Promising role of Carob (Ceratonia siliqua L) phytochemical components against neurotoxicity induced by monosodium glutamate

The phytochemical constituents of Carob (Ceratonia siliqua L) showed therapeutic medical importance especially concerning neurotoxicity which represents the major public health problem. Neurodegenerative disorders are developed from different metabolic diseases and chemical component such as monosodium glutamate. It is the widely used chense sodium salt of the non-essential glutamic amino acid. It is one of the most popular fl avor enhancer. Monosodium glutamate is excitatory neurotransmitter in brain, increased the perception of wetness and saltiness as a taste sensation UMAMI. Treatment with the carob extract or their phytochemical constituents either protect or ameliorates these diseases which is promising. Review Article Promising role of Carob (Ceratonia siliqua L) phytochemical components against neurotoxicity induced by monosodium glutamate Hassan IH El-Sayyad*, Wafaa ME Elkholy and Wafaa A E Hamed Zoology Department, Faculty of Science, Mansoura Univ, Egypt Dates: Received: 25 May, 2017; Accepted: 28 June, 2017; Published: 30 June, 2017 *Corresponding author: Hassan IH El-Sayyad, Department of Zoology, Faculty of Science, Mansoura University, Mansoura, Egypt, Tel: 0020502254850; E-mail:


Introduction
Phytotherapy is of medical importance due to the side effects of pharmaceutical drugs. Knowing the phytochemical components of plants and pharmacologic action of each constituents and standardization procedures for use and its clinical effective. Neurodegeneration is the progressive breakdown of neurons leading to neurological disorder such as Parkinson's and Alzheimer's, and Huntington's diseases [1]. Monosodium glutamate (MSG) is excitatory neurotransmitter in brain, mediating fast synaptic transmission and increased the perception of wetness and saltiness as a taste sensation UNAMI [2]. It is a water soluble bad chemical component showing a potent UNAMI comes from the fi fth taste receptors on the tongue which are quite different from that of the brain [3]. This led individual to consume a large amount of food due to its characteristic fl avor enhancer which alter physiological processes, especially the functioning of the nervous system [4,5].
The glutamate is produced by the brain and serves as a as a nerve impulse transmitter in the brain to manage the functional activity of body organs [6]. The brain generates its n glutamate with an intricate own transport system to protect the brain cells. The excess circulating glutamate derived from the food material is kept separated from the glutamate inside the brain. The shifted glutamate concentration being increased in the intracellular region and low in the extracellular ones.
This may exert strokes and damage the blood-brain barrier [7,8].
Administration of glutamate to experimental animals and humans [9,10], led to the development of depression and anxiety in the form of imbalance of mood and emotions, abnormalities of limbic system structures [11], and disruption of the hypothalamic pituitary adrenal axis [12]. Glutamate was linked to many diseases such as Alzheimer's disease, Huntington's disease and Wernicke's encephalopathy [13,14], as well as retinal ischemia leading to loss of ganglion cells [15]. In vitro studies of MSG (20 mM) on astrocyte culture cells revealed increased a liberation of reactive oxygen species and apoptotic cell death [16].
The present review aimed to illustrate the neurologic disorders induced by monosodium glutamate and the promising role of carob extracts or their phytochemical constituents in treating or protecting the brain disorders.

Carob (Ceratonia siliqua L)
Carob fruit of Ceratonia siliqua L. is belong to Leguminosae family. It is widely cultivated in the Mediterranean region for ornamental and industrial purposes. Carob fruit is dark-brown with an elongated or curved shape and composed of two main components: the pulp (90%) and the seeds (10%). Its seeds contain approximately 90% galactomannans and used in food industry [17]. Papagiannopoulos et al. [18] [29].The carob pods is a rich source of polyphenol reaching approximately 80% with high antioxidant activity [20,23,30]. Also, it is rich in linoleic and alpha-linolenic acid [31]. The antioxidant of ethyl acetate extracts of carob tree leaves scavenge 1,1-diphenyl-2-picrylhydrazyl liberated radicals than the diethyl ether and dichloromethane extracts [32].
Ceratonia siliqua extracts, showed a potential DNA damage of murine leukaemia cells L1210 as well as protect against oxidative stress of H2O2 [34].

