Neuroimaging of Serotonergic System in Rat Models of Parkinson’s Disease with Xenografts and MDMA-induced Axotomy

• Main Authors: Chiung-Hsin Chiu, 邱創新
• Other Authors: Kuo-Hsing Ma
• Format: Others
• Language: zh-TW
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/25992405702114412692

博士 === 國防醫學院 === 醫學科學研究所 === 104 === Parkinson’s disease (PD) is a neurodegenerative disorder that characterized by the progressive loss of dopaminergic neurons in substantial nigra and the deficiency of dopamine (DA) in the striatum. The most effectively therapeutic strategy for PD is “cell replacement” utilized the ventral mesencephalic tissue of human embryo as a resource of dopaminergic neurons. However, the usage of human embryo leads to ethical controversy. Hopefully, porcine embryonic neural tissue has been considered an alternative source to human fetal grafts in neurodegenerative disorders because its use avoids major practical and ethical issues. The first study was designed to evaluate the effects of embryonic day 27 (E27) porcine mesencephalic tissue transplantation on serotonin system in a 6-OHDA-lesioned rat model of Parkinson’s disease (PD) while also investigating the usefulness of 4-[18F]-ADAM (a serotonin transporter imaging agent) coupled with animal-PET (positron emission tomography) for imaging serotonin transporters (SERTs). Our experimental results revealed that the parkinsonian rats rotate substantially on apomorphine-induced contralateral turning, and the mean striatal specific uptake ratio (SUR) level of 4-[18F]-ADAM/animal-PET decreased by 44 % (compared to that for the contralateral intact side) after 6-OHDA-lesioned. At the 4th week post-grafting, the mean SUR level of 4-[18F]-ADAM/animal-PET restored to 71 %, which together with the abundant survival of tyrosine hydroxylase (TH) neurons accounted for functional recovery of behaivral test. In regard to the extent of donor-derived cells, we found the neurons of the xenografts from E27 transgenic pigs harboring red fluorescent protein (RFP) localized with TH-ir cells and SERT-ir in the grafted area. Thus, transplanted E27 porcine mesencephalic tissue may restore dopaminergic and serotonergic systems in the parkinsonian rat. In the first study, we have found that 6-OHDA lesions of the MFB affect most of the dopaminergic system and partially serotonergic system in a rat model of PD. To futher investigate serotonergic system, we use manganese-enhanced magnetic resonance imaging (MEMRI) to assess the effect of MDMA-induced serotonergic neurotoxicity including decreased SERTs and distal axotomy of raphe nucleus projecting axons. Several previous studies had reported that MEMRI detects specific brain circuits of morphological and functional responses of specific brain circuits that are essential to the central effects of a drug challenge. Furthermore, intracranial administration of manganese ion (Mn2+) can be served as a neuronal tract-tracing tracer. In the second study, Mn2+ was ere stereotactically injected into the raphe nucleus and a series of MEMRI was acquired over a period of 38 h to monitor the evolution of Mn2+ in response to MDMA (5 mg/kg, s.c.) or saline once daily for a total of six injections. Our experiment results revealed that MDMA-induced loss of striatial SERTs was clearly evidenced by immunohistological staining and consistent with the decrease of Mn2+-induced signal enhancement observed across the MFB and striatum. Importantly, MEMRI revealed the disruption of the serotonergic raphe-striatal projections and the variable effect of MDMA on the kinetics of Mn2+ accumulation in the MFB and striatum as distal axotomy which has never been visualized directly in vivo. In summery, above-menteioned experiments used neuroimaging of serotonergic system in rat models of Parkinson’s disease with 4-[18F]-ADAM/animal-PET xenografts and MDMA-induced axotomy with MEMRI in vivo.