Although L-glutamate (L-Glu) is not an essential amino acid, it is a vital excitatory neurotransmitter that plays a critical role in brain function. An excess of L-Glu levels over 1 mM within excitatory synaptic cleft has been linked to neurotoxicity in neurodegenerative diseases (NDDs) and stroke. Monosodium glutamate (MSG) is a highly used food enhancer and food additive worldwide, and excessive consumption of it can cause extreme levels of L-Glu to build up in the cerebrospinal fluid (CSF), leading to neuronal death. The native South American palm berry known as the acai berry (Euterpe sp.) is a potential nutraceutical that contains several bio-active phytochemicals with multi-pharmacological effects. Several studies in recent years have shown that acai berries and their bioactive contents can relieve inflammation, act as antioxidants, prevent carcinogenesis, and protect the nervous system. The first thesis aim was to conduct a systematic review of existing literature to examine how L-Glu affects neuronal viability and its implications for NDDs. A systematic review of 71 studies that met eligibility criteria found that exposure to L-Glu in vitro or in vivo is associated with multiple pathogenic mechanisms that affect neuronal viability, including oxidative stress, antioxidant defence decline, neuroinflammation, neurotransmitter levels dyshomeostasis, aberrant protein aggregation, excitotoxicity, mitochondrial malfunction, calcium level dyshomeostasis, and abnormalities in neuronal histology, cognitive function, and animal behaviour. Thus, identifying and understanding these diverse mechanisms might enable the design of more effective and efficient agents targeting multiple L-Glu-based pathways for NDDs. Moreover, the following research project aimed to evaluate L-Glu (0.137 - 100 mM), acai aqueous and ethanolic extracts (0.001 µg/mL - 1000 µg/mL) toxicity and investigate the neuroprotection effects of acai berry extracts. The evaluation was carried out using various methods, including dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays to assess cell viability, and to assess mitochondrial function the adenosine 5′-triphosphate (ATP) bioluminescent, and mitochondrial membrane potential (MMP) measurements as well as oxidative stress measurement using the 2,7-dichlorodihydrofluorescein diacetate (DCFHDA) assay. A whole-cell patch-clamp assay was conducted to investigate the effects of L-Glu and acai berry extracts on NMDARs. This study investigated human neuroblastoma cells SH-SY5Y and differentiated human rhabdomyosarcoma cells TE671. The impact of acai berry extracts and L-Glu toxicity was also investigated in differentiated SH-SY5Y cells and human cortical neural progenitor cells (ReNcell CX) via MTT assay. L-Glu caused a significant reduction in cell viability (p < 0.01 - p < 0.0001), ATP levels (p < 0.05 - p < 0.0001), and MMP level (p < 0.05 - p < 0.0001) and increased ROS production (p < 0.05 - p < 0.0001) in human undifferentiated SH-SY5Y and differentiated TE671 cells. Whole-cell patch-clamp recordings showed that L-Glu and glycine (Gly) administration did not activate currents in SH-SY5Y cells, while activated currents were observed in differentiated TE671 cells. Although acai berry extracts alone had some adverse effects high concentration at 1-1000 µg/mL reduced cell viability, ATP, and MMP level and increased ROS production in undifferentiated SH-SY5Y and differentiated TE671 cells. However, the co-application of acai berry extracts to L-Glu provided neuroprotection against L-Glu with sustained cell viability, decreased LDH production, restored ATP levels, preserved MMP levels and reduced ROS levels. Moreover, the results of this thesis showed novel results that the acai berry aqueous extract significant inhibits (0.001, 100, 1000 µg/mL, p < 0.001, p < 0.0001, and p < 0.0001, respectively) L-Glu + Gly-activated currents in differentiated TE671 cells in a concentration-dependent manner. Furthermore, differentiated SH-SY5Y cells showed no significant reduction in viability after exposure to L-Glu (0.137 - 100 mM), but ReNcell CX cells experienced significant (p < 0.0001) toxicity impacts after exposure to L-Glu at concentration range 0.03 - 100 mM. In ReNcell CX cells, aqueous acai berry extract (0.0001 - 100 µg/mL) co-applied to neurons exhibited significant (p < 0.05 - p < 0.0001) neuroprotection against L-Glu. Thus, this study showed that acai berries contain nutraceuticals with antioxidant and anti-excitotoxicity properties, making them a potentially beneficial dietary component to prevent pathological deficits caused by excessive levels of L-Glu. The third project in this dissertation is designed to evaluate the potential nutraceutical benefits of acai berry extracts in vitro by examining their ability to inhibit cholinesterase enzymes (ChE) and scavenging free radicals by using 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) assays. Furthermore, several antioxidant effects were assessed, including hydrogen peroxide (H2O2) or hydroxyl radical (OH•) scavenging, nitric oxide radical (NO•) scavenging, lipid peroxidation (LPO) inhibition, and ferric ion reduction (Fe+3). Total polyphenols (TPC) and flavonoids (TFC) were determined in both acai extracts. In addition, acai berry extracts were fractionated and analyzed by liquid chromatography mass spectrometry (LC-MS) to identify phytochemicals that may possess anti-cholinesterase and antioxidant properties. Acai berry extracts showed novel action in their ability to inhibit acetyl- and butyryl-cholinesterase with estimated IC50 of 0.001 µg/mL, and 6.378 mg/mL, respectively. Moreover, both acai extracts exhibited effective concentration-dependent antioxidant and free radical scavenging properties. The acai ethanolic extract showed the most potent antioxidant capability and exhibited the highest phenolic and flavonoid contents 101.39 ± 4.61 milligram gallic acid equivalents/gram of acai berry extracts (mg GAE/g) and 11.78 ±1.42 milligram quercetin equivalents/gram of extract (mg QUER E/g), respectively. Fractionation and analysis of acai berry extracts with LC-MS identified several phytochemicals that may have provided antioxidants and anti-cholinesterase effects. Therefore, acai berry extracts could be a potentially dietary supplements that reduce the pathogenic impairments seen in AD. Taken together, the data in this thesis suggest that excessive L-Glu intake has adverse effects, including neuronal tissue degradation, similar pathomechanisms found in NDDs and stroke. Moreover, this thesis reveals that acai berry extracts may include neuroprotective compounds and could be exploited to develop drugs to treat NDDs and strokes, which are linked to excessive buildup and toxicity of L-Glu. In addition, acai extracts may present a novel approach for prospective AD therapy if further fractionated due to their novel anti-cholinesterase and antioxidant properties. However, it is still necessary to validate these findings using human primary cell lines, 3D neuronal models, and in vivo models to explore the influences of L-Glu and acai berry extracts exposure in humans.

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Neuroprotective Activities of Acai Berries (Euterpe sp.) Against Monosodium Glutamate Induced Toxicity in Neural Cells	19

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