Sodium Benzoate in Therapies for Nervous System Disorders

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1		Łucja Justyna Walczak-Nowicka	--	3929	2022-06-28 13:20:12	\|
2	Reference format revised.	Lindsay Dong	Meta information modification	3929	2022-06-29 04:24:22	\|

This entry is adapted from the peer-reviewed paper 10.3390/nu14071497

One of the compounds known as a preservative with a high safety profile is sodium benzoate. While some studies show that it can be used to treat conditions such as depression, pain, schizophrenia, autism spectrum disorders, and neurodegenerative diseases, others report its harmfulness. For example, it was found to cause mutagenic effects, generate oxidative stress, disrupt hormones, and reduce fertility.

food additives sodium benzoate neurodegenerative diseases

1. Introduction

Due to the advancing chemicalization of food in recent years, an increasing number of consumers have declared their interest in such food features as sensation, health, and, above all, safety ^[1]^[2]^[3]^[4]^[5]. For fear of the adverse effects of chemicals added to food in order to improve its taste and appearance or extend its shelf life, the choice of the least-processed products that do not contain additives, including preservatives, has become more and more popular, thus creating the trend of the so-called “clean label”.

Sodium benzoate (according to the European nomenclature E211) is a salt of benzoic acid and is well soluble in water, tasteless, and odorless, and due to its antifungal and antibacterial properties, it is a preservative added to food in strictly defined doses. It inhibits the growth of bacteria, yeast, and mold ^[6]. Sodium benzoate was approved as the first of all food preservatives by the Food and Drug Administration (FDA). The permissible limit of its consumption is 0–5 mg/kg of body weight. It also has a GRAS (generally regarded as safe) status according to the FDA ^[7]. Sodium benzoate is considered safe for human health if it is consumed in amounts of less than 5 mg/kg of body weight per day. At this level, the Acceptable Daily Intake (ADI) was established. It determines the dose of a given substance that can be consumed by a person daily throughout his or her life without suffering any health damage.

Sodium benzoate does not accumulate in the body. Benzoate is conjugated with glycine to form hippurate in the liver and kidney in a reaction occurring in the mitochondrial matrix ^[8]. Upon entering the matrix, the compound is converted to benzoyl-coenzyme A (CoA) (ligase) and then to hippurate (glycine N-acyltransferase), which leaves the mitochondrion. It is excreted primarily through the urinary system. The administration of sodium benzoate causes a strong but transient increase in anthranilic acid (involved in tryptophan metabolism) and acetylglycine. The benzoate is one of the cinnamon metabolites ^[9]^[10]. Cinnamon contains cinnamaldehyde, which is converts to cinnamic acid in the liver and is then β-oxidized to benzoate (sodium salt or benzoyl-CoA). It is easily absorbed from the gastrointestinal tract and metabolized in the liver into hypuronic acid. In this form, it is excreted from the body with urine usually within 6 h of ingestion.

Due to its properties, sodium benzoate is used to preserve food products with an acidic pH, such as fruit pulp and purees, jams, pickles, pickled herring and mackerel, margarine, olives, beer, fruit yogurts, canned vegetables, and salads ^[11]. Most often, sodium benzoate is added to carbonated drinks, sauces, mayonnaises, margarines, tomato paste, and fruit preserves. In turn, in its natural form, it is present in, among other things, cinnamon, mushrooms, cranberries, blueberries, and cloves. Therefore, sodium benzoate is classified as a compound with a broad safety profile. It is also approved for therapeutic use in the form of two drugs: Ammonul/Ucephan and Buphenyl ^[12]^[13]. The indications for their use are urea cycle disorders, as well as hyperammonemia. Moreover, some studies report that not only is sodium benzoate an excellent preservative, but it may also have potential therapeutic uses in the treatment of diseases such as major depressive disorder (MDD), schizophrenia, autism spectrum disorder (ASD), and neurodegenerative diseases. Officially, sodium benzoate is regarded as not harmful—only when consumed in large amounts can it cause allergic reactions or contribute to the exacerbation of disease symptoms in aspirin-induced asthma (with hypersensitivity to aspirin and other non-steroidal anti-inflammatory drugs) ^[14]^[15]^[16]. However, in recent years, some reports have provided for its adverse health effects. Interestingly, various and often contradictory results of scientific research prove that sodium benzoate has unfavorable or, on the contrary, beneficial effects on the body (especially in the treatment of certain diseases) by engaging in the same mechanisms of action.

