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Cellular basis of neurodegeneration - The possible role of ryanodine receptor and potassium channel in neuronal death and neuroprotection

Zhang, Jin 2012. Cellular basis of neurodegeneration - The possible role of ryanodine receptor and potassium channel in neuronal death and neuroprotection. PhD Thesis, Cardiff University.
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Neuronal death is induced by a series of pathogeneses in different neurodegenerative diseases, and one of them, which has been widely accepted previously, is the overload of intracellular calcium (Ca2+) in neurones. This study has investigated ryanodine receptor (RyR) on the endoplasmic reticulum (ER) and several potassium (K+) channels which might be neuroprotective, such as the large conductance Ca2+-activated K+ channel (BK) and adenosine-5’-triphosphate (ATP)-sensitive K+ channel, in both neuronal and astrocytoma cell lines. The reverse transcription (RT)-polymerase chain react (PCR) results in this Thesis show that the messages of RyR, BK channel and ATP-sensitive K+ channel (KATP) exist at the messenger ribonucleic acid (RNA) level in those cell lines. And, the expression of RyRIII message was found being increased in SH-SY5Y cells but decreased in NTERA-2 cells after differentiation. The BK channel was confirmed as functional in SH-SY5Y cells with patch clamp recording. Cell insults which increase intracellular Ca2+ ([Ca2+]i), such as cobalt (II) chloride (CoCl2), hydrogen peroxide (H2O2), beta-amyloid (Aβ1-42) and glutamate, were found to reduce cell number in those cell lines in cell proliferation MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] assays, and the cells with higher expression of RyRIII message were more sensitive to CoCl2 and H2O2 insults. In cell proliferation assays testing RyR or K+ channel modulators in the presence of insults, it has been found that generic blockade of RyR or K+ channel might be neuroprotective, and the activation of RyR or BK channel and the blockade of KATP channel may aggravate the insults. Selective blockade of RyRI and RyRII cannot protect the cells, which probably indicates that RyRIII is the key target in neuroprotection. Activators of the KATP channel cannot protect the cells at a low dose of CoCl2 but might be protective at a high dose, although cromakalim was an exception. Hence, blockade of RyRIII and the BK channel, and activation of the KATP channel, could be possible neuroprotective strategies. Future study should measure [Ca2+]i and cell apoptosis through Ca2+ imaging and fluorescence-activated cell sorting (FACS) respectively, and design selective a RyRIII blocker.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: neurodegeneration, neuroprotection, ryanodine receptor, BK, KATP, cell proliferation MTS assay, quantitative PCR
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 22:56

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