Ginkgo biloba extract alleviates oxidative stress and some neurotransmitters changes induced by aluminum chloride in rats

doi:10.1016/j.nut.2016.10.012

Nutrition

Volume 35, March 2017, Pages 93-99

https://doi.org/10.1016/j.nut.2016.10.012 Get rights and content

Highlights

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Administration of AlCl3 caused a decrease in glutathione, catalase, and superoxide dismutase and an increase in thiobarbituric acid reactive substance in testicular and brain tissue.
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Administration of AlCl3 caused a decrease in neurotransmitters (NE,DA,5-HT), serum Zn, Cu, Mg, and testosterone; and an increase in serum Fe, acid phosphatase, and alkaline phosphatase. Histologic changes in brain and testicular tissue was observed in AlCl3 group.
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Administration of rats with ginkgo biloba extract can ameliorate AlCl3 hazardous effects.

Abstract

In the present study, twenty four adult male albino rats were classified into four groups. The control group received normal diet and water; the second group was treated daily with oral dose of Ginkgo biloba (200 mg/kg body weight [b.wt]) for 3 mo; the third group was treated daily with oral dose of aluminum chloride (10 mg/kg b.wt) for 3 mo; and the fourth group was treated with both Ginkgo biloba and aluminum chloride (200 and 10 mg/kg b.wt, respectively) using a stomach tube for 3 mo. The results showed that administration of AlCl₃ to rats induced significant increase (P < 0.05) in thiobarbituric acid reactive substance and decrease (P < 0.05) in glutathione, catalase, and superoxide dismutase in brain and testis homogenates. The data also showed significant decrease (P < 0.05) in noradrenaline, dopamine, and serotonin (5-HT) levels in brain tissue. The rats administered AlCl₃ showed significant decrease (P < 0.05) in serum zinc (Zn) and copper (Cu), significant increase (P < 0.05) in serum iron (Fe), and non-significant decrease in magnesium (Mg). Furthermore, significant increase (P < 0.05) in serum alkaline phosphatase and acid phosphatase and significant decrease (P < 0.05) in testosterone were recorded. The histologic examination showed some degenerative changes in both brain and testis tissues while significant improvement in biochemical and histologic changes were observed in the aluminum chloride plus Ginkgo biloba group. It could be concluded that the protective effect of Ginkgo biloba may be attributed to its antioxidant properties.

Graphical abstract

Introduction

Aluminum (Al) is found in combination with oxygen, silicon, fluorine, and other elements in soil, rocks, clay, and gems and comprises about 8% of the Earth's crust [1] and its salts are daily used in our diets, food additives, drinking water, and some beverages. The main sources of ingested Al are found in corn, yellow cheese, processed cheese, baking powder, flour, and cake [2], [3].

Al is also widely employed in medicine such as eye drops, antiperspirants [4], antacids, phosphate binders, aspirins, vaccines, allergic injections [5], and toothpaste [3]. The daily intake of Al has been estimated to be 3.5 to 51.6 mg [6], where 20% of this amount comes from aluminum cooking utensils [7], [8]. Overexposure to Al is inevitable, and its accumulation in human blood and tissues depend on time, duration, route, and form of exposure.

It has been clearly established that Al is a potent neurotoxin [9] and a possible contributing factor in several neurodegenerative disorders including Alzheimer disease [10], [11], dialysis encephalopathy [4], and alternative function of exchange between the blood–brain barriers and peripheral circulation [12]. The increased Al burdens can cause biochemical metabolic disorders which cause metabolic bone diseases via induction of parathyroid dysfunction [13], inhibition of some enzymes such as hexokinase, acid and alkaline phosphatases (ALP), phosphodiesterase and phosphooxydase [14], impairment in glucose utilization, lipid peroxidation, accumulation of free radical mediated cytotoxicity, impact on DNA and RNA gene expression, and altered protein phosphorylation [15], [16]. Conversely, Al can cause lipid peroxidation and decrease in some antioxidant enzymes in plasma and tissues of male rabbits [17] and decrease in acetyl-coenzyme A [18], acetylcholine transferase [19], and acetylcholine esterase [20].

