Abstract
This systematic review analyzes monosodium glutamate (MSG) in the Alzheimer’s disease-like condition to enhance translational research. Our review seeks to understand how MSG affects the brain and causes degenerative disorders. Due to significant preclinical data linking glutamate toxicity to Alzheimer’s disease and the lack of a comprehensive review or meta-analysis, we initiated a study on MSG’s potential link. We searched PubMed, ScienceDirect, ProQuest, DOAJ, and Scopus for animal research and English language papers without time constraints. This study used the PRISMA-P framework and PICO technique to collect population, intervention or exposure, comparison, and result data. It was registered in PROSPERO as CRD42022371502. MSG affected mice’s exploratory behaviors and short-term working memory. The brain, hippocampus, and cerebellar tissue demonstrated neuronal injury-related histological and histomorphometric changes. A total of 70% of MSG-treated mice had poor nesting behavior. The treated mice also had more hyperphosphorylated tau protein in their cortical and hippocampus neurons. Glutamate and glutamine levels in the brain increased with MSG, and dose-dependent mixed horizontal locomotor, grooming, and anxiety responses reduced. MSG treatment significantly decreased phospho-CREB protein levels, supporting the idea that neurons were harmed, despite the increased CREB mRNA expression. High MSG doses drastically lower brain tissue and serum serotonin levels. In conclusion, MSG showed AD-like pathology, neuronal atrophy, and short-term memory impairment. Further research with a longer time span and deeper behavioral characterization is needed.

Abstract
L-serine is a non-essential amino acid that plays a vital role in protein synthesis, cell proliferation, development, and sphingolipid formation in the central nervous system. It exerts its effects through the activation of glycine receptors and upregulation of PPAR-γ, resulting in neurotransmitter synthesis, neuroprotection, and anti-inflammatory effects. L-serine shows potential as a protective agent in various neurological diseases and neurodegenerative disorders. Deficiency of L-serine and its downstream products has been linked to severe neurological deficits. Despite its crucial role, there is limited understanding of its mechanistic production and impact on glial and neuronal cells. Most of the focus has been on D-serine, the downstream product of L-serine, which has been implicated in a wide range of neurological diseases. However, L-serine is approved by FDA for supplemental use, while D-serine is not. Hence, it is imperative that we investigate the wider effects of L-serine, particularly in relation to the pathogenesis of several neurological deficits that, in turn, lead to diseases. This review aims to explore current knowledge surrounding L-serine and its potential as a treatment for various neurological diseases and neurodegenerative disorders.

Neurodegenerative diseases are age-related diseases characterized by cognitive impairment, such as Alzheimer's disease (AD), Parkinson's disease, and schizophrenia (Wu et al., 2022[10]). As a nonessential amino acid, serine plays fundamental roles in neurodegenerative diseases and has two optical isomers of L-serine and D-serine (Zhang and Bai, 2023[11]).

Supplementary L-serine ameliorates cognitive dysfunction in both animals and humans (Handzlik and Metallo, 2023[3]). In the brain, L-serine is predominantly synthesized de novo from glucose in astrocytes by 3-phosphoglycerate dehydrogenase due to the low permeability of the blood-brain barrier (BBB) for L-serine, and is indispensable to the biosynthesis of selenoproteins for the maintenance of cognitive functions (Zhang and Bai, 2023[11]). Although the diffusion of D-serine through the BBB still remains slow and weak, its permeability across the BBB is higher than L-serine (Bai et al., 2023[1]). Compared to L-serine, D-serine is a more potent neurotransmitter and a gliotransmitter for neurodegenerative diseases. D-serine is concentrated in the brain, especially the cerebral cortex and hippocampus. As an endogenous amino acid, D-serine is converted from L-serine by pyridoxal 5′-phosphate-dependent enzyme serine racemase (SR) in neurons and astrocytes (Bai et al., 2023[1]), and degraded by D-amino acid oxidase (DAAO) in astrocytes (Ni and Mori, 2022[9]). Overexpression and deficiency of SR are associated with some neurodegenerative diseases, such as AD (Madeira et al., 2015[7]) and schizophrenia (Labrie et al., 2009[5]) since D-serine content depends on SR.

D-serine is a potent co-agonist for N-methyl-D-aspartate glutamate receptor (NMDAR), which plays important pathophysiology roles in synaptic functions, such as synaptic plasticity, learning, and memory. D-serine-mediated NMDAR activation is crucial for the regulation of neurodegenerative diseases, however, the overactivation of NMDAR induces excitotoxicity, thus leading to cognitive impairment (Mota et al., 2014[8]). D-serine is considered as a biomarker of neurodegenerative diseases because low D-serine levels were observed in AD animals and patients (Le Douce et al., 2020[6]; Madeira et al., 2015[7]). However, D-serine was not significantly different in cerebrospinal fluid between schizophrenic patients and healthy controls (Fuchs et al., 2008[2]). Oral D-serine supplementation for 2 weeks restored the spatial memory deficits in transgenic AD mice (Le Douce et al., 2020[6]), and oral 4-week D-serine at doses of 60 and 120 mg/kg/day effectively improved persistent symptoms and neurocognitive dysfunction in schizophrenic patients (Kantrowitz et al., 2010[4]).