Monosodium glutamate related neurotoxicity
Monosodium glutamate (MSG) is the sodium salt of the glutamic acid. It is a non-essential amino acid, having unique fl avor-enhancing widely used as a food additive ( Figure 1).
Glutamic acid is abundant in protein rich food stuffs such as milk, meat, fi sh, cheese, tomato products, and soy sauces. It is one of the most popular fl avor enhancer. It is excitatory neurotransmitter in brain, mediating fast synaptic transmission in one third of all CNS synapses. It increased the perception of wetness and saltiness as a taste sensation UMAMI and is used in many commercial packed food (Maggi Noddles, Knorr Soup etc), restaurant and household cooking.
It is a natural components of many fermented or aged foods, such assoy sauce, fermented bean paste, and cheese, and is also in yeast extract [1]. In European countries, the intake of glutamate from food ranged from 5 to 12 g/day compared to Asian countries which reached from 1.2 to 1.7 g/day [35]. Glutamate-induced neurotoxicity characterized by neuronal damage [36,37], via intracellular increase of Ca2C levels through increase liberation of the N-methyl-D-aspartate receptors [38], or enhancement secretion of glutaminase utilizing glutamate as a substrate [39].
Glutamate released its signal through ionotropic and metabotropic glutamate receptors. Ionotropic receptors promote the ion channel pore that activates when glutamate binds to the receptor meanwhile metabotropic receptors enhanced ion channels on the cell membrane via a signaling cascade that form G-protein-coupled receptors primarily on neurons and glial cells [40,41]. Ionotropic receptors divided into four subtypes depending on their ligand binding properties such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptors), kainite receptors, N-methyl-D-aspartate receptor (NMDA receptors) and delta receptors, They promote the excitatory synaptic transmission in the central nervous system for synaptic plasticity, which is important for learning and memory [42]. Thee synaptic receptors located primarily on the membranes of neuronal cells. The interactions of glutamate with its ionotropic NMDA receptors led to neurotoxic changes due to the release excessive amounts of calcium to enter the neuron [43,44] and consequently contributed to the development of neurodegenerative disorders [45][46][47].
The receptor AMPA located in the different parts of the brain mediating the synaptic transmission which categorized into four subunits including GluR1, GluR2, GluR3 and GluR4.
Its dimerization start in the endoplasmic reticulum [48].
The second type is kinate receptors. They have both presynaptic and postsynaptic actions with a limited distribution in the brain comparing to the other types of ionotropic receptors. Kainic acid induced seizures, through the activation of kainate receptors containing both GluK2 subunit and AMPA receptors [49], N-methyl-D-aspartate receptor is a glutamate receptor and ion channel protein found in brain cells. It is activated when glutamate and glycine (or D-serine) bind together and activated for permeability of positively charged ions to pass through the cell membrane. The NMDA receptor is responsible for controlling synaptic plasticity and memory function [50].
Ionotropic glutamate delta 2 receptor is a protein that encoded in the human GRID2 gene. The receptors are expressed mainly in Purkinje cells in the cerebellum [51], and promote the synaptogenesis, synaptic plasticity, and motor coordination [52].
Glutamate is a naturally occurring amino acids reaching to 4 to 15% of all amino acids [53], and its level in the brain attained 10 4 μM. It is synthesized by neurons and not cross the blood-brain barrier [54]. It is responsible for maintaining developmental plasticity and memory [55]. However, intake diet containg MSG is followed by an increase in plasma glutamate level for 1 to 3 hours [56]. The fi rst step of excitotoxicity is the release of Mg(2+) from mitochondria to the cytosol and accumulation of Ca(2+) [57]. Also, glutamate is then converted into glutamine in astrocyte through a glutamine-reuptake system and loss its function [58]. Most of the excitatory neurons in the brain are glutamatergic; moreover, it is found that many of the nerve-endings release Glutamate is linked to many neurological diseases such as Alzheimer's disease, Huntington's disease, glaucoma and Wernicke's encephalopathy [61]. Also, it is associated with "kindling" limbic seizures in hippocampus of rodent and cerebral cortex of patients via repeated electrical stimulation dependent on the activation of N-methyl-D-aspartate (NMDA) receptors. Microdialysis increased the extracellular concentration of glutamate and aspartate before or during seizure onset, as a result of either enhanced amino acid release or impaired uptake contributed to seizure occur [60].
In vitro studies revealed that the excitatory amino acids such as L-aspartate and L-glutamate and micromolar kainic acid induced massive shedding of the rod photoreceptor disc and loose the contact with the pigment epithelium in eye cups of Xenopus laevis [62]. In postnatal rodents, daily injection of MSG led to impairment of vision via increase of retinal lesions and optic nerve degeneration [63]. Acute retinal ischemia was incorporated in retinal damage associated with accumulation of glutamate in aqueous humor [64] leading to retinal detachment in patients [65], and increase retinal damage in neonatal rats [66].

