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Protective Capabilities of Allopregnanolone Against Induced Toxicity in SH-SY5Y Cells Relative to Alzheimer´S Disease

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Protective Capabilities of Allopregnanolone Against Induced Toxicity in SH-SY5Y Cells Relative to Alzheimer´S Disease VT 2020 Protective capabilities of allopregnanolone against induced toxicity in SH-SY5Y cells relative to Alzheimer´s disease Mohamed Mustafa Degree Project in Pharmaceutical pharmacology, 30 hp, Spring semester 2020 Examiner: Mathias Hallberg Department of Pharmaceutical Biosciences Division for Pharmacology Faculty of Pharmacy Uppsala University Abstract When the brain is exposed to a traumatic injury, the brain produces high amounts of neurosteroids like allopregnanolone and progesterone which show protective and neurogenic capacities. Alzheimer’s disease patients also have lower amounts of these neurosteroids in brain tissue. Neurosteroids act on GABAA receptors and cholesterol receptors which is interesting since both the cholesterol transporter ApoE and excitotoxicity seems to be issues plaguing the patients. To study if there is a relationship between Alzheimer’s disease and neurosteroids, there are ongoing phase one studies but neurobiological studies are equally important in order to understand the mechanism. In this work protective capabilities of allopregnanolone on induced toxicity was investigated in human neuroblastoma SH-SY5Y cells. Protection and induced toxicity were assessed by studying cell viability with MTT assay. Toxins used were the oxidative stress inducing agent t-BHP, excitotoxic glutamate and amyloid β25-35. Previous studies have found allopregnanolone to induce neurogenesis, decrease ROS levels, inhibit apoptosis and to have immunoregulatory capabilities. The present study did see an increase in cell viability when treated to 1x10-8 M allopregnanolone but this effect was not observed when the concentration was increased further to 1x10-7 M and 1x10-6 M. When the SH-SY5Y cells were treated with toxins after pretreatment of allopregnanolone, additional decrease was seen when compared to cells only treated with toxins. The present study discovered the influence of components like cell density and cell generation which is of value for researchers planning future neurobiological studies. These neurobiological studies give insight of the correct mechanisms in the brain, opening up opportunities for new efficient drugs to be developed. Contents ABSTRACT .................................................................................................................................................... 2 INTRODUCTION .......................................................................................................................................... 4 ALZHEIMER’S DISEASE ........................................................................................................................................ 4 NEUROSTEROIDS ................................................................................................................................................. 5 ALLOPREGNANOLONE’S MECHANISM OF ACTION ................................................................................................ 6 ALLOPREGNANOLONE IN CLINICAL TRIALS ......................................................................................................... 7 AIM ................................................................................................................................................................. 7 MATERIALS AND METHODS .................................................................................................................... 8 RESULTS ....................................................................................................................................................... 9 DISCUSSION ................................................................................................................................................ 13 CONCLUSION ..................................................................................................................................................... 16 SVENSK POPULÄRVETENSKAPLIG TEXT ........................................................................................... 17 REFERENCES ............................................................................................................................................. 