Posttraumatic Stress Disorder (PTSD) is a psychiatric condition that can develop following exposure to a traumatic event involving actual or threatened death or serious injury. Responses include intense fear, helplessness or horror. Symptoms are characterised into clusters, described as re-experiencing, avoidance, and arousal. These symptoms, which are also evident in other conditions, have been associated with dysfunctions in the central acetylcholinergic system. Benefits from administering acetylcholinesterase inhibitors (AChEI) to people suffering these symptoms have been demonstrated. Donepezil hydrochloride, a reversible inhibitor of the enzyme acetylcholinesterase, is used in the treatment of conditions with difficulties in cognitive function, but has not been used in PTSD. The aim of this thesis was to determine (1) whether there was a difference in the ACh system in people with PTSD and (2) whether administration of an AChEI would change the symtomatology. IDEX (I¹ ² ³ iododexetimide) has been useful in imaging muscarinic-ACh receptors using Single Photon Emission Computerised Tomography (SPECT) and was utilised to investigate whether cholinergic activity in PTSD is altered. One hundred and sixty eight potential subjects were screened and eleven PTSD subjects were enrolled in the IDEX SPECT study. Three healthy non-PTSD control subjects also completed the study. Due to technical complications only the data obtained from eight PTSD and two control subjects was available for analysis. Imaging data for 2 further healthy non-PTSD control subjects were obtained from another study. Sixteen subjects were enrolled in the donepezil open label study (assessed at baseline, Week 2, 6 and 10). Nine PTSD subjects completed the 10-week trial and seven withdrew prematurely (at or after Week 2) due to side effects or a worsening of PTSD symptoms. For the IDEX SPECT study, a voxel-by-voxel statistical analysis of the PTSD subject group versus the control group showed both areas of reduced and increased IDEX uptake. Significant clusters in the PTSD group with a reduced IDEX uptake centred around the bilateral hippocampus, left insula and right precuneus, while increased IDEX uptake appeared in the caudate head. For the donepezil study, in the per-protocol analysis (including only the 9 subjects that completed the protocol), all psychological assessments revealed a difference between the totals obtained at the Week 10 visit compared to those at the Baseline visit and the improvement was in the order of 51%. The intention-to-treat analysis (including all 16 subjects), a repeated measures Analysis of Variance (ANOVA) with a mixed models approach showed that all psychological measures demonstrated statistically significant benefits of the treatment. All subjects who completed the protocol recounted considerable improvement in their overall PTSD symptom profile, which covered symptoms in each of the three clusters. The results of the IDEX SPECT study suggest that alterations in ACh binding in PTSD are evident and may begin to explain a part of the altered cognitive symptomatology apparent in this condition. The pilot open label donepezil trial provided some preliminary evidence that treatment with an AChEI can lessen the intrusions and distress associated with traumatic memories in people with PTSD. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1374974 / Thesis (M.Med.Sc.) -- University of Adelaide, School of Medicine, 2009

Posttraumatic Stress Disorder (PTSD) is a psychiatric condition that can develop following exposure to a traumatic event involving actual or threatened death or serious injury. Responses include intense fear, helplessness or horror. Symptoms are characterised into clusters, described as re-experiencing, avoidance, and arousal. These symptoms, which are also evident in other conditions, have been associated with dysfunctions in the central acetylcholinergic system. Benefits from administering acetylcholinesterase inhibitors (AChEI) to people suffering these symptoms have been demonstrated. Donepezil hydrochloride, a reversible inhibitor of the enzyme acetylcholinesterase, is used in the treatment of conditions with difficulties in cognitive function, but has not been used in PTSD. The aim of this thesis was to determine (1) whether there was a difference in the ACh system in people with PTSD and (2) whether administration of an AChEI would change the symtomatology. IDEX (I¹ ² ³ iododexetimide) has been useful in imaging muscarinic-ACh receptors using Single Photon Emission Computerised Tomography (SPECT) and was utilised to investigate whether cholinergic activity in PTSD is altered. One hundred and sixty eight potential subjects were screened and eleven PTSD subjects were enrolled in the IDEX SPECT study. Three healthy non-PTSD control subjects also completed the study. Due to technical complications only the data obtained from eight PTSD and two control subjects was available for analysis. Imaging data for 2 further healthy non-PTSD control subjects were obtained from another study. Sixteen subjects were enrolled in the donepezil open label study (assessed at baseline, Week 2, 6 and 10). Nine PTSD subjects completed the 10-week trial and seven withdrew prematurely (at