Objective: Our aim was to investigate the relation between unilateral hippocampal and/or nigral alpha-synucleinopathy and cognitive dysfunction, anxiety and anhedonia.Materials and Methods: Female Sprague-Dawley rats were stereotactically injected adeno-associated viruses carrying alpha-synuclein (α-syn) into unilateral dentate gyrus (DG), substantia nigra (SN) or both SN + DG.The animals were tested for motor functions and memory, spatial learning, anxiety and hedony.Levels of α-syn and synaptophysin were evaluated by Western blot (WB) analysis.Results: In apomorphine-induced rotation test, a mild motor dysfunction was found in SN-α-syn group compared to control.DG-α-syn group showed memory impairment in novel object recognition test.All the α-syn injected groups spent more time to find the platform compared to controls in Morris water maze but this difference did not reach statistical significance.DG-α-syn group consumed more sucrose solution in sucrose consumption test and spent more time on the open arm in elevated plus maze, while the opposite was observed in SN-α-syn group compared to controls.We showed α-syn protein expression in the injected areas of all α-syn groups by WB and immunohistochemical staining.In WB analysis, both hippocampal and striatal synaptophysin expression levels were lower in the α-syn groups compared to controls.Conclusion: Parkinson's disease (PD) is characterized by both motor and non-motor symptoms (NMS).However, an animal model recapitulating NMS with the background of dopaminergic denervation is still lacking.This model may help to investigate hippocampal α-syn pathology correlated especially with cognitive dysfunction and other NMS of PD.
Parkinson's disease (PD) is a progressive disease due to dopaminergic cell loss in the substantia nigra and dopaminergic terminal lost in the striatum, which is the projection area of substantia nigra.It is characterized by resting tremor, bradykinesia, rigidity, and postural instability.In PD, non-motor symptoms such as cognitive impairment, anhedonia, apathy, and autonomic nervous system impairments affect quality of life as much as motor symptoms.PD may affect multiple systems and the underlying mechanisms are not known.However, developing new methods of treatment to slow or stop the rate of disease progression, to lessen or to cure the symptoms is crucial.The aim of this review was to discuss the alternative treatments that may be useful for both motor and non-motor symptoms.Symptomatic treatments with dopaminergic drugs aim to relieve motor symptoms and to increase the patient's life standards for a limited time.However, possible neuroprotective treatments that inhibit neuronal cell death can extend life span and provide higher quality of life.Lewy bodies, which are formed mainly from misfolded and native alpha-synuclein protein, is a pathologic hallmark of PD.Therefore, inhibiting the protein misfolding or clearing the aggregates could be a promising new therapeutic approach for the disease.
Our aim is to reduce the side effects and increase the efficiency of donepezil by formulating donepezil-loaded poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) nanoparticles (NPs) directly targeting amyloid beta (Aβ) fibrils in the brain and evaluate behavioral changes in this fibril model of AD.AD model was developed by intracerebroventricular injection of pre-aggregated β25-35 fibrils. Rats were intravenously administered either solvent, donepezil-loaded NPs (15µg/kg) or free donepezil (1mg/kg) 3 times for a week except for naïve controls. The effect of treatments on anxiety, motor functions, and cognitive functions was tested by elevated plus maze, locomotor activity, novel object recognition, and Morris's water maze tests, respectively.Accumulation of Aβ25-35 fibrils in brain sections was confirmed. Anxiety-like behavior was observed in the Aβ Alzheimer and free donepezil treatment groups while donepezil-loaded NP treatment showed hypo-anxiety-like behavior. Donepezil-loaded NPs were successful in treatment of short-term memory deficit better than free donepezil injection. In Morris's water maze, both donepezil-loaded NPs and free donepezil groups found the platform in shorter time compared to Aβ Alzheimer group. In locomotor activity test, both donepezil treated groups moved less than the Aβ Alzheimer group and naïve controls. After the pharmacological experiments, acetylcholinesterase activity was determined and showed an increase in Aβ Alzheimer group compared to controls. Donepezil-loaded NPs inhibited the acetylcholinesterase activity more efficiently than the free donepezil group.Targeting with donepezil-loaded PLGA-b-PEG-NPs increases efficiency, helps to inhibit acetylcholinesterase activity more substantially, improves cognitive decline due to its longer duration of action and destabilizing effect on amyloid fibrils.
