificada da cepa de Neisseria meningitidis do sorogrupo B juntamente com a capacidade adjuvante de whole cells de Bordetella pertussis. Foram imunizados camundongos BALB/c neonatos em um intervalo de 3 a 12 dias entre 1 e 4 doses da proteína de classe 3 mais adjuvante, pela via intranasal e no 21º dia pela via intramuscular com a proteína de classe 3 emulsificada com hidróxido de alumínio. Os resultados demonstraram que após 2 doses pela via intranasal e 1 dose pela via intramuscular houve rápido estímulo das células imunes nos camundongos adultos BALB/c e neonatos BALB/c e outbred. Todos os soros foram analisados por ELISA e immunoblot. O adjuvante B. pertussis administrado pelas vias intranasal ou intramuscular, aumentou a resposta imune comparada com os controles. Anticorpos bactericidas e de alta afinidade foram produzidos. / Proteins of class 3 sound candidates in the preparation of vaccine against meningococcal illness. The aim of this study was to determine the immunogenicity of class 3 proteins purified of Neisseria meningitidis of the serogroup B along with whole cells of Bordetella pertussis as adjuvant. BALB/c and outbred neonate mice between 3 and 12 days old were immunized with 1 to 4 doses of the purified class 3 proteins with or without adjuvant given by the intranasal route, and on the 21st day the animals received an intramuscular dose of the class 3 proteins with or without aluminum hydroxide. The results demonstrated that after 2 doses by the intranasal route and 1 dose intramuscular there was a rapid stimulation of the immune cells in BALB/c adult mice as well as BALB/c and outbred neonates mice. All sera were analyzed by ELISA and immunoblot. The adjuvant B. pertussis used in the present investigation and given via the intranasal or intramuscular route increased the immune response compared with the controls. High affinity and bactericidal antibodies were produced.

<p>Drug delivery to the nasal and ocular mucosa faces several obstacles. One of these is from the effective clearance mechanisms present in the nose and eye. Polymer gels with suitable rheological properties can facilitate the absorption of poorly absorbed drugs by increasing the contact time of the drug with the mucosa. This has been attributed to the rheological and mucoadhesive properties of the gel. The main objective of this thesis was to investigate the importance of these features for the anticipated in vivo contact time, here exemplified by the ocular and nasal routes of administration.</p><p>The in situ gelling polymer gellan gum was found to have a favourable rheological and in vivo performance. When administered in the nasal cavity of rats, a gel was formed that could remain at the site of administration for up to 4 hours. In addition, the epithelial uptake and transfer of a 3 kDa fluorescein dextran was higher than for a mannitol solution. Therefore, it was concluded that a gellan gum formulation should be a promising strategy for nasal drug delivery.</p><p>The potential mucoadhesive properties of a variety of polymer gels were investigated using a rheological method and by measuring the tensile force required to detach the gel from a mucosa. With both methods the rheological properties of the gel were a determining factor for the results obtained. The rheological method was found to have several limitations. One of these was that a positive response, interpreted as mucoadhesion, was only seen with weak gels. The tensile method could, in contrast, detect strengthening of the mucus only for strong gels. However, this method reflects the in vivo performance of the gel better than the rheological method.</p><p>Finally, dielectric spectroscopy was explored as a tool for investigating the likelihood of intimate surface contact between the gel and the mucus layer. This novel approach involved determining the ease with which a charged particle can pass the gel-mucus interface layer, and may enable the study of the events at the interface closer to the molecular level, than is possible with the rheological and tensile strength methods.</p>

Drug delivery to the nasal and ocular mucosa faces several obstacles. One of these is from the effective clearance mechanisms present in the nose and eye. Polymer gels with suitable rheological properties can facilitate the absorption of poorly absorbed drugs by increasing the contact time of the drug with the mucosa. This has been attributed to the rheological and mucoadhesive properties of the gel. The main objective of this thesis was to investigate the importance of these features for the anticipated in vivo contact time, here exemplified by the ocular and nasal routes of administration. The in situ gelling polymer gellan gum was found to have a favourable rheological and in vivo performance. When administered in the nasal cavity of rats, a gel was formed that could remain at the site of administration for up to 4 hours. In addition, the epithelial uptake and transfer of a 3 kDa fluorescein dextran was higher than for a mannitol solution. Therefore, it was concluded that a gellan gum formulation should be a promising strategy for nasal drug delivery. The potential mucoadhesive properties of a variety of polymer gels were investigated using a rheological method and by measuring the tensile force required to detach the gel from a mucosa. With both methods the rheological properties of the gel were a determining factor for the results obtained. The rheological method was found to have several limitations. One of these was that a positive response, interpreted as mucoadhesion, was only seen with weak gels. The tensile method could, in contrast, detect strengthening of the mucus only for strong gels. However, this method reflects the in vivo performance of the gel better than the rheological method. Finally, dielectric spectroscopy was explored as a tool for investigating the likelihood of intimate surface contact between the gel and the mucus layer. This novel approach involved determining the ease with which a charged particle can pass the gel-mucus interface layer, and may enable the study of the events at the interface closer to the molecular level, than is possible with the rheological and tensile strength methods.

