| Summary: | 碩士 === 國防醫學院 === 藥理學研究所 === 98 === Withdrawal from chronic methamphetamine (MA) results in behavioral changes that may be analogous to some aspects of depression in humans, and these behaviors opposite to those seen after treatment with antidepressant drugs. The loss of neurogenesis or neural progenitor cells of hippocampus are associated with behaviors and functional changes in brain regions in depressive-like animal models and the major depressive disorder human. Thiazolidinediones (TZDs), such as pioglitazone and rosiglitazone, are synthetic PPAR (peroxisome proliferator-activated receptor ) agonists originally developed as antioxidants and subsequently introduced as insulin-sensitizing treatments for Type 2 diabetes mellitus (DM). A newly established database documented that TZDs exert not only a glucose-lowering effect, but may also mediate neuroprotection, neurotrophic and anti-inflammatory processes, oxidative stress and excitotoxicity cross-referenced with the individual mood and dementing disorders (e.g. major depressive disorder and Alzheimer’s disease). The purpose of this thesis was to determine if pioglitazone may reverse the neurotoxic effects of chronic MA-withdrawal induced depressive behavior by means of disparate mechanisms, notably Wnt-GSK3-catenin signaling, neurogenic effect and anti-apoptosis responses. Methods: Escalating administration of MA (1-5 mg/kg x 3 daily for 10 days) then withdrawal for 7 and 21 days was to establish as a depressive-like animal model. MA withdrawal rats were given pioglitazone (10 mg/kg, twice daily, i.p.) for 7 or 21 days. The Wnt3-GSK-3β-catenin and Akt-Bcl2-Caspase 3 pathways were determined by Western blotting. Adult hippocampal neurogenesis and neuronal protection of pioglitazone were measured by immunohistochemistry. Results: MA withdrawal animals increased the latency time of Novelty-suppressed feeding behavior test (NSF, a depressive-like behavior), alleviated BrdU positive and neuronal immunoreactivities in the hippocampus and cortex. Inhibition of Wnt3- GSK-3β-catenin and Akt-Bcl2-Caspase 3 pathways after MA withdrawal resulted in a significant neurogenesis loss, neuronal damage and depressive-like behavior. Pioglitazone therapy provided efficiency neuroprotective function to reverse these abnormalities induced by chronic MA withdrawal. Taken together, pioglitazone therapy may constitute a potentially novel and innovative treatment approach for mood disorder associated with depressive syndromes. The mechanisms of action of pioglitazone form a neurosychiatric perspective is unclear, particularly Wnt signaling pathway may indicate a novel strategy for depressive therapy.
|
|---|