Abstract
Ginseng, the root of the Panax ginseng, has been a popular and widely-used traditional herbal medicine in Korea, China, and Japan for thousands of years. Now it has become popular as a functional health food and is used globally as a natural medicine. Evidence is accumulating in the literature on the physiological and pharmacological effects of P. ginseng on neurodegenerative diseases. Possible ginseng- or ginsenosides-mediated neuroprotective mechanisms mainly involve maintaining homeostasis, and anti-inflammatory, anti-oxidant, anti-apoptotic, and immune-stimulatory activities. This review considers publications dealing with the various actions of P. ginseng that are indicative of possible neurotherapeutic efficacies in neurodegenerative diseases and neurological disorders such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis and multiple sclerosis.

Abstract
We performed a randomized, double-blind phase I clinical trial for six months on the effects of oral L-serine in patients with ALS. The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18–85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%. Patients were randomly assigned to four different oral twice-daily dose regimens (0.5, 2.5, 7.5, or 15 g/dose). Blood, urine and CSF samples, ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) were obtained throughout the trial. Disease progression was compared with matched historical placebo controls from five previous ALS therapeutic trials.

Of 20 patients enrolled, one withdrew before receiving study drug and two withdrew with gastro-intestinal problems. Three patients died during the trial. L-serine was generally well tolerated by the patients and L-serine did not appear to accelerate functional decline of patients as measured by slope of their ALSFRS-R scores. Based on this small study, L-serine appears to be generally safe for patients with ALS.

This is a Phase IIa, randomized, double-blind, placebo controlled trial. Subjects for participation in this study will be identified by the Investigator based on their Clinical Dementia Rating score which will be completed as part of standard practice. Patients meeting the criteria for early Alzheimer's disease will be considered for study participation, with the Investigator taking the additional inclusion/exclusion criteria into consideration. Up to 40 subjects will be enrolled. Subjects participating in the study will be randomized to receive either gummies containing L-Serine or placebo gummies, with the Investigator and study staff blinded to the group assignments.

Whether distinct blood metabolomic profiles can distinguish Parkinson’s disease (PD) patients from healthy controls (HC) is still a matter of debate. Here, we employed ¹H-NMR and UPLC/MS analyses on serum samples from a cohort of PD patients and HC. Compared to HC, PD patients showed: (1) higher glutamine, serine, pyruvate and lower α-ketoglutarate levels (1H-NMR); (2) higher glycine and lower glutamic acid concentrations (UPLC/MS). Several pathways associated with amino acids, mitochondrial and antioxidant metabolism emerged as dysregulated in PD. Our findings highlight a prominent disruption of cellular bioenergetic pathways and amino acid homeostasis in PD.

Ginseng, the root of the Panax ginseng, has been a popular and widely-used traditional herbal medicine in Korea, China, and Japan for thousands of years. Now it has become popular as a functional health food and is used globally as a natural medicine. Evidence is accumulating in the literature on the physiological and pharmacological effects of P. ginseng on neurodegenerative diseases. Possible ginseng- or ginsenosides-mediated neuroprotective mechanisms mainly involve maintaining homeostasis, and anti-inflammatory, anti-oxidant, anti-apoptotic, and immune-stimulatory activities. This review considers publications dealing with the various actions of P. ginseng that are indicative of possible neurotherapeutic efficacies in neurodegenerative diseases and neurological disorders such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis and multiple sclerosis.

Brief Summary
This is a Phase IIa, randomized, double-blind, placebo controlled trial. Subjects for participation in this study will be identified by the Investigator based on their Clinical Dementia Rating score which will be completed as part of standard practice. Patients meeting the criteria for early Alzheimer's disease will be considered for study participation, with the Investigator taking the additional inclusion/exclusion criteria into consideration. Up to 40 subjects will be enrolled. Subjects participating in the study will be randomized to receive either gummies containing L-Serine or placebo gummies, with the Investigator and study staff blinded to the group assignments.
Detailed Description
L-serine (C3H7NO3; 105.09 g/mol; synonym (S)-2-amino-3-hydroxypropanoic acid) is a naturally-occurring dietary amino acid. It is abundant in soy products, some edible seaweeds, sweet potatoes, eggs, and meat. Since some L-serine is produced by astrocytes in the brain, it is considered a non-essential amino acid. L-serine is directly involved in the biosynthesis of purines, pyrimidines, and other amino acids. Serine residues are found in most proteins and within proteins function as a site for phosphorylation.

L-serine is considered as GRAS (generally recognized as safe) by the FDA and has been approved as a normal food additive under CFR172.320. It is widely sold as a dietary supplement. A pilot study of L-serine supplementation of 14 patients with hereditary sensory neuropathy has been published, and subsequent trial is on-going (ClinicalTrials.gov identifier NCT01733407). The authors did not report adverse effects at doses of 400mg/kg/day, which for an average American of 75.5kg is about 30 grams, the dose which we propose to use in this study.

L-serine will be administered orally through gummies. Each gummy contains 1 g L-serine (treatment) and will be packaged in a foil packet containing 15 pieces to be taken both morning and evening for nine months. The placebo will be a gummy containing no L-serine, packaged and taken in the same manner. In order to assess tolerability in patients, we have designed a 4 week dose ramp-up. We will monitor side-effects and amino acid balances in blood samples in the early Alzheimer's Disease patients during a dose ramp-up period. If a patient cannot tolerate the full dose of gummies, they will remain in the study taking a total of 1 package of gummies split into two time periods within the day. The same ramp-up schedule and procedures will be observed for both placebo and L-serine patients. Patients will be assessed at baseline, 3 months, 6 months, and 9 months.