Anti-inflammatory and anti-oxidant neuroprotection in the prevention of Alzheimer's disease

Stuchbury, Grant David (2010) Anti-inflammatory and anti-oxidant neuroprotection in the prevention of Alzheimer's disease. PhD thesis, James Cook University.

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Current therapy for Alzheimer's disease addresses the symptoms of the disease and results in moderate improvements in cognitive functions. Acetylcholinesterase inhibitors, the main treatment of choice, increase the availability of acetylcholine in the brain, thereby enhancing synaptic transmission and improving cognition. This approach however, does not prevent or delay the onset of the disease. The new class of drug in the treatment of Alzheimer's disease, NMDA-receptor antagonists, do offer some protection of neurons against excitotoxic insult, but are only effective following diagnosis and do not possess anti-inflammatory properties.

The elucidation of the inflammatory processes responsible for Alzheimer's disease has demonstrated similarities to other inflammation-associated diseases. It is therefore not surprising that therapies used for the treatment of other medical conditions, namely Nonsteroidal anti-inflammatory drugs, statins and antioxidants, may be of benefit in Alzheimer's disease. Closer inspection however, reveals that only selected drugs within these groups appear to provide neuroprotection. The aim of this study was to determine whether this effect translates to the in vitro situation and if so, the causes of the disparity between drugs within the same class.

A co-culture model of Alzheimer's disease was designed containing human microglia and fluorescent neurons, to allow determination of neuronal viability separately from microglial viability. The establishment of stably-expressing fluorescent neurons for this purpose required significant optimization of transfection and stable selection, resulting in a methods paper [1]. The primary outcome of this article is that although linearization of DNA can increase the production of stable clones, it is dependent on the site of restriction enzyme digestion and requires plasmid-specific optimization.

Initially, the aim of this study was to assay anti-inflammatory compounds in three distinct culture models of neurodegeneration. The development of these models highlighted important aspects of neurodegeneration in vitro. Transferral of activated microglial media to neurons and activation of microglia when separated from neurons in co-culture, both failed to induce neuron death in the presence of pro-inflammatory mediators Lipopolysaccharide and Interferon-γ. These mediators however, induced significant neuron death when microglia and neurons were co-cultured with direct cell to cell contact. Thus, neuron death in vitro is dependent on microglial proximity and is likely to be due to short-lived toxic factors such as free radicals, as opposed to long-lived cytokines and other inflammatory mediators. Furthermore, inhibitors of Nitric oxide synthase were found to rescue neurons from microglial insult, indicating that the free radical nitric oxide is highly involved in the induction of neurodegeneration.

The direct co-culture system found to induce neuron death was utilized to assay numerous compounds, from the non-steroidal anti-inflammatory drug, statin and antioxidant classes, for their neuroprotective abilities. In agreement with in vivo studies, it was found that not all compounds within a drug class shared neuroprotective properties. Moreover, the neuroprotection conveyed by ibuprofen, indomethacin and sulindac sulphide in this in vitro system coincides with epidemiological observations that suggest these therapies provide greater protection against the onset of Alzheimer's disease compared to other non-steroidal anti-inflammatory drugs. Selected therapeutics from the statin and nutraceutical antioxidant classes also provided neuroprotection and although the pathways or targets responsible for neuroprotection were not determined, it is clear that the inhibition of Nitric oxide via direct or antioxidant mechanisms plays a role.

The findings in this study indicate that some currently available anti-inflammatory therapies protect neurons against inflammation-dependent degeneration in vitro. In the clinical setting, this neuroprotective action may translate to a delay in the onset and perhaps progression of Alzheimer's disease. The relatively safe toxicity profiles and ease of access to currently available anti-inflammatory and nutraceutical therapies renders them attractive as interim therapies until more specific therapies for Alzheimer's disease are developed. Furthermore, investigation into the shared targets of these anti-inflammatory therapies that are responsible for neuroprotection may assist in the identification of candidate targets for future drug development.

Item ID: 39166
Item Type: Thesis (PhD)
Keywords: Alzheimer disease; Alzheimer's disease; anti-inflammatory compounds; anti-inflammatory drugs; antioxidants; anti-oxidants; dementia; disease prevention; inflammation; neurodegeneration; neurodegenerative diseases; neuron protection; neuroprotection
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Publications arising from this thesis are available from the Related URLs field. The publications are:

Article 1: Stuchbury, Grant, and Münch, Gerald (2010) Optimizing the generation of stable neuronal cell lines via pre-transfection restriction enzyme digestion of plasmid DNA. Cytotechnology, 62 (3). pp. 189-194

Date Deposited: 05 Aug 2015 23:39
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences > 111502 Clinical Pharmacology and Therapeutics @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920112 Neurodegenerative Disorders Related to Ageing @ 100%
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