or after Week 2) due to side effects or a worsening of PTSD symptoms. For the IDEX SPECT study, a voxel-by-voxel statistical analysis of the PTSD subject group versus the control group showed both areas of reduced and increased IDEX uptake. Significant clusters in the PTSD group with a reduced IDEX uptake centred around the bilateral hippocampus, left insula and right precuneus, while increased IDEX uptake appeared in the caudate head. For the donepezil study, in the per-protocol analysis (including only the 9 subjects that completed the protocol), all psychological assessments revealed a difference between the totals obtained at the Week 10 visit compared to those at the Baseline visit and the improvement was in the order of 51%. The intention-to-treat analysis (including all 16 subjects), a repeated measures Analysis of Variance (ANOVA) with a mixed models approach showed that all psychological measures demonstrated statistically significant benefits of the treatment. All subjects who completed the protocol recounted considerable improvement in their overall PTSD symptom profile, which covered symptoms in each of the three clusters. The results of the IDEX SPECT study suggest that alterations in ACh binding in PTSD are evident and may begin to explain a part of the altered cognitive symptomatology apparent in this condition. The pilot open label donepezil trial provided some preliminary evidence that treatment with an AChEI can lessen the intrusions and distress associated with traumatic memories in people with PTSD. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1374974 / Thesis (M.Med.Sc.) -- University of Adelaide, School of Medicine, 2009

Le système cholinergique joue un rôle important dans de nombreuses fonctions cognitives telles que l'attention et l'apprentissage perceptuel. La stimulation pharmacologique du système cholinergique par le donépézil, un inhibiteur de l’acétylcholinestérase, est un moyen efficace pour améliorer les fonctions cognitives et le traitement cortical via les récepteurs muscariniques et nicotiniques. En effet, le donépézil permet l'accumulation d'acétylcholine dans la fente synaptique. Toutefois, l’effet de la stimulation pharmacologique du système cholinergique sur le traitement visuel complexe et l’apprentissage perceptuel n’est pas encore bien défini. L'objectif de cette thèse est d'étudier, d'une part, l'effet de la combinaison d’un entrainement visuel répétitif avec une stimulation cholinergique sur les capacités visuelles chez le rat et l’humain et, d'autre part, l’effet de la stimulation pharmacologique du système cholinergique sur la restauration des capacités visuelles dans un modèle de déficit visuel chez les rats. Nos résultats ont montré qu’un entrainement visuel/cholinergique entraînait : 1) une potentialisation à long terme de la réponse visuelle corticale chez le rat, 2) une récupération plus rapide des capacités visuelles chez la rat suite un écrasement du nerf optique 3) une amélioration de la performance dans une tâche perceptivo-cognitive de haut niveau plus rapide et conservée dans le temps chez les jeunes sujets sains. Le patron d’électroencéphalographie chez le sujet humain pratiquant une tâche d’attention visuelle n’est cependant pas modifié par l’administration d’une dose unique de donépézil. Ensembles, ces résultats soulignent le bénéfice considérable de la combinaison d’une stimulation du système cholinergique lors de l’entrainement visuel répétitif afin d'obtenir des améliorations de la perception visuelle. Cela présente une avenue très intéressante pour la réhabilitation chez les humains. / The cholinergic system plays an important role in many cognitive functions such as attention and perceptual learning. Pharmacological stimulation of the cholinergic system via donepezil, an acetylcholinesterase inhibitor, is an efficient tool for enhancing cognitive functions and cortical processing via muscarinic and nicotinic receptors. In fact, donepezil allows the build-up of acetylcholine in the synaptic cleft. However, whether pharmacological manipulation of the cholinergic system has an effect on complex visual processing and perceptual learning remains unclear. The goal of this thesis is to investigate on the one hand the effect of combining repetitive visual training with cholinergic enhancement on visual capacities in rats and humans and on the other hand the effect of the pharmacological stimulation of the cholinergic system on visual restoration in a model of visual deficit in rats. Our results showed that cholinergic potentiation induces 1) a long-term potentiation of visual cortical response following repetitive visual stimulation, 2) a faster recovery of brightness discrimination in rats with an optic nerve crush, 3) a faster progression of and a sustained performance in a highly demanding perceptual-cognitive task for healthy young humans. However, the EEG pattern for subjects performing a visual attention task is not modified by a single administration of donepezil. Together these results underline the substantial benefice of combining cholinergic enhancement with visual training in order to obtain visual perception improvements, which presents an interesting avenue for visual rehabilitation paradigm in humans.

