Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2006. / Includes bibliographical references (leaves 215-232). Also available in electronic version.

Thesis (doctoral)--Karolinska Institutet, Stockholm, 1991. / Extra t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (doctoral)--Karolinska Institutet, Stockholm, 1991. / Extra t.p. with thesis statement inserted. Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2002. / Includes bibliographical references (leaves 78-91). Also available in electronic version. Access restricted to campus users.

Several endogenous amino acids including L-glutamate and L-aspartate have potent excitatory effects in the central nervous system. They are thought to act as synaptic transmitters in many neural pathways including those in the spinal cord. Three distinct receptors have been described through which these excitatory amino acids exert their effects. These are referred to as quisqualate, kainate and N-methyl-D-aspartate (NMDA) receptors, after the exogenous excitants most specific for each. In addition, sub-types of the NMDA receptor have been proposed to account for differences observed in the actions of the endogenous excitant quinolinate (2,3-pyridine dicarboxylate) in various regions of the nervous system. The characterization of excitant amino acid receptors has been accomplished primarily using two or more potent antagonists which include D-(-)-2-amino-5-phosphonovalerate (APV), a specific NMDA antagonist, and kynurenate, a compound related to quinolinate which potently attenuates the actions of NMDA- and kainate-like excitants. Structure-activity studies of amino acid receptors were undertaken using standard extracellular recording and iontophoretic techniques in the dorsal horn of the spinal cord in vivo, and compared with the neocortex of the rat. In addition, a spinal cord slice preparation was developed wherein dorso-ventral longitudinal slices were prepared from the lumbar enlargement of weanling rats (50 - 125 g). The slices were maintained in an "interface" tissue bath of novel design. Extracellular recording of several hours duration and up to 8 hours after slice preparation were routinely possible. Conformationally restricted analogues of glutamate, aspartate and quinolinate were examined for agonist and antagonist actions in the rat spinal cord in vivo and in vitro. Compounds found to be excitants were compared directly with quisqualate, kainate, and NMDA for sensitivity to blockade by APV and kynurenate applied both iontophoretically and in the bathing medium; antagonist dose-response curves were constructed for the actions of APV and kynurenate against quisqualate, kainate, quinolinate and NMDA. The conformationally restricted compounds found to be antagonists were examined to determine their potency and specificity against excitations elicited by quisqualate, kainate, quinolinate and NMDA. Although quinolinate is known to be NMDA-like in the hippocampus and cortex, when compared to quisqualate, kainate and NMDA in the spinal cord in vitro, it proved to be unique. A fourth receptor (the "QUIN" receptor) is proposed to account for its actions in the spinal cord. Three of the isomers of 1-amino-1,3-cyclopentane dicarboxylate (ACPD), conformationally restricted analogues of glutamate, were potently blocked by APV and KYNA and were therefore classified as NMDA-like. The fourth, D-trans-ACPD. was indistinguishable from quinolinate in terms of both potency and sensitivity to antagonists. The (-) isomer of trans-1-amino-1,2-cyclopentane dicarboxylate proved to be an antagonist with greater potency against excitations elicited by quisqualate and kainate than those of NMDA. These findings are, in many ways, different from what has been observed in the hippocampal slice. Several pyridine derivatives were examined; 2,5- and 2,6-pyridine dicarboxylate were weak excitants behaving like quisqualate in the presence of APV and kynurenate. No other pyridines were excitatory; however 2,4-pyridine dicarboxylate was observed to be a weak, non-specific antagonist similar in action to acridinate (an antagonist closely related to kynurenate). None of the pyridine derivatives, save quinolinate, are excitatory in the hippocampus. Structural analysis of the active compounds tested, in consideration of previous studies, shows that three points of attachment (two carboxyl and one amino group) are necessary for activation of NMDA, quisqualate and quinolinate receptors in the spinal cord. The location of the distal or y-carboxyl group relative to the a ionic groups appears to be the primary factor determining the activity of a conforrnationally restricted compound. The absolute distance between the Y-carboxyl and α-carbon appears to play a secondary role in determining the action of a compound. / Medicine, Faculty of / Graduate

Tingan Chen. / "March 2000." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (p. 100-142). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 6 uppsatser.

