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Role of Oxidative Stress in the Onset of Alzheimer’s Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Tasnuva Sarowar, Md. Hafiz Uddin
The proposed metal hypothesis of AD has clarified that the sequestration of Zn ions in abeta plaques and the unavailability of Zn ions in synaptic cleft have a potential role in the pathology of the diseases. Therefore, several drugs have been tried to retain the normal level of Zn in the neurons. Such approaches include metal protein attenuating compounds (MPACs) like clioquinol (CQ) and PBT2 (8-hydroxyquinoline analog) (Lannfelt et al. 2008). These MPACs bind extracellular Zn, can pass the cell membrane, and make Zn available to the cell again. Although PBT2 has been shown to improve cognitive skill in phase 2, the end result remained inconclusive (Adlard et al. 2015).
Alzheimer's Disease
Published in Marc E. Agronin, Alzheimer's Disease and Other Dementias, 2014
Clioquinol (PBT1) and PBT2 are metal protein attenuating compounds that are believed to interfere with Ab42 aggregation and toxicity by removing extracellular copper and zinc that is coupled to it. Clioquinol has been shown to reduce Ab deposits in transgenic mice but also to induce myelinopathies in the central nervous system (Zhang et al., 2013). A small Phase II, placebo-controlled trial of clioquinol in 36 AD patients failed to show clinical improvement in cognition, and one patient developed impaired visual acuity and color vision likely due to the medication (Sampson, Jenagaratnam, & McShane, 2012). A similar study of PBT2 indicated that it was well tolerated in mild AD patients and appeared to benefit two tests of executive function, although not a larger outcome measure of cognition (Lannfelt et al., 2008). Additional studies of PBT2 are likely.
Differentiation of dental pulp stem cells into neuron-like cells
Published in International Journal of Neuroscience, 2020
Fatemeh Rafiee, Zahra Pourteymourfard-Tabrizi, Mohammad-Reza Mahmoudian-Sani, Ameneh Mehri-Ghahfarrokhi, Amin Soltani, Morteza Hashemzadeh-Chaleshtori, Mohammad-Saeid Jami
In this study, immunocytochemical analyses were carried out in cell cultures on either fibronectin-coated 35-mm dishes or glass coverslips coated with poly-l-lysine (20 μg/ml) (Sigma-Aldrich) and fibronectin (10 μg/ml). Cells were also fixed at room temperature in 4% paraformaldehyde (Merck, NJ) for 10–15 min. Besides, blocking of nonspecific binding sites and cell permeabilization was carried out in PBT1 solution [phosphate-buffered saline (PBS)], containing 0.1% Triton X-100 and 1% BSA for 15 min. The primary antibody was then added (diluted in PBT1) and incubated for 3 h at room temperature. In general, the primary antibodies used in this study were rabbit monoclonal antibody against Nestin (Sigma-Aldrich; used at a 1:300 dilution) and rabbit polyclonal antibody against SOX2 (Abcam; used at a dose of 1 µg/ml). After being incubated with the primary antibody, the cultures were washed with PBS several times at room temperature before adding the secondary antibody into PBT2 solution (PBS containing 0.1% Triton X-100 and 1% BSA). Nuclear DNA was also counterstained with 4′, 6-diamidino-2-phenylindole (DAPI; Sigma-Aldrich, Saint-Louis), and samples were observed under a fluorescence microscope (Eclipse 90i, Nikon, Japan).
Drug development for Alzheimer’s disease: review
Published in Journal of Drug Targeting, 2019
Kejing Lao, Naichun Ji, Xiaohua Zhang, Wenwei Qiao, Zhishu Tang, Xingchun Gou
Differ from traditional chelators, metal protein attenuating compounds (MPACs) only have moderate affinity for metal ions and are capable of crossing the blood–brain barrier [92] (Figure 7). PBT-1 (20) inhibits Aβ aggregation by interfering with interactions between Aβ and metal ions. Evidence from Phase II clinical trials suggested that PBT1 could halt cognitive decline in AD. Unfortunately, further Phase II/III studies were halted owing to manufacturing toxicity issues [93]. Subsequently, its analogue, PBT-2 (21), was developed as a metal–protein attenuating compound that affects the metal-mediated toxic oligomerization. It has a better blood–brain barrier (BBB) permeability than does PBT1 [94]. The positive results from Phase II also showed that PBT2 reduced Aβ42 CSF concentrations and improved cognition function with quality safety and tolerance [95].
Metal chaperones: a novel therapeutic strategy for brain injury?
Published in Brain Injury, 2019
S. D. Portbury, A. Sedjahtera, K. Perrones, C. Sgambelloni, M. Zhang, P. J. Crack, D. I. Finkelstein, P. A. Adlard
While we did not interrogate the specific signaling pathways impacted by PBT2 in this study, the effects of the compound described observed herein are therefore consistent with our previously reported effects of PBT2 in the aged brain, where the impact of acute PBT2 treatment was to induce a breadth of alterations in key cellular pathways that are critical to cognition and synaptic plasticity, as well as to improve neuronal health and connectivity (24,46).