2. The Harmfulness of Sodium Benzoate

It is believed that benzoate can be transformed by decarboxylation into toxic benzene, especially in combination with vitamin C, and then become a compound of high toxicity, mutagenicity, and teratogenicity ^[17]. There are also reports that sodium benzoate has a weak genotoxic effect. Moreover, it was shown to increase the DNA damage in human lymphocytes in vitro. The compound did not affect the rate of replication, but it did reduce the mitotic rate ^[18]. Mutagenic and genotoxic effects were also demonstrated in another study on human lymphocytes ^[19]. This compound caused micronucleus formation and chromosome breakage. In addition, the research shows that sodium benzoate generates oxidative stress and has an adverse effect on the immune system, liver, kidneys, and fertility.

2.1. The Effect of Sodium Benzoate on the Oxidative Stress and Inflammation

The effect of sodium benzoate (6.25, 12.5, 25, 50, and 100 μg/mL) on the increasing oxidative stress was observed in erythrocytes in an in vitro study ^[20]. After the treatment of cells with benzoate, there was observed increased lipid peroxidation, as well as decreased levels of antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione S-transferase. In another study, its effect on the induction of apoptosis was observed ^[21]. In addition, inhibition of antioxidant enzymes, decreased levels of glutathione (GSH), increased levels of nitric oxide (NO), and inflammation (increased in IL-6 and TNF α) were noted.

2.2. Effect of Sodium Benzoate on the Embryos

A teratogenic study on sodium benzoate was reported in a zebrafish model ^[22]. At low doses (1–1000 ppm), the embryos exhibited a 100% survival rate, but higher doses caused deformation of the larvae. Another study based on the same model also showed that embryo survival depended on the time and dose ^[23]. The larvae were also characterized by reduced locomotor activity and decreased expression of tyrosine hydroxylase and dopamine transporter. In another study, it was reported that the effect of benzoate may be cumulative when it affects hormones ^[24]. It is possible that such an effect is also noted for other parameters. Moreover, some experiments were conducted on pregnant female rats administered with sodium benzoate (0.5, 1, and 1.5 mg/mL) ^[25]. This compound had little effect on maternal weight gain, but no toxic effects were observed. Perinatal mortality was significantly increased in the 1% and 1.5% benzoate dose groups. However, no fetal malformations or weight loss were observed. Benzoate also showed genotoxic effects on liver tissue in both fetuses and mothers. In contrast, in another study, sodium benzoate (doses 9.3 and 18.6 mmol/kg b.w.) decreased the fetal weight of rats and increased their mortality ^[26].

2.3. Effect of Sodium Benzoate on Hormone Levels

It should be noted that benzoate was shown to affect the sperm motility (1 mg/kg b.w./day) ^[21]. It caused changes in the reproductive organs and affected the levels of sex hormones. Moreover, in another study, sodium benzoate affected the male reproductive system. The compound caused a 50% reduction in sperm count compared to the control group, as well as increased oxidative stress ^[27]. Another study also reported testicular dysfunction in rats after the administration of sodium benzoate at 100 mg/kg of body weight for 28 days ^[28]. This was associated with impaired semen quality and endocrine function of the testes and changes in their structure. In another in vivo study, the compound (0.01 mg/kb b.w.) also affected sex hormone levels (follicle-stimulating hormone (FSH), luteinizing hormone (LH), and free testosterone) ^[29].

2.4. Effect of Sodium Benzoate on Liver and Kidney Function

The sodium benzoate in animals affected the lipid profile and liver and kidney parameters. Moreover, there were observed histopathological and dose-dependent changes in the biochemical markers of liver damage (150–700 mg /kg b.w) ^[30]^[31]. It affected the histology of the kidney and liver. In addition, it was found that sodium benzoate may rather affect the kidneys than the liver ^[32]. This compound (100 mg/kg bw) was added to drinking water for 15 weeks.