A epilepsia é um transtorno do funcionamento cerebral caracterizado por crises epilépticas recorrentes que acomete cerca de 1 a 2% da população mundial. A epilepsia do lobo temporal (ELT) é o subtipo mais prevalente. A refratariedade aos medicamentos é comum e cerca de 40 % destes pacientes apresentam transtornos psiquiátricos. Neste trabalho utilizamos o método de TacMan real time PCR para quantificar o mRNA de subtipos dos receptores de noradrenalina, dopamina, serotonina e substância P em hipocampos cirurgicamente removidos de pacientes com ELT para conhecer o papel destes na ELT com ou sem comorbidade psiquiátrica (depressão ou psicose). Nossa amostra foi de 48 pacientes com ELT sem (Epilepsia - 24) ou com comorbidade psicótica (Psicose - 10) ou depressiva (Depressão - 14) e 8 Controles (necrópsias). O receptor adrenérgico-α2A (AD2A) apresentou diferença entre os grupos (p = 0,0059) com significância para a variável Antiepiléptico (p = 0,0374) e pós-teste significante de maior expressão do mRNA de AD2A no grupo Epilepsia comparado com Controle e com Psicose. A ativação dos receptores α2A no hipocampo pelos antiepilépticos pode explicar nossos achados do grupo Epilepsia comparado ao Controle, corroborando a literatura acerca do AD2A na epilepsia e em relação aos antiepilépticos. O AD2C mostrou diferença entre os grupos (p = 0,0016), sem significância nas variáveis de controle e significante maior expressão do mRNA de AD2C no grupo Epilepsia comparado ao Controle e Psicose. O AD2C é encontrado em áreas que processam informações sensoriais e controlam atividades motoras e emocionais relacionadas, o que pode explicar nossos resultados. Parece ser importante na patologia relacionada à ELT e merece ser estudado. A não diferença entre Epilepsia e Depressão para AD2A e AD2C, parecem confirmar uma relação bi-direcional ou um mecanismo patogênico comum entre epilepsia e depressão, enquanto a menor expressão de AD2A e AD2C nos psicóticos parece indicar diferenças nos mecanismos adrenérgicos ligados a psicose e epilepsia. D2 mostrou diferença entre os grupos (p = 0,0125) com resultado significativo para a variável Subtipo de Diagnóstico Psiquiátrico (p = 0,0239), provavelmente devido a cronicidade da doença e a quantidade de episódios depressivos apresentados pelos sujeitos. Quanto maior a freqüência das crises (p = 0,0381) maior a expressão do D2 no grupo Epilepsia e no Depressão comparados ao Controle. Estes achados sugerem a participação deste receptor na depressão comórbida na ELT; corroboram que o monitoramento dopaminérgico límbico pode ser útil para desenvolver novos antidepressivos e propõem pesquisas futuras sobre D2 em epilépticos. A participação de 5-HT2A na ELT é indicada, pois, sua maior expressão no grupo Epilepsia em relação ao Controle foi significativa (p = 0,0273). Quanto maior a freqüência das crises epilépticas maior a expressão do 5-HT2A (p = 0, 0433). Não encontramos resultados significativos referentes aos receptores D4, 5-HT1A, 5-HT2C e NK1. Nossos resultados mostraram a possibilidade da aplicação do TacMan real time PCR no estudo de receptores de neurotransmissores, sugeriu a importância dos receptores estudados na ELT e comorbidades psiquiátricas, e que outras estruturas límbicas, como a amígdala, sejam focos de investigação. / Epilepsy is a mental functional disorder characterized by recurrent seizures that affect about 1 to 2% of world population. Temporal lobe epilepsy (TLE) is the most prevalent subtype. The refractory to medication is common and about 40% of these patients have psychiatric disorders. This study used the TacMan real time PCR method to quantify noradrenergic, dopaminergic, serotoninergic and substance P receptors subtypes mRNA expression in hippocampus surgically removed from patients with TLE to know their role in TLE with or without psychiatric commorbity (depression or psychosis). Our sample consisted of 48 TLE patients without (Epilepsy - 24) or with psychotic (Psychosis - 10) or depressive (Depression - 14) commorbity and 8 Controls (necropsies). The α2A adrenergic receptor (AD2A) showed difference between groups (p = 0.0059) with significance for Antiepileptic Medication variable (p = 0.0374) and post-hoc test significantly greater AD2A mRNA expression of Epilepsy group compared with Control and Psychosis. The activation of hippocampus