Le glaucome est la deuxième cause de cécité irréversible dans le monde. La perte de vision qui se produit lors du glaucome s’explique par une dégénérescence du nerf optique et une mort progressive et sélective des cellules ganglionnaires de la rétine (CRG). L'hypertension oculaire est un facteur de risque majeur dans le glaucome, mais des défauts du champ visuel continuent à se développer chez un contingent de patients malgré l'administration de médicaments qui abaissent la pression intraoculaire (PIO). Par conséquent, bien que la PIO représente le seul facteur de risque modifiable dans le développement du glaucome, son contrôle ne suffit pas à protéger les CRGs et préserver la fonction visuelle chez de nombreux patients. Dans ce contexte, j'ai avancé l'hypothèse centrale voulant que les stratégies de traitement du glaucome visant à promouvoir la protection structurale et fonctionnelle des CRGs doivent agir sur les mécanismes moléculaires qui conduisent à la mort des ces neurones. Dans la première partie de ma thèse, j'ai caractérisé l'effet neuroprotecteur de la galantamine, un inhibiteur de l'acétylcholinestérase qui est utilisé cliniquement dans le traitement de la maladie d'Alzheimer. Cette étude s’est basée sur l'hypothèse que la galantamine, en modulant l'activité du récepteur de l'acétylcholine, puisse améliorer la survie des CRGs lors du glaucome. Nous avons utilisé un modèle expérimental bien caractérisé d'hypertension oculaire induite par l’administration d'une solution saline hypertonique dans une veine épisclérale de rats Brown Norway. Les résultats de cette étude (Almasieh et al. Cell Death and Disease, 2010) ont démontré que l'administration quotidienne de galantamine améliore de manière significative la survie des corps cellulaires et des axones CRGs. La protection structurelle des CRGs s’accompagne d’une préservation remarquable de la fonction visuelle, évaluée par l'enregistrement des potentiels évoqués visuels (PEV) dans le collicule supérieur, la cible principale des CRGs chez le rongeur. Une autre constatation intéressante de cette étude est la perte substantielle de capillaires rétiniens et la réduction du débit sanguin associé à la perte des CRGs dans le glaucome expérimental. Il est très intéressant que la galantamine ait également favorisé la protection de la microvascularisation et amélioré le débit sanguin rétinien des animaux glaucomateux (Almasieh et al. en préparation). J'ai notamment démontré que les neuro-et vasoprotections médiées par la galantamine se produisent par iv l'activation des récepteurs muscariniques de l'acétylcholine. Dans la deuxième partie de ma thèse, j'ai étudié le rôle du stress oxydatif ainsi que l'utilisation de composés réducteurs pour tester l'hypothèse que le blocage d'une augmentation de superoxyde puisse retarder la mort des CRG lors du glaucome expérimental. J'ai profité d'un composé novateur, un antioxydant à base de phosphineborane (PB1), pour tester sur son effet neuroprotecteur et examiner son mécanisme d'action dans le glaucome expérimental. Les données démontrent que l'administration intraoculaire de PB1 entraîne une protection significative des corps cellulaire et axones des CRGs. Les voies moléculaires conduisant à la survie neuronale médiée par PB1 ont été explorées en déterminant la cascade de signalisation apoptotique en cause. Les résultats démontrent que la survie des CRGs médiée par PB1 ne dépend pas d’une inhibition de signalisation de protéines kinases activées par le stress, y compris ASK1, JNK ou p38. Par contre, PB1 induit une augmentation marquée des niveaux rétiniens de BDNF et une activation en aval de la voie de survie des ERK1 / 2 (Almasieh et al. Journal of Neurochemistry, 2011). En conclusion, les résultats présentés dans cette thèse contribuent à une meilleure compréhension des mécanismes pathologiques qui conduisent à la perte de CRGs dans le glaucome et pourraient fournir des pistes pour la conception de nouvelles stratégies neuroprotectrices et vasoprotectrices pour le traitement et la gestion de cette maladie. / Glaucoma is the second cause of irreversible blindness worldwide. Loss of vision in glaucoma is accompanied by progressive optic nerve degeneration and selective loss of retinal ganglion cells (RGCs). Ocular hypertension is a major risk factor in glaucoma, but visual field defects continue to progress in a large group of patients despite the use of drugs that lower intraocular pressure (IOP). Therefore, although IOP is the sole modifiable risk factor in the development