The leaf extract of Ginkgo biloba (EGb 761) has antioxidant and free radical scavenger properties that work by increasing the endogenous antioxidants and inhibiting free radical formation [21], [22]. Ginkgo biloba extract (GbE) is also used in treating cerebral disorders that result from aging and hypoxia [23]. In addition, the psychological and physiological benefits of Ginkgo biloba are based on its primary action of regulating neurotransmitters and exerting neuroprotective effects.

Due to the properties of Ginkgo biloba, it was selected as a subject to investigate the potential capacity of its leaf extract as a protector against the possible toxic effects of AlCl₃ on the brain and testis of male rats through the evaluation of some biochemical parameters in serum and through the histologic changes in brain and testis of male rats treated with AlCl₃ and/or GbE for 3 mo.

Section snippets

Chemicals

Anhydrous aluminum chloride (AlCl₃) was supplied from BDH Laboratory Supplies (BDH, GPR, Safat, Kuwati) and Ginkgo biloba was purchased from Pharo Pharmaceuticals for EMA Pharm Pharmaceuticals (Cairo, Egypt).

Animals

Twenty four adult male albino rats (180–200 g) were used in the present study and obtained from the animal house of the Nuclear Research Center, Atomic Energy Authority, Cairo, Egypt. The rats were kept in plastic cages under normal conditions: temperature was (29 ± 2°C), relative humidity

Biochemical study

Data in Table 1 shows that rats administered AlCl₃ revealed a significant increase (P < 0.05) in TBARS in both brain and testis (+33.61% and +47.33%, respectively) and significant decreases (P < 0.05) in SOD, CAT, and GSH in brain tissue (−34.36%, −34.27%, and −56.0%, respectively) and testis tissue (−36.95%, −36.06%, and −47.75%, respectively) as compared to the control group. On the other hand, treatment of rats with GbE + AlCl₃ was markedly ameliorated the increase in TBARS and the decrease

Discussion

The present study showed that the ingestion of AlCl₃ for 3 mo induced oxidative stress and biochemical alterations because SOD, CAT, and GSH have been decreased in these rats as measured in testis and brain, whereas the level of TBARS was increased. The brain is known to contain high concentrations of polyunsaturated fatty acids that are highly susceptible to lipid peroxidation [36], [37]. This result is more related to the ability of Al to enhance the production of reactive oxygen

Conclusions

The present results showed that the brain is particularly susceptible to aluminum toxic effects, which significantly enhance neuronal lipoperoxidative damage, decrease Mg, Cu, and Zn, and increase Fe with concomitant alterations in the antioxidant defense status that may be responsible for the rise in the cell load as a result of oxidative stress, which affects the levels of neurotransmitters. On the other hand, administration of Ginkgo biloba extract with aluminum chloride improved some