2.5. Sodium Benzoate and Children’s Hyperactivity

Attention-deficit hyperactivity disorder (ADHD) is mainly associated with symptoms of hyperactivity, inattention, and impulsivity ^[33]. Beverages containing benzoate preservatives in their composition were given (45 mg/day) to 3-year-old children, who then experienced an increase in hyperactivity ^[34]. These behaviors were reduced after the withdrawal. Another study showed a similar effect of sodium benzoate in 8-, 9-, and 3-year-old children ^[35]. Furthermore, a survey was conducted among college students that examined the association between the consumption of sodium benzoate-rich beverages and symptoms associated with ADHD ^[36]. Thus, it was shown that the consumption of such beverages was associated with a higher prevalence of symptoms of ADHD. However, it should be noted that due to the nature of this study (i.e., a survey), the feelings of the respondents were subjective.

2.6. Sodium Benzoate—Irritating Effect on the Gastric Mucosa

The effect of benzoate (oral provocation with 20 mg of sodium benzoate) on gastric mucosa was studied in a clinical trial ^[37]. It was shown that it increased the release of allergic mediators, i.e., histamine and prostaglandins, from the mucosa compared to the control group. The same study suggested that benzoate-related allergic reactions may be mediated by prostacyclins and histamine.

2.7. Sodium Benzoate with Vitamin C

Although there are no studies that clearly confirm the harmfulness of these additives, it has been proven that when used as a preservative, sodium benzoate can react with vitamin C and thus form carcinogenic benzene ^[17]. In practice, this combination is often used in colorful, sweetened drinks. In many studies, elevated levels of benzene were reported in carbonated beverages, fruit juices, and other products where benzoate was present in combination with vitamin C ^[38]^[39]^[40]^[41]. It has been shown that the hydroxyl radical, formed by the metal-catalyzed reduction in O₂ and H₂O₂ by ascorbic acid, can attack benzoic acid to form benzene ^[42].

2.8. Effects of Sodium Benzoate on Memory and Anxiety Processes

Wistar (healthy) rats received sodium benzoate in different concentrations in water (from 0.5–2%) ^[43]. This compound was shown to increase anxiety-like, depressive, and antisocial behaviors. Similar results were observed in another study where rats were given benzoate at a dose of 200 mg/kg/day ^[44]. Animals treated with these compounds experienced an increase in anxiety-like behaviors and impaired motor skills. The researchers suggest that this may be related to decreased levels of glycine in the body (it is consumed as a result of benzoate detoxification) and disruption of processes affected by this amino acid or disruption of zinc levels.

3. Beneficial Properties of Sodium Benzoate

Sodium benzoate, especially when taken in high doses, can pose a health risk through various action mechanisms. However, other studies indicate that this substance, through the same or similar mechanisms of action, has beneficial properties and may, in the future, be used in the development of therapeutic strategies for certain diseases.

3.1. Effects of Sodium Benzoate on Oxidative Stress and Inflammation

Inflammatory responses of microglia and astroglia have been observed in various disease entities related to the nervous system. In lipopolysaccharide (LPS)-stimulated microglia cells, benzoate (>100–500 μm) suppresses NO production and decreases inducible nitric oxide synthase (iNOS) expression by inhibiting NFκB activation ^[45]. Furthermore, it inhibits the production and decreases the expression of TNF- α and IL-1 β. LPS increases the expression of MHC class II and B7-1 and B7-2 stimulatory molecules, and sodium benzoate counteracts these effects by suppressing their expression. In addition, the compound decreases CD11b expression (overexpression is associated with increased microglia activation) in microglia cells. It also inhibits LPS-induced activation of p21^ras. It also affects astroglia cells, namely by decreasing the expression of iNOS but also by inhibiting the increased expression of glial fibrillary acidic protein (GFAP). The researchers suggest that the reduction in mevalonate pathway intermediates is likely responsible for the observed anti-inflammatory effects. Moreover, the compound reduces in vivo cholesterol levels in mice by 28% after 7 days of therapy. In another study, similar results were obtained, i.e., reduction in the proinflammatory cytokines TNFα and IL-6, as well as in cholesterol levels (sodium benzoate doses: 250, 500 mg/kg b.w.) ^[46].

