L-glutamate (L-Glu) is a nonessential amino acid, but an extensively utilised excitatory neurotransmitter with critical roles in normal brain function. Aberrant accumulation of L-Glu has been linked to neurotoxicity and neurodegeneration. To investigate this further, we systematically reviewed the literature to evaluate the effects of L-Glu on neuronal viability linked to the pathogenesis and/or progression of neurodegenerative diseases (NDDs). A search in PubMed, Medline, Embase, and Web of Science Core Collection was conducted to retrieve studies that investigated an association between L-Glu and pathology for five NDDs: Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Together, 4060 studies were identified, of which 71 met eligibility criteria. Despite several inadequacies, including small sample size, employment of supraphysiological concentrations, and a range of administration routes, it was concluded that exposure to L-Glu in vitro or in vivo has multiple pathogenic mechanisms that influence neuronal viability. These mechanisms include oxidative stress, reduced antioxidant defence, neuroinflammation, altered neurotransmitter levels, protein accumulations, excitotoxicity, mitochondrial dysfunction, intracellular calcium level changes, and effects on neuronal histology, cognitive function, and animal behaviour. This implies that clinical and epidemiological studies are required to assess the potential neuronal harm arising from excessive intake of exogenous L-Glu.

There are currently no pharmacological treatments available that completely halt or reverse the progression of Parkinson’s Disease (PD). Hence, there is an unmet need for neuroprotective therapies. Lewy bodies are a neuropathological hallmark of PD and contain aggregated α-synuclein (α-syn) which is thought to be neurotoxic and therefore a suitable target for therapeutic interventions. To investigate this further, a systematic review was undertaken to evaluate whether anti-α-syn therapies are effective at preventing PD progression in preclinical in vivo models of PD and via current human clinical trials. An electronic literature search was performed using MEDLINE and EMBASE (Ovid), PubMed, the Web of Science Core Collection, and Cochrane databases to collate clinical evidence that investigated the targeting of α-syn. Novel preclinical anti-α-syn therapeutics provided a significant reduction of α-syn aggregations. Biochemical and immunohistochemical analysis of rodent brain tissue demonstrated that treatments reduced α-syn-associated pathology and rescued dopaminergic neuronal loss. Some of the clinical studies did not provide endpoints since they had not yet been completed or were terminated before completion. Completed clinical trials displayed significant tolerability and efficacy at reducing α-syn in patients with PD with minimal adverse effects. Collectively, this review highlights the capacity of anti-α-syn therapies to reduce the accumulation of α-syn in both preclinical and clinical trials. Hence, there is potential and optimism to target α-syn with further clinical trials to restrict dopaminergic neuronal loss and PD progression and/or provide prophylactic protection to avoid the onset of α-syn-induced PD.

Introduction: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline, primarily due to dysfunction of acetylcholine caused by acetylcholinesterase and butyrylcholinesterase. While synthetic cholinesterase inhibitors like donepezil, rivastigmine, and galantamine are commonly used, they have notable side effects, prompting interest in natural alternatives. Medicinal plants, rich in bioactive compounds like flavonoids and alkaloids, have shown potential as cholinesterase inhibitors with additional antioxidants and anti-inflammatory benefits. This study aimed to evaluate the cholinesterase-inhibiting effects of various plant species and their compounds to identify new therapeutic candidates and reduce side effects. Method: A PRISMA-compliant review was conducted, screening studies from multiple databases, with a final inclusion of 64 in vivo studies. Results: These studies highlighted plant extracts such as Ferula ammoniacum, Elaeagnus umbellata, Bacopa monnieri, and Centella asiatica, which improved memory, reduced oxidative stress, and provided neuroprotection. Some extracts also reduced amyloid plaques, enhanced neuronal integrity, and restored cholinesterase activity, indicating their potential as therapeutic agents for AD and other neurodegenerative diseases. Conclusions: The findings underscore the promise of plant-based compounds in treating cognitive decline and cholinergic dysfunction in AD, advocating for further research into their therapeutic potential.