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Ginkgo biloba L. (Ginkgoaceae), known as a "living fossil,"has a long history of medicinal use. Both its leaves and nutshave been widely prescribed for the treatment of various ailments, including pulmonary diseases, alcohol abuse, bladder inflammation, heart and lung dysfunction, and skin infections. Currently, there are different forms of G. biloba available in the market, including extracts and isolated compounds such as terpenoids, flavonoids, bioflavonoids, and organic acids. Despite the significant medicinal importance of this plant, there is a lack of updated reviews encompassing its pharmacology and other relevant aspects. Therefore, the objective of this review is to collect and analyze existing literature on the phytochemical, ethnobotanical, and pharmacological aspects of G. biloba.
Electronic databases including PubMed, Embase, Scopus, and Google Scholar were searched for keywords “Ginkgo biloba” or “ginkgo” in combination with “phytochemistry”, “ethnobotany”, “pharmacology”, “nervous system”, and “cardiovascular”, etc. to collect the relevant articles. There was no language restriction.
Retrieved studies showed that the extracts and isolated compounds from G. bilobahave beneficial activities in cerebrovascular, nervous, cardiovascular, endocrine, muscular and skeletal, renal, respiratory, digestive, and immunity systems.
Numerous in vitro and in vivo studieshave been conducted to investigate the therapeutic potential of G. biloba in the treatment and improvement of various diseases. Additionally, there is a substantial body of clinical research on G. biloba preparations and isolated compounds. However, further investigations, particularly human-controlled trials, are recommended to determine the efficacy and safety of G. biloba. These trials would provide more robust evidence regarding the potential benefits and risks associated with the use of G. biloba in clinical settings.
γ-Aminobutyric acid promotes the inhibition of hair growth induced by chronic restraint stress
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Stress plays a critical role in hair loss, although the underlying mechanisms are largely unknown. γ-aminobutyric acid (GABA) has been reported to be associated with stress; however, whether it affects stress-induced hair growth inhibition is unclear. This study aimed to investigate the potential roles and mechanisms of action of GABA in chronic restraint stress (CRS)-induced hair growth inhibition. We performed RNA-seq analysis and found that differentially expressed genes (DEGs) associated with neuroactive ligand-receptor interaction, including genes related to GABA receptors, significantly changed after mice were treated with CRS. Targeted metabolomics analysis and enzyme-linked immunosorbent assay (ELISA) also showed that GABA levels in back skin tissues and serum significantly elevated in the CRS group. Notably, CRS-induced hair growth inhibition got aggravated by GABA and alleviated through GABA_A antagonists, such as picrotoxin and ginkgolide A. RNA sequencing analysis revealed that DEGs related to the cell cycle, DNA replication, purine metabolism, and pyrimidine metabolism pathways were significantly downregulated in dermal papilla (DP) cells after GABA treatment. Moreover, ginkgolide A, a GABA_A antagonist extracted from the leaves of Ginkgo biloba, promoted the cell cycle of DP cells. Therefore, the present study demonstrated that the increase in GABA could promote CRS-induced hair growth inhibition by downregulating the cell cycle of DP cells and suggested that ginkgolide A may be a promising therapeutic drug for hair loss.
Integration of morphological, physiological, cytological, metabolome and transcriptome analyses reveal age inhibited accumulation of flavonoid biosynthesis in Ginkgo biloba leaves
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The medicinal components of ginkgo leaf, especially G. biloba extract (GbE), encompass diverse plant secondary metabolites, such as flavonoids and terpene lactones (Lu et al., 2021). GbE is used to treat a variety of diseases, such as age-related spatial memory deficits (Stackman et al., 2003), neurotransmitter changes (Mohamed and Abd El-Moneim, 2017), and neurological disorders (Fang et al., 2020). The components of GbE include 24 % flavonoids and 6 % terpene lactones (Christen and Maixent, 2002).
Age affects the content of flavonoids in ginkgo (Ginkgo biloba L.) leaves, such that only 1-to-5-year-old ginkgo leaves are suitable for the extraction of medicinal compounds. Nevertheless, the relationship between age and flavonoids in ginkgo leaves is unclear. In this study, we compared 1-to-7-year-old ginkgo trees, and found that the flavonoid content decreased with age. The total flavonol aglycones content of 1-year old ginkgo was 9.88 ± 0.27 mg/g, significantly higher than those of 4- and 7-year-old gingko, and there was a marked difference in quercetin content. Next, we extensively compared the transcriptome and metabolome in leaves of 1-, 4-, and 7-year-old ginkgo. Metabolome profiles showed that flavonoid metabolites were the most abundant in different metabolities, and 82 % of the flavonoids exhibited a decreasing trend with increasing age. Downregulation of key structural genes (chalcone synthase, CHS; flavanone 3-hydroxylase, F3H; flavonol synthase, FLS) in the flavonoid biosynthesis pathway may explain the decreased flavonoid content with age. Furthermore, GO and KEGG analysis revealed photosynthesis- and hormone-related genes were downregulated with increasing age, implying that photosynthesis, salicylic acid, and jasmonic acid influence the flavonoid content. These results provide a theoretical basis for leaves ginkgo seedlings and new clues for understanding how age regulates flavonoids.
Conjugated linoleic acid downregulates Alzheimer's hallmarks in aluminum mouse model through an Nrf2-mediated adaptive response and increases brain glucose transporter levels