18 Introduction In the event of a traumatic brain injury, an induced physiological shift is observed. In mice, the neurosteroid progesterone and its metabolite allopregnanolone which is also a neurosteroid, were significantly higher in brain tissue after injury (Lopez-Rodriguez et al., 2016). Interestingly, an increase of neurosteroids is attributed to neuroprotection as a higher degree of neuroprotection in pregnant female rats versus male rats with lower hormone levels could be detected in a previous study (Meffre et al., 2007). The natural increase of progesterone and allopregnanolone in pregnant rats is believed to have granted protective and rehabilitation properties for brain tissue. This coupled with the fact that a decrease in neurosteroids have been spotted in Alzheimer’s mice raises the question of the possible relationship of neurosteroids, neuroprotection and Alzheimer’s disease (Naylor et al., 2010). Alzheimer’s disease Alzheimer’s disease is characterized by dementia caused partly by a disrupted production and clearance ratio of amyloid proteins. The unsolvable plaques of amyloid β act as reservoirs for soluble oligomers which are believed to be the actual harmful perpetrator. Amyloid β with 40 and 42 amino acids are the main components of amyloid plaques (Ibanez et al., 2004). The exact mechanism of toxicity caused by amyloid β peptides is disputed but some pathways have been discovered. It has been seen that amyloid β oligomers disrupts the cell-membrane by producing breaches in it (Kayed and Lasagna-Reeves, 2013). Others have come to the conclusion that it is in fact through activating NDMA-receptors the harm is done by decreasing long-term-potentiation (LTP) (Li et al., 2011). A third possible pathway has been found as well where amyloid β oligomers affect depolarization through Ca2+-channels which leads to excitotoxicity and sensitization of the mitochondrial membrane and finally apoptosis (Morkuniene et al., 2015). Apolipoprotein E (ApoE), a cholesterol distribution protein, have shown to have an effect on the levels of amyloid β. There is a polymorphism in the gene encoding the protein, 13.7% having the ApoE 3 allele, 77.9%, the ApoE 4 allele and the rest of the population the ApoE 2 allele (Farrer et al., 1997). Carrying the ApoE 4 allele have shown to come with greater risk for Alzheimer’s disease (Corder et al., 1993). The exact mechanism is not fully understood but ApoE 4 carriers suffer from greater amyloid β secretion by neurons to the interstitial space (Schmechel et al., 1993) and simultaneously decreased amyloid β clearance by microglia versus ApoE 3 carriers (Lin et al., 2018). Alzheimer’s disease and other dementias are currently impacting 50 million people worldwide and the prevalence is estimated to grow. Alzheimer’s disease is a rapidly growing problem that more and more countries are in impinged by as the average life expectancy is increasing. The illness is costing governments 818 billion USD each year which is 1% of the total global GDP (Alzheimer’s Disease International, 2015). Even though the illness causes such a dent on the global economy and healthcare system, there are currently only treatments relieving symptoms. Galantamine and memantine are two commonly prescribed treatments. Galantamine contributes to better cognitive functions and memory by acting as an acetylcholinesterase inhibitor (Greenblatt et al., 1999). As acetylcholinesterase lowers the amount of acetylcholine in the brain, an inhibitor such as galantamine raises the brain levels of acetylcholine. This makes sense as a treatment as Alzheimer’s patient commonly suffer from degradation of the cholinergic pathways of the brain. The other neurochemical treatment, memantine which inhibits N-metyl-D-aspartate (NMDA) receptors instead, has also shown to been symptom relieving (Epperly et al., 2017). None of these drugs significantly slow down the progression of the disease on a reliable scale. Beta-secretase (BASE) inhibitors, were once promising prospects due to the fact that they limit the production of amyloid β (Chatila et al., 2018). But recently many studies have detected too severe adverse effect like suicidal ideations and even worsening the progression of the disease (Egan et al., 2019). Today the vision of a BASE-inhibitor as an Alzheimer’s disease treatment is diminishing. Neurosteroids The classification of neurosteroids embark every steroid that is synthesized in the brain. There is a large variety of neurosteroids with a variety of mechanism of actions. Some neurosteroids like DHEA-S have shown to have an impact on dendrite length but have yet to have an established mechanism of action known (Krug et al., 2009). Progesterone is a pleiotropic steroid and can act through many pathways like progesterone receptor (PR) (Kastner et al., 1990) and membrane progesterone receptors (mPRs) (Zhu et al., 2003). PR is a steroid nuclear receptor which acts through genome manipulation as it is a transcriptional factor. Allopregnanolone on the other hand do not act as a traditional steroid. It is a metabolite of progesterone but can act through ionotropic gamma-aminobutyric acid (GABA) receptors on the cell membrane (Gee et al., 1988). PR-/- and PR+/- knock-out mice had noticeably lower protection versus PR+/+ mice against stroke damage, which hints at progesterone offering protection through the PR receptor
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