Neuropharmacological Analysis of the Mechanism of Action of L-Prolyl-L-Leucyl-Glycinamide (PLG) in Relation to Movement Disorders
| Autor: | Chiu, Simon S. |
|---|---|
| Rok vydání: | 2010 |
| Předmět: | |
| Druh dokumentu: | Diplomová práce |
| Popis: | Centrally active peptides have increasingly been implicated in diverse neuro-psychiatric disorders in humans. Although several clinical studies have attested to the therapeutic potential of L-Prolyl-L-Leucyl-Glycinamide (PLG) in Parkinson's disease, no unifying hypothesis concerning its mode of action can be formulated. The present critical analysis of the pharmacological property of PLG was predicated on the hypothesis that there exist putative receptor sites of PLG manifesting differential modulatory effects on dopaminergic neurotransmission. The action of PLG was examined in behavioral paradihms reflecting dopamine dependent extrapyramidal motor dysfunction: haloperidol-and morphine-induced catalepsy in rats. Chronic, but not acute, treatment of PLG significantly antagonized hoth morphine and haloperidol catalepsy. The influence of PLG on in vitro dopamine receptor function was evaluated, and the resutls showed that PLG selectively enhanced the affinity of the specific binding of the agonist H-apomorphine to doapmine receptors in rat striatum. PLG, however, failed to alter ³H-spiroperidol binding in vitro. A radioligand binding assay was developed to identify specific putative binding sites of PLG in normal rat and human brain. ³H-PLG bound to membrane homogenates from both human and rat striatum with high affinity and in a saturable manner. The regional distribution profile of the specific ³H-PLG binding demonstrated that human substantia nigra exhibited thehighest level of ³H-PLG binding sites, followed by the striatum and hypothalamus. In the rat brain, the striatum was highly enriched with PLG binding sites. Pharmacologically active analogues of PLG completed for specific ³H-PLG binding with relative potencies paralleling their in vitro biological activities. The potential anti-dyskinetic activity of PLG was evaluated in the pharmacological animal model of tardive dyskinesia. In rats, PLG, when administered concurrently with haloperidol of chlorpromazine, antagonized the enhancements in specific ³H-spiroperidol binding in the striatum as associated with chronic neuroleptic treatment. The results of the present study support the hypothesis that putative PLG binding sites are functionally coupled to dopamine/neuroleptic adenylate cyclase complex and raise the issue as to the feasibility of specific peptidergic dysfunction and peptide replacement therapy in neuro-psychiatric disorders. Doctor of Philosophy (PhD) |
| Databáze: | Networked Digital Library of Theses & Dissertations |
| Externí odkaz: |
|