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Notably, studies aimed at investigating the neuroprotective efficacy of natural substances against Al-induced neurotoxicity are characterized by the fact that the doses of Al ranged from 8.3 to 500 mg/kg/body weight and for a duration ranging from 28 to 90 days. Moreover, in most of these preclinical studies the allometric conversion of both Al and potentially therapeutic molecule doses (i.e. quantity normalized to a dose comparable to human exposure/consumption) (human-equivalent dose; HED) [7] was not calculated [8–12] and dietary molecules were sometimes administered through a non-physiological route (e.g. intraperitoneal) [11,12]. There is much evidence indicating that mitochondrial malfunction, characterized by a respiratory chain impairment and increased yield of reactive oxygen species (ROS), is a hallmark of AD [13].
Mitochondrial dysfunction, oxidative stress, inflammation and glucose dysmetabolism are pathological signs of Alzheimer's disease (AD). Dietary aluminum (Al) overload is often used to induce AD in rodents and trigger the onset of oxidative-stress hallmarks resembling those of the human disease.
The Nuclear factor erythroid 2–related factor 2 (Nrf2), owing to its key role in redox homeostasis, mitochondrial function and inflammation, is a promising drug target for neurological disorders, but only a few data are available on its modulatory effects on glucose transporter expression levels. While it has been found that the protective effect of Conjugated linoleic acid (CLA) occurs through the activation of an Nrf2-mediated adaptive response, its beneficial effect on the considered pathological signs in the Al-induced model has not been established yet.
Thirty-five male BalbC mice were divided into 5 groups: two Al-intoxicated groups were treated for 5 weeks with low or high Al doses (8 or 100 mg/kg/day in drinking water, respectively; L or H). Two groups of animals, orally supplemented with CLA (600 mg/kg bw/day) for 7 weeks (2 preliminary weeks plus the 5-week treatment with Al; CLA + L, CLA + H) were used to investigate its protective effect, while untreated mice were used as control (Cntr).
We provide evidence that mitochondrial dysfunction, Nrf2 alteration, inflammation and Acetylcholinesterase (AChE) hyperactivation can occur even from L exposure. Interestingly, animal pre-treatment with an allometric CLA dose led to significant downregulation of the toxic effects elicited by L or H, likely through the activation of an adaptive response.
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Tinnitus is defined as the perception of sound in the absence of external acoustic stimuli. Frequent comorbidities or associated factors are depression, anxiety, concentration problems, insomnia, resignation, helplessness, headache, bruxism, or social isolation, just to name a few.
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Our review will give a brief overview about preclinical models, presenting the heterogeneity of tinnitus sub-types depending on the different inner ear and brain structures involved in tinnitus etiology and pathogenesis. Based on these models we introduce the different target structures and transmitter systems implicated in tinnitus development and provide an extensive overview on preclinical drug-based therapeutic approaches that have been explored in various animal models.
As the special extract from Ginkgo biloba leaves EGb 761® has been the most widely tested drug in both non-clinical tinnitus models as well as in clinical trials, a special focus will be given to EGb 761®. The efficacy of terpene lactones, flavone glycosides and proanthocyanidines with their distinct contribution to the overall efficacy profile of the multi-constituent drug EGb 761® will be discussed.
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Increased mitochondrial ROS can injure the mitochondrial membranes, DNA and proteins, ultimately leading to mitochondrial dysfunction (Higgins et al., 2010). Neurotoxic metals may disrupt the homeostasis of neurotransmitters in the hippocampus related to memory and learning, such as DOP, SER, AChE and DOPAC (Mohamed and Abd El-Moneim, 2017). Therefore, the underlying mechanisms beyond learning and memory impairments and oxidative stress due to AlCl3 treatment in the female mice in this study may involve neurotransmitter dysregulation, such as the GABAergic (Cordeiro et al., 2003), serotoninergic (Laabbar et al., 2014) and cholinergic (Zatta et al., 2002) systems.
Aluminum is a neurotoxic element that can accumulate in the brain and cause neurodegenerative disorders. In addition, the antioxidants found in pomegranate juice (PJ) are much more than those existing in other fruits. It was proven to provide protection against neurodegenerative diseases.
This experiment aimed to clarify the amelioration efficiency of PJ against aluminum chloride-induced neurobehavioral and biochemical disorders in female mice.
The female mice were given oral administrations for 35 days as follows. The control group received tap water, the PJ groups received 20% and 40% pomegranate juice, the aluminum chloride (AlCl₃) group was treated with 400 mg/kg AlCl₃, and the last two groups received AlCl₃ + 20% PJ and AlCl₃ + 40% PJ, respectively. The neurobehavioral features were assessed by shuttle box, T-maze, and Morris water maze devices. Furthermore, the neurotransmitters and oxidative indicators in the brains of the female mice were determined at the end of experiment.
Significant effects of AlCl₃ were observed on female mice in the body weight, during the behavioral tasks (shuttle box, T-maze, and Morris water maze), and in neurotransmitters and oxidative stress parameters. Pomegranate juice, especially at low concentrations, induced remarkable improvements in body weight, spatial memory and learning during T-maze, Morris water maze and shuttle box tasks, as well as in neurotransmitters and oxidative biomarkers in the AlCl₃-treated female mice.
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: The authors acknowledge the expert assistance rendered by Dr. K.A. Ahmed, Professor of Veterinary Pathology, Faculty of Veterinary Medicine, Cairo University, Egypt, for performing the histologic examinations and interpretations and also thank Dr. N.I. Hazzaa, Professor of Radiobiology, MERRCAC, Egypt. The authors declare no conflict of interest.