Purpose: To comparatively assess the clinical features and therapeutic outcomes in patients that underwent embryo transfer (ET) under transvaginal (TV) and transabdominal (TA) ultrosonographic guidance. Materials and Methods: ET was performed under TV ultrasonography in 184 cases, whereas TA ultrasonography was used in 188 cases. These two groups were compared in terms of therapeutic outcome including rates of implantation and clinical pregnancy. Results: Two groups displayed similar results in terms of rates of implantation and clinical pregnancy. However, duration of ET procedure was significantly shorter (p = 0.001), but pain during the ET intervention was more prominent (p p = 0.002). Conclusion: Attributed to the notable differences with respect to ease of procedure, patient comfort, and duration, selection of the appropriate mode of guidance must be made on individualized basis for each case.
Amaç: Dondurulmuş-çözülmüş embriyo transferi ovulasyon sonrası doğal siklus veya endometriyumun dışarıdan steroidler ile hazırlanması sonrası gerçekleştirilebilir. Doğal siklus ve hormonal kontrollü siklus arasında dondurulmuş-çözülmüş embriyo transferi sonrası implantasyon, gebelik ve canlı doğum oranları karşılaştırıldı. Gereç ve Yöntemler: Bu tek merkezli, retrospektif çalışma bizim üçüncü basamak merkezimizde, Ocak 2012-Haziran 2015 tarihleri arasında başarılı şekilde donmuş embriyo transferi yapılmış olan 244 hasta verisinden gerçekleştirildi. Çalışmada 2 grup oluşturuldu: Grup 1 spontan ovulasyon sonrası donmuş embriyo transferi yapılmış olan 101 kadını içerirken; Grup 2 hormonal replasman tedavisi ile endometriyal hazırlık sonrası donmuş embriyo transferi yapılan 143 hastayı içermektedir. Gruplar implantasyon, klinik gebelik ve canlı doğum oranları açısından karşılaştırıldı. Bulgular: Temel özellikler açısından iki grup birbirine benzerdi (embriyo dondurma ve embriyo transferi sırasındaki maternal yaş, önceki taze ve dondurulmuş embriyo transfer siklus sayısı, doğal sikluslarda elde edilen oosit ve olgun oosit sayıları) (p>0,05). İki grup arasında klinik gebelik (p=0,13), implantasyon (p=0,19) ve canlı doğum (p=0,26) oranları açısından fark yoktu. Sonuç: Bu çalışmanın bulguları dondurulmuş embriyo transferi işleminde doğal siklus ve hormon replasman tedavisinin klinik sonuçlarının benzer olduğunu gösterdi. Objective: Frozen-thawed embryo transfer can be accomplished during a natural cycle after spontaneous ovulation or after artificial preparation of endometrium with exogenous steroids. The implantation, pregnancy and live birth rates following frozen-thawed embryo transfer (FET) were compared between in a natural and hormonal control cycle. Material and Methods: This single-center, retrospective trial was implemented on data derived from a series of 244 women who had successful FET in our tertiary care center between January 2012 and June 2015. Two groups were constituted: Group 1 consisted of 101 women who underwent FET after spontaneous ovulation; while 143 women had FET after endometrial preparation with hormone replacement therapy. Rates of implantation, clinical pregnancy, and live birth were compared between two groups. Results: Two groups were similar on baseline characteristics (maternal ages at time of freezing and transfer of embryos, the number of previous fresh and frozen embryo transfer cycles, the number of oocytes and mature oocytes obtained in natural cycles) (p>0.05). There was no difference between 2 groups regarding rates of clinical pregnancy (p=0.13), implantation (p=0.19) and live birth (p=0.26). Conclusion: The findings of this study indicated that the clinical outcomes were comparable between the spontaneous natural cycle and hormone replacement treatment in FET.