Monosodium glutamate and amyloid deposition
Monosodium glutamate (MSG) is the main cause of excitotoxicity associated with brain disorders including brain ischemia and neurodegenerative disorders [74]. In Alzheimer's disease temporal cortex, there was a marked decrease of glutamate uptake comparing with non-changed NMDA receptor [75].    [83].
Investigating hippocampal slice cultures of rat,

Phytotherapy of glutamate neurotoxicity
Phytotherapy involve the wide application of medicine which is of great importance and less side than the organochemical compounds. Hydrogen peroxide and peroxynitrite impaired glutamate uptake by astrocytes dependent on the concentration level and increased following inhibition of catalase. This led to marked increase of neurotoxicity. Carobsupplementation before or followed monosodium glutamate treatment reduced the accumulation of hydrogen peroxide in the extracellular space of the assayed brain tissues, and exerted a potential therapeutic effects [92].
Administration of MSG to neonatal rats increased body mass index and serum glucose Špolcová et al. [85], mentioned abnormally hyperphosphorylated tau protein at Ser396 and It inhibited apoptotic morphology, active caspase-3 protein expression, and PARP cleavage induced by glutamatetreatment [95].
Many plant-extracts and their chemical constituents are reported to have benefi cial effects on brain function [96], (Kennedy and Wightman, 2011). Carob-supplementation before or followed monosodium glutamate treatment reduced the accumulation of hydrogen peroxide in the extracellular space of the assayed brain tissues, and exerted a potential therapeutic effects [97].
Several phytochemical components such as ferulic acid [98], and epigallocatechin-3-gallate [99], protects against free radical mediated cell damage. Also, carob constituents ferulic acid improved AD through reduction of amyloid beta (Abeta) and AChE levels in the hippocampus related to development of cognition induced by glutamate [100].
Alzheimer and Parkinson are developed from increased oxidative stress. Ferulic acid is a natural antioxidant [101].
One-year-old mice with established β-amyloid plaques received daily doses of OG and FA alone or in combination for 3 months. APP/PS1 mutant transgenic mice received dimeric derivatives of ferulic acid KMS4001 at doses of 3 and 30mg/ kg/day via drinking water showed the signifi cantly enhanced novel-object recognition memory at both 1.5 and 3 months and decreased amyloid peptide Aβ1-40 and Aβ1-42 levels in the frontal cortex [103].
PSAPP mice receiving combination therapy of octyl gallate (OG) and ferulic acid (FA) for 3 months had statistically signifi cantly improved cognitive function through reductions of β-amyloid deposits in brain parenchymal and cerebral vascular tissues the main cause of Alzheimer's disease [104]. A series of novel Novel Tacrine-Ferulic Acid Hybrids [105], and ferulic acid-O-alkylamines derivatives were proved to be a good choice against Alzheimer's disease [106].
Cinnamon (CE) (the phenolic component of carob fruit) supplementation improved Alzheimer's disease (AD) induced by MSG-treatment in non-transgenic rat model of AD rats [107].
Chloroform: methanolic (80:20) extract of C. asiatica (CA; 100 and 200 mg/kg),improved monosodiumglutamate impaired locomotor activity and CAl a region of the hippocampus coincides with impaired lipid peroxides and ameliorated catalase, super oxide desmutase and lipid peroxides levels in hippocampus and striatum regions [108]. MSG (2 g/kg, 7 days i.p.) -treatment for seven days decreased the activities of SOD and increased malondialdhyde in serum, brain, liver and kidney of Sprague-Dawley female rats and improved after tannic acid-treatment (50 mg/kg, 3 days) [109].
Chlorogenic acid a polyphenol of carob fruit protect against glutamate-induced neuronal cell death in invitro cultures of mouse cerebral cortex through inhibition of release of intracellular concentrations of Ca(2+) and nitric oxide the causes of neuronal cell death [112].Several dtudies reported that the Chlorogenic acid exerted therapeutic potential including neuroprotection, cardioprotection, weight loss, chemopreventive properties, anti-infl ammatory activity, decreased blood pressure, decreased diet-induced insulin resistance, decreased blood pressure, anxiolytic effects, and antihyperalgesic effects [113]. The neuroprotective properties of Chlorogenic acid is occurred by inhibiting acetylcholinesterase and butyrylcholinesterase, activities as well as preventing oxidative stress-induced neurodegeneration [114,115].  Also, it is the primary site of reactive oxygen species production enhancing cell damage and causing oxidative stress. Resveratrol was found to decrease intracellular ROS production, through NMDA, AMPA/KA, intracellular Ca(2+) and the heme oxygenase 1 (HO1) pathway [117].
The author fi nally concluded that carob micro-constituents showed phytotherapeutic potential against neurotoxicity.