The use of adjuvant L-arginine in schizophrenia: A behavioural and neurochemical analysis
Notice bibliographique
Résumé
Schizophrenia is a complex neurodevelopmental illness that often requires a combination of treatments to adequately control its symptoms. Despite the availability of several neuroleptic medications on the market, many patients with schizophrenia remain symptomatic. Research has shifted emphasis towards impaired glutamate signaling as a major contributor to the illness. Drug targets specific to the glutamate-nitric oxide (NO) pathway may offer a promising new approach to treatment. The therapeutic effect of the amino acid L-arginine (Arg), the substrate for the NO-producing enzyme neuronal nitric oxide synthase (nNOS) was examined in this thesis. As an augmenting strategy, Arg was administered (at 6g per day) to patients with schizophrenia in an attempt to improve the efficacy of antipsychotic therapy. Responders to Arg therapy had a reduction in anxiety symptoms that were previously resistant to prescribed medication. The anxiolytic effect of Arg may be directly related to an increase in endogenous central NO production and the downstream induction of cyclic guanosine monophosphate (cGMP)-mediated signaling cascades. L-Arginine also proved to be a safe strategy in the treatment of schizophrenia and did not exacerbate any of the known side-effects that were already present as a result of ongoing antipsychotic therapy. This thesis also investigated genetic influences on glutamate N-methyl-D-aspartate (NMDA) receptor functioning and treatment response to Arg therapy. The Neuronal Period-Arylhydrocarbon Nuclear Translocator (ARNT)-Single-minded (PAS) domain containing 3 (NPAS3) gene codes for a protein that functions as a transcription factor. NPAS3 and its related variants may be important for the development of functional postsynaptic density (PSD-95) scaffolding proteins that directly link the NMDA receptor to the nNOS enzyme in the brain. Variants associated with NPAS3 and schizophrenia were examined to elucidate the integrity of the PSD-95 protein and used to predict the outcome of the effects of adjuvant Arg therapy. Two carriers of a NPAS3 variant who did not respond to Arg treatment may have had compromised NMDA receptor function related to altered neurodevelopmental processes that occurred during early brain development. Participants were also genotyped for the catechol-O-methyltransferase (COMT ) enzyme single nucleotide polymorphism (SNP) p.V158M to explore the relationship between this genetic marker and clinical outcomes. No significant gene-gene interaction between NPAS3 and COMT was determined that would influence treatment response to Arg therapy. Preclinical experiments were also included in this thesis to determine the behavioural and neurochemical mechanisms by which Arg was able to exert its therapeutic effect. Competing metabolic enzymes that utilize Arg as a substrate were investigated by measurement of related amino acids ornithine (Orn) and citrulline (Cit). The immediate potentiation of whole brain Cit levels following Arg administration suggested that NO is produced quickly and NOS enzymes require a much lower concentration of Arg than that of the arginase enzymes. This thesis was also able to confirm the utility of phencyclidine (PCP) as a comprehensive pharmacological model of psychosis and the ability of antipsychotic drugs to reduce PCP-induced hyperlocomotor activity. The administration of Arg alone in a rodent PCP model had no significant effect on hyperlocomotor activity (a behavioural measure of the positive symptoms of psychosis) and it also did not enhance the locomotor-reducing effects of antipsychotic drugs. These results were consistent with the clinical trial data where no significant changes in positive symptoms were also found when augmenting antipsychotic treatment with Arg. Although Arg therapy was unable to potentiate antipsychotic effects in schizophrenia, work presented in this thesis does support the use of Arg as a tolerable and effective strategy that may target intrinsic anxiety in treatment-refractory schizophrenia.
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».