α2A receptors by antiepileptic drugs can explain our findings of the Epilepsy group compared with Control, corroborating the literature about the AD2A in epilepsy and for antiepileptic drugs. The AD2C showed differences between groups (p = 0.0016) without significance in the variables of control and significantly greater AD2C mRNA expression of the Epilepsy group compared to Control and Psychosis. The AD2C is found in areas that process sensory information and control motor and emotional related activities, which may explain our results. It seems to be important in the pathology related to TLE and deserves to be studied. No differences between Epilepsy and Depression to AD2A and AD2C seem to confirm a bi-directional relation or a common pathogenic mechanism between epilepsy and depression, while the lowest AD2A and AD2C expression within psychotics seem suggests differences in adrenergic mechanisms linked to psychosis and epilepsy. D2 showed differences between groups (p = 0.0125) with significant results for the variable Subtype of Psychiatric Diagnosis (p = 0.0239), probably due to chronic disease and the number of depressive episodes presented by subjects. The higher the frequency of seizures (p = 0.0381) the higher was the D2 expression within Epilepsy group compared with Control and Depression compared to Control. These findings suggest the involvement of this receptor in TLE commorbid depression; corroborate that limbic dopaminergic monitoring may be useful in developing new antidepressants and propose future research on D2 in epileptics. The participation of 5-HT2A in TLE is indicated, therefore its significant higher expression in the Epilepsy group in relation to Control (p = 0.0273). The higher the frequency of seizures the higher was the 5-HT2A expression (p = 0.0433). We found no significant results for the D4, 5-HT1A, 5-HT2C and NK1 receptors. Our results showed the possibility of TacMan real time PCR method application in TLE neurotransmission receptors study, suggested the importance of the studied receptors in TLE and psychiatric commorbities and that other limbic structures, as the amygdala, should be investigation targets.

A epilepsia é um transtorno do funcionamento cerebral caracterizado por crises epilépticas recorrentes que acomete cerca de 1 a 2% da população mundial. A epilepsia do lobo temporal (ELT) é o subtipo mais prevalente. A refratariedade aos medicamentos é comum e cerca de 40 % destes pacientes apresentam transtornos psiquiátricos. Neste trabalho utilizamos o método de TacMan real time PCR para quantificar o mRNA de subtipos dos receptores de noradrenalina, dopamina, serotonina e substância P em hipocampos cirurgicamente removidos de pacientes com ELT para conhecer o papel destes na ELT com ou sem comorbidade psiquiátrica (depressão ou psicose). Nossa amostra foi de 48 pacientes com ELT sem (Epilepsia - 24) ou com comorbidade psicótica (Psicose - 10) ou depressiva (Depressão - 14) e 8 Controles (necrópsias). O receptor adrenérgico-α2A (AD2A) apresentou diferença entre os grupos (p = 0,0059) com significância para a variável Antiepiléptico (p = 0,0374) e pós-teste significante de maior expressão do mRNA de AD2A no grupo Epilepsia comparado com Controle e com Psicose. A ativação dos receptores α2A no hipocampo pelos antiepilépticos pode explicar nossos achados do grupo Epilepsia comparado ao Controle, corroborando a literatura acerca do AD2A na epilepsia e em relação aos antiepilépticos. O AD2C mostrou diferença entre os grupos (p = 0,0016), sem significância nas variáveis de controle e significante maior expressão do mRNA de AD2C no grupo Epilepsia comparado ao Controle e Psicose. O AD2C é encontrado em áreas que processam informações sensoriais e controlam atividades motoras e emocionais relacionadas, o que pode explicar nossos resultados. Parece ser importante na patologia relacionada à ELT e merece ser estudado. A não diferença entre Epilepsia e Depressão para AD2A e AD2C, parecem confirmar uma relação bi-direcional ou um mecanismo patogênico comum entre epilepsia e depressão, enquanto a menor expressão de AD2A e AD2C nos psicóticos parece indicar diferenças nos mecanismos adrenérgicos ligados a psicose e epilepsia. D2 mostrou diferença entre os grupos (p = 0,0125) com resultado significativo para a variável Subtipo de Diagnóstico Psiquiátrico (p = 0,0239), provavelmente devido a cronicidade da doença e a quantidade de episódios depressivos apresentados pelos sujeitos. Quanto maior a freqüência das crises (p = 0,0381) maior a expressão do D2 no grupo Epilepsia e no Depressão comparados ao Controle. Estes achados sugerem a participação deste receptor na depressão comórbida na ELT; corroboram que o monitoramento dopaminérgico límbico pode ser útil para desenvolver novos antidepressivos e propõem pesquisas futuras sobre D2 em epilépticos. A participação de 5-HT2A na ELT é indicada, pois, sua maior expressão no grupo Epilepsia em relação ao Controle foi significativa (p = 0,0273). Quanto maior a freqüência das crises epilépticas maior a expressão do 5-HT2A (p = 0, 0433). Não encontramos resultados significativos referentes aos receptores D4, 5-HT1A, 5-HT2C e NK1. Nossos resultados mostraram a possibilidade da aplicação do TacMan real time PCR no estudo de receptores de neurotransmissores, sugeriu a importância dos receptores estudados na ELT e comorbidades psiquiátricas, e que outras estruturas límbicas, como a amígdala, sejam focos de investigação. / Epilepsy is a mental functional disorder characterized by recurrent seizures that affect about 1 to 2% of world population. Temporal lobe epilepsy (TLE) is the most prevalent subtype. The refractory to medication is common and about 40% of these patients have psychiatric disorders. This study used the TacMan real time PCR method to quantify noradrenergic, dopaminergic, serotoninergic and substance P receptors subtypes mRNA expression in hippocampus surgically removed from patients with TLE to know their role in TLE with or without psychiatric commorbity (depression or psychosis). Our sample consisted of 48 TLE patients without (Epilepsy - 24) or with psychotic (Psychosis - 10) or depressive (Depression - 14) commorbity and 8 Controls (necropsies). The α2A adrenergic receptor (AD2A) showed difference between groups (p = 0.0059) with significance for Antiepileptic Medication variable (p = 0.0374) and post-hoc test significantly greater AD2A mRNA expression of Epilepsy group compared with Control and Psychosis. The activation of hippocampus α2A receptors by antiepileptic drugs can explain our findings of the Epilepsy group compared with Control, corroborating the literature about the AD2A in epilepsy and for antiepileptic drugs. The AD2C showed differences between groups (p = 0.0016) without significance in the variables of control and significantly greater AD2C mRNA expression of the Epilepsy group compared to Control and Psychosis. The AD2C is found in areas that process sensory information and control motor and emotional related activities, which may explain our results. It seems to be important in the pathology related to TLE and deserves to be studied. No differences between Epilepsy and Depression to AD2A and AD2C seem to confirm a bi-directional relation or a common pathogenic mechanism between epilepsy and depression, while the lowest AD2A and AD2C expression within psychotics seem suggests differences in adrenergic mechanisms linked to psychosis and epilepsy. D2 showed differences between groups (p = 0.0125) with significant results for the variable Subtype of Psychiatric Diagnosis (p = 0.0239), probably due to chronic disease and the number of depressive episodes presented by subjects. The higher the frequency of seizures (p = 0.0381) the higher was the D2 expression within Epilepsy group compared with Control and Depression compared to Control. These findings suggest the involvement of this receptor in TLE commorbid depression; corroborate that limbic dopaminergic monitoring may be useful in developing new antidepressants and propose future research on D2 in epileptics. The participation of 5-HT2A in TLE is indicated, therefore its significant higher expression in the Epilepsy group in relation to Control (p = 0.0273). The higher the frequency of seizures the higher was the 5-HT2A expression (p = 0.0433). We found no significant results for the D4, 5-HT1A, 5-HT2C and NK1 receptors. Our results showed the possibility of TacMan real time PCR method application in TLE neurotransmission receptors study, suggested the importance of the studied receptors in TLE and psychiatric commorbities and that other limbic structures, as the amygdala, should be investigation targets.