Alzheimer’s disease (AD) is characterised by progressive neuronal atrophy and the loss of neuronal function as a consequence of multiple pathomechanisms. Current AD treatments primarily operate at a symptomatic level to treat a cholinergic deficiency and can cause side effects. Hence, there is an unmet need for healthier lifestyles to reduce the likelihood of AD as well as improved treatments with fewer adverse reactions. Diets rich in phytochemicals may reduce neurodegenerative risk and limit disease progression. The native South American palm acai berry (Euterpe oleraceae) is a potential source of dietary phytochemicals beneficial to health. This study aimed to screen the nutraceutical potential of the acai berry, in the form of aqueous and ethanolic extracts, for the ability to inhibit acetyl- and butyryl-cholinesterase (ChE) enzymes and scavenge free radicals via 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) or 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) assays. In addition, this study aimed to quantify the acai berry’s antioxidant potential via hydrogen peroxide or hydroxyl scavenging, nitric oxide scavenging, lipid peroxidation inhibition, and the ability to reduce ferric ions. Total polyphenol and flavonoid contents were also determined. Acai aqueous extract displayed a concentration-dependent inhibition of acetyl- and butyryl-cholinesterase enzymes. Both acai extracts displayed useful concentration-dependent free radical scavenging and antioxidant abilities, with the acai ethanolic extract being the most potent antioxidant and displaying the highest phenolic and flavonoid contents. In summary, extracts of the acai berry contain nutraceutical components with anti-cholinesterase and antioxidant capabilities and may therefore provide a beneficial dietary component that limits the pathological deficits evidenced in AD.

Dietary interventions rich in fruits and vegetables in aging people can reverse or mitigate age-related cognitive declines, delay the onset of neurodegenerative diseases (NDDs), and provide long-term health dividends. The novel food, popularly known as "Acai", is a berry belonging to the Euterpe genus of tropical palms trees and natively found in South America. Euterpe oleracea has been given much attention among scientists due to its high antioxidant capacity compared to other fruits and berries. Additionally, acai pulp composition analysis found that it contains various biologically active phytochemicals. In this review, we focused on current evidence relating to acai berry neuroprotection mechanisms and its efficacy in preventing or reversing neurodegeneration and age-related cognitive decline. A number of studies have illustrated the potential neuroprotective properties of acai berries. They have shown that their chemical extracts have antioxidant and anti-inflammatory properties and maintain proteins, calcium homeostasis, and mitochondrial function. Moreover, acai berry extract offers other neuromodulatory mechanisms, including anticonvulsant, antidepressant, and anti-aging properties. This neuromodulation gives valuable insights into the acai pulp and its considerable pharmacological potential on critical brain areas involved in memory and cognition. The isolated chemical matrix of acai berries could be a new substitute in research for NDD medicine development. However, due to the limited number of investigations, there is a need for further efforts to establish studies that enable progressing to clinical trials to consequently prove and ratify the therapeutic potential of this berry for several incurable NDDs.

Aberrant accumulation of the neurotransmitter L-glutamate (L-Glu) has been implicated as a mechanism of neurodegeneration, and the release of L-Glu after stroke onset leads to a toxicity cascade that results in neuronal death. The acai berry (Euterpe oleracea) is a potential dietary nutraceutical. The aim of this research was to investigate the neuroprotective effects of acai berry aqueous and ethanolic extracts to reduce the neurotoxicity to neuronal cells triggered by L-Glu application. L-Glu and acai berry effects on cell viability were quantified using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays, and effects on cellular bioenergetics were assessed via quantitation of the levels of cellular ATP, mitochondrial membrane potential (MMP), and production of reactive oxygen species (ROS) in neuroblastoma cells. Cell viability was also evaluated in human cortical neuronal progenitor cell culture after L-Glu or/and acai berry application. In isolated cells, activated currents using patch-clamping were employed to determine whether L-Glu neurotoxicity was mediated by ionotropic L-Glu-receptors (iGluRs). L-Glu caused a significant reduction in cell viability, ATP, and MMP levels and increased ROS production. The co-application of both acai berry extracts with L-Glu provided neuroprotection against L-Glu with sustained cell viability, decreased LDH production, restored ATP and MMP levels, and reduced ROS levels. Whole-cell patch-clamp recordings showed that L-Glu toxicity is not mediated by the activation of iGluRs in neuroblastoma cells. Fractionation and analysis of acai berry extracts with liquid chromatography-mass spectrometry identified several phytochemical antioxidants that may have provided neuroprotective effects. In summary, the acai berry contains nutraceuticals with antioxidant activity that may be a beneficial dietary component to limit pathological deficits triggered by excessive L-Glu accumulations.