Parkinson’s disease (PD) is a complex, chronic, and progressive neurodegenerative disease that is characterized by irreversible dopaminergic neuronal loss in the substantia nigra. Alpha-synuclein is normally a synaptic protein that plays a key role in PD due to pathological accumulation as oligomers or fibrils. Clustered alpha-synuclein binds to the Toll-like receptors and activates the microglia, which initiates a process that continues with pro-inflammatory cytokine production and secretion. Pro-inflammatory cytokine overproduction and secretion induce cell death and accelerate PD progression. Microglia are found in a resting state in physiological conditions. Microglia became activated by stimulating Toll-like receptors on it under pathological conditions, such as alpha-synuclein aggregation, environmental toxins, or oxidative stress. The interaction between Toll-like receptors and its downstream pathway triggers an activation series, leads to nuclear factor-kappa B activation, initiates the inflammasome formation, and increases cytokine levels. This consecutive inflammatory process leads to dopaminergic cell damage and cell death. Microglia become overactive in response to chronic inflammation, which is observed in PD and causes excessive cytotoxic factor production, such as reactive oxidase, nitric oxide, and tumor necrosis factor-alpha. This inflammatory process contributes to the exacerbation of pathology by triggering neuronal damage or death. Current treatments, such as dopaminergic agonists, anticholinergics, or monoamine oxidase inhibitors alleviate PD symptoms, but they can not stop the disease progression. Finding a radical treatment option or stopping the progression is essential when considering that PD is the second most reported neurodegenerative disorder. Many cytokines are released during inflammation, and they can start the phagocytic process, which caused the degradation of infected cells along with healthy ones. Therefore, targeting the pathological mechanisms, such as microglial activation, mitochondrial dysfunction, and oxidative stress, that should be involved in the treatment program is important. Neuroinflammation is one of the key factors involved in PD pathogenesis as well as alpha-synuclein accumulation, synaptic dysfunction, or dopaminergic neuronal loss, especially in the substantia nigra. Therefore, evaluating the therapeutic efficiency of the mechanisms is important, such as microglial activation and nuclear factor-kappa B pathway or inflammasome formation inhibition, and cytokine release interruption against neuroinflammation may create new treatment possibilities for PD. This study examined the pathological relation between PD and neuroinflammation, and targeting neuroinflammation as an opportunity for PD treatments, such as Toll-like receptor antagonists, NOD-like receptor family pyrin domain containing-3 inflammasome inhibitors, cytokine inhibitors, peroxisome proliferator-activated receptor-γ agonists, reactive oxygen species inhibitors, and nonsteroidal anti-inflammatory drugs.
In Parkinson’s disease (PD), pathological intracellular aggregation of alpha-synuclein plays a key role in the neurodegenerative process. In this study, we aimed to investigate the progression of motor dysfunction and related changes in synaptic organization in an alpha-synuclein overexpressing viral vector model of Parkinson’s disease (PD) in rats. Adeno-associated viral vectors (AAV) were stereotaxically injected bilaterally into substantia nigra (SN) together with dentate gyrus (DG). Further 7 animals were used as naive controls. All animals were tested for locomotor activity for an hour from 3rd to 15th week. After that rats striati were analyzed by Western blotting for alpha-synuclein, tyrosine hydroxylase and synaptophysin expression. Alpha-synuclein injected group moved less distance compare to control and their movement decreased by time till the 7th week then start to increase but yet slightly lower than the controls. Synaptophysin level was 13% and TH level was 25% decreased in alpha-synuclein group compare to controls. Due to compensation mechanisms to protect neurons from neuronal death or alpha-synuclein accumulation in DG, alpha-synuclein group sustained to move in open field locomotor activity test. Although the model is open for improvement, it is useful to study early stage of PD and motor dysfunctions that occur due to alpha-synuclein overexpression.