Untersuchung zur Wirkung von intranasal verabreichtem Xylometazolin bei brachy- und normozephalen Hunden: Impuls-Oszillometrie und akustische Rhinometrie P. Franco, J. P. Hueber, G. U. Oechtering Klinik für Kleintiere, Arbeitsgruppe Brachyzephalie, Universität Leipzig Einleitung: Die zuchtbedingte Verkürzung des Gesichtsschädels brachy - zephaler Hunderassen hat zu einer Reihe klinisch relevanter morphologischer und physiologischer Veränderungen geführt. Hierzu zählen stenotische Naseneingänge, eine durch fehlgebildete Conchen obstruierte Nasenhöhle sowie ein verdicktes und verlängertes Gaumensegel. Diese Einengung der oberen Atemwege führt zu Atemnot und ausgeprägter Belastungsintoleranz, was als Brachyzephales Atemnotsyndrom (BAS) bezeichnet wird. Xylometazolin ist ein für den Menschen zugelassenes Alpha-Sympathomime - tikum. Topische und systemische Sympathomimetika werden beim Menschen zur Behandlung nasaler Kongestionen zum Abschwellen der Nasenschleimhaut eingesetzt. Zielstellung: Ausgehend von der Hypothese, dass Xylometazolin auch bei Hunden zu einem Abschwellen der Nasenschleimhaut führt und dass die Morphologie der Nasenmuscheln sich zwischen den zwei Zielgruppen unterscheidet, sollte der intranasale Strömungswiderstand bei brachy- und normozephalen Hunden vor und nach Xylometazolingabe mit Impuls- Oszillometrie untersucht werden. Zusätzlich wurden in der Beaglegruppe mit akustischer Rhinometrie das Nasenhöhlenvolumen und die minimale Querschnittsfläche bestimmt. Methodik: Die Messungen erfolgten nach dem Prinzip der Impuls-Oszillometrie (IOS) und akustischer Rhinometrie. In einer prospektiven klini - schen Studie wurden 10 brachyzephale Hunde (5 Möpse, 5 Französische Bulldoggen) und 6 Beagles untersucht. Bei den anästhesierten, spontan atmenden Tieren wurde der intranasale Strömungswiderstand mit Impuls- Oszillometrie unmittelbar vor und 30 Minuten nach intranasal verabreichtem Xylometazolin gemessen. Messungen mit akustischer Rhinometrie erfolgten zusätzlich vor und nach Xylometazolingabe. Bei allen Tieren wurden die oberen Atemwege endoskopisch und computertomographisch untersucht. Ergebnisse: Der aus drei Messungen gemittelte intranasale Strömungswiderstand bei Patienten mit BAS betrug vor Xylometazolingabe 0,87 ± 0,097 kPa/(L/s). Nach Xylometazolingabe reduzierte sich der intranasale Strömungswiderstand um etwa 48% auf 0,42 ± 0,55 kPa/(L/s). Vergleich - bare Ergebnisse ermittelten wir in der Beaglegruppe. Nach Xylometazolingabe ergab sich bei den Beagles eine Zunahme des Nasenvolumens und der minimalen Querschnittsfläche. Schlussfolgerungen: Wir konnten erstmals zeigen, dass Xylometazolin auch bei Hunden zum Abschwellen der Nasenschleimhaut führt und sich das Abschwellverhalten zwischen brachy- und normozephalen Hunden kaum voneinander unterscheidet. A13 Abstracts 18. Jahrestagung der DVG-FG InnLab © Schattauer 2010 Tierärztliche Praxis Kleintiere 1/2010