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Basic nutritional investigationGinkgo biloba extract alleviates oxidative stress and some neurotransmitters changes induced by aluminum chloride in rats

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemicals

Animals

Biochemical study

Discussion

Conclusions

Food Chem Toxicol

Brain Res Bull

Neurotoxicology

Neurosci Biobehav Rev

Toxicology

Free Radic Biol Med

J Mol Cell Cardiol

Life Sci

Brain Res

Am J Obstet Gynecol

Anal Biochem

J Neurosci Methods

J Chromatogr B Analyt Technol Biomed Life Sci

Neurotoxicology

Brain Res Bull

Neurochem Int

Free Radic Biol Med

Brain Res Bull

Int J Dev Neurosci

Brain Res

Neurotoxicology

Pharmacol Biochem Behav

Food Chem Toxicol

Pharmacol Rep

Mol Aspects Med

Brain Res

J Trace Elem Med Biol

J Nutr

Toxicology

J Biol Chem

Metal ions in dialysis dementia syndrome and aluminum intoxication

Nephron

Developmental toxicity of aluminum from high doses of AlCl3 in mice

J Appl Res

Gastrointestinal absorption of aluminum from aluminum containing antacids

N Engl J Med

Aluminum

Searching for other sources of aluminum contamination

Aluminum levels in food stimulating solvents and various foods cooked in aluminum pans

J Agric Food Chem

Mitochondrial electron transport chain in heavy metal induced- neurotoxicity: Effects of cadmium, mercury and copper

ScientificWorldJournal

Reversible alcohol related dementia: A five year follow up study using FDG-PET and neuropsychological tests

Intern Med

Basic nutritional investigation
Ginkgo biloba extract alleviates oxidative stress and some neurotransmitters changes induced by aluminum chloride in rats

Developmental toxicity of aluminum from high doses of AlCl₃ in mice