of glaucoma, its regulation is not sufficient to protect RGCs and preserve visual function in many affected patients. To address this issue, I put forward the central hypothesis that effective therapeutic strategies for glaucoma must interfere with molecular mechanisms that lead to RGC death to successfully promote structural and functional protection of these neurons. In the first part of my thesis, I characterized the neuroprotective effect of galantamine, an acetylcholinesterase inhibitor that is clinically used for the treatment of Alzheimer’s disease. The specific hypothesis of this study was that galantamine, by modulating acetylcholine receptor activity, can improve the survival of injured RGCs in glaucoma. A well characterized experimental model of ocular hypertension induced by administration of a hypertonic saline into an episcleral vein of Brown Norway rats was used. The results of this study (Almasieh et al. Cell Death and Disease, 2010) demonstrated that daily administration of galantamine significantly improved the survival of RGC soma and axons in this model. Structural protection of RGCs correlated with substantial preservation of visual function, assessed by recording visual evoked potentials (VEPs) from the superior colliculus, the primary target of RGCs in the rodent brain. An interesting finding during the course of my thesis was that there is a substantial loss of retinal capillaries and a reduction in retinal blood that correlates with RGC loss in experimental glaucoma. Interestingly, galantamine also promoted the protection of the microvasculature and improved retinal blood flow in ocular hypertensive animals (Almasieh et al. in preparation). Importantly, I demonstrated that galantamine-mediated neuro- and vasoprotection occur through activation of muscarinic acetylcholine receptors. In the second part of my thesis, I investigated the role of oxidative stress and the use of reducing compounds to test the hypothesis that blockade of a superoxide burst may delay RGC death in experimental glaucoma. I took advantage of a novel phosphinevi borane based antioxidant compound available to us (PB1) to investigate its neuroprotective effect and mechanism of action in experimental glaucoma. The data demonstrate that intraocular administration of PB1 resulted in significant protection of RGC soma and axons. I also explored the molecular pathways leading to PB1-mediated neuronal survival by analyzing the components of survival and apoptotic signaling pathways involved in this response. My results show that PB1-mediated RGC survival did not correlate with inhibition of stress-activated protein kinase signaling, including ASK1, JNK or p38. Instead, PB1 led to a striking increase in retinal BDNF levels and downstream activation of the pro-survival ERK1/2 pathway (Almasieh et al. Journal of Neurochemistry, 2011). In conclusion, the findings presented in this thesis contribute to a better understanding of the pathological mechanisms underlying RGC loss in glaucoma and might provide insights into the design of novel neuroprotective and vasoprotective strategies for the treatment and management of this disease.

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In preclinical research on Alzheimer's disease pharmacotherapy, attention is paid to multipotent compounds, enabling intensification of the effect by targeting multiple pathophysiological mechanisms. The aim of the thesis was to assess the effect of multipotent compounds and combination therapy in models of cognitive deficit in the rat. The mechanism of action of the tested compounds was modulation of neurotransmitter systems. The aim of the first part of the study was to compare the effect of experimental monotherapy and combination therapy with an N-methyl-D-aspartate (NMDA) receptor antagonist and a γ-aminobutyric acid type A (GABAA) receptor positive modulator in the trimethyltin-induced model. Superiority of the combination therapy was proven by histological analysis of hippocampal neurodegeneration; however, it did not reach statistical significance in the cognitive test. The other part of the thesis focused on multipotent tacrine derivatives. We demonstrated a positive effect of 6- chlorotacrine-6-nitrobenzothiazole hybrid, as well as 6-chlorotacrine-L-tryptophan hybrid, acting as acetylcholinesterase inhibitors, in the scopolamine-induced model of cognitive deficit. Besides, we demonstrated a low risk of serious side effects of other tacrine derivatives acting as NMDA receptor antagonists....