3.2. Sodium Benzoate in Major Depressive Disorder and Anxiety

Sodium benzoate was shown to reduce homocysteine levels in an animal ^[47]. High homocysteine levels are thought to be associated with the etiopathogenesis of MDD and anxiety ^[48]^[49]. Therefore, reducing its levels should contribute to reducing the symptoms associated with these diseases. However, homocysteine levels have not been measured in any case report or animal model of MDD or anxiety. In addition, sodium benzoate has been shown to have anti-inflammatory effects through its effect on the NFκB factor ^[45]. Its use in MDD therapy may be related to its cytokine theory, according to which there is an increase in pro-inflammatory cytokines but also activation of NFκB ^[50]^[51]^[52]. In addition, as previously mentioned, this compound inhibits tryptophan degradation and decreases neopterin production ^[53] and transiently increases anthranilic acid levels ^[8]. Increased tryptophan levels have been shown to be associated with decreased depressive symptoms ^[54]^[55], and anthranilic acid has also been shown to play an important role in the treatment of MDD ^[56]^[57]. In addition, high neopterin levels have been associated with the number of MDD episodes and also correlate with neuropsychiatric abnormalities ^[58]^[59].

Sodium benzoate was tested on mouse adipocyte cultures after LPS stimulation ^[60]. Under the influence of LPS, there was a decrease in leptin levels and an increase in IL-6 levels. Benzoate caused an even greater decrease in leptin levels in stimulated adipocytes, but did not affect IL-6 levels. Interestingly, low leptin levels were noted in women after a recent suicide attempt, which also suggests a link between the hormone itself and increased anxiety and overactivity of the hypothalamic–Pituitary–Adrenal (HPA) axis ^[61]^[62]. This link is confirmed by in vivo studies in rats in which elevated corticosterone levels were reported after benzoate administration ^[24]. Benzoate at a dose of 50 mg/kg b.w. did not affect these levels after one week, but after three weeks, elevated levels were already observed. Moreover, in higher concentrations, this compound already affected these levels after a week. Elevated corticosterone levels are closely related to the HPA axis. It should be noted that the effects of this compound on the human body may be cumulative due to the fact that the duration of exposure and its dose played a significant role in terms of hormone levels.

Ciliary neurotrophic factor (CNTF) is a neuronal survival factor ^[63]. Sodium benzoate was shown to increase its expression ^[64]. However, the correlation between CNTF and depressive and anxiety behaviors is quite unclear. Mice lacking this factor demonstrated behaviors similar to anxiety and depression ^[65]. In contrast, patients with MDD had elevated levels of CNTF compared to controls ^[66]. Other researchers suggest that in women, the inhibition of CNTF by progesterone reduces depressive symptoms, while in men, this factor has an antidepressant effect ^[67]. Perhaps this ambiguous effect of benzoate on depression may be related to sex hormones, due to the fact that benzoate affects the levels of both male and female sex hormones ^[29]^[68]. However, more research should be done in this direction because it is a compound with a high safety profile, and perhaps for some patients who poorly tolerate standard anti-anxiety or antidepressant therapy, it may be that sodium benzoate therapy can reduce such symptoms.

3.3. Sodium Benzoate in Schizophrenia

Sodium benzoate, by inhibiting D-AAO, also increases the level of synaptic D-serine, which is a co-agonist of the NMDA receptor ^[69]. This causes an increase in the receptor excitability, which in turn is associated with the normalization of the receptor function (Figure 1). The reduced levels of D-serine are often associated with schizophrenia and bind more strongly to the NMDA receptor than D-glycine does ^[70]. As previously mentioned, sodium benzoate exerts an effect to increase d-glycine levels, and this amino acid is thought to be involved in the development of schizophrenia ^[71]. It was observed to have increased serum levels in patients with this disease. However, many researchers consider that by increasing its levels, symptoms of schizophrenia can be reduced. The above factors would suggest that benzoate could find potential use as a drug for schizophrenia because it increases the levels of two major NMDA receptor co-agonists.

/media/item_content/202206/62bbb425a5f59nutrients-14-01497-g001.png

Figure 1. Summary of the beneficial effects of sodium benzoate in schizophrenia. ”−‘’ inhibition/reduction; “+’’increase.

Notably, the injection of sodium benzoate into rats increased extracellular dopamine in the frontal cortex ^[72]. The researchers suggest that it might be necessary to further investigate the mechanism of action of D-AAO inhibitors. Increased levels of dopamine in patients with schizophrenia contribute to the positive symptoms of the disease, and excessively low levels contribute to the negative symptoms. The action of inhibitors of this enzyme may also have a markedly different effect on the dopaminergic system than the drugs used for this disease, which act on dopamine receptors.

3.4. Sodium Benzoate in Neurodegenerative Diseases

Sodium benzoate does not only attenuate LPS-mediated microglia iNOS expression, as previously mentioned, but it also attenuates it after induction by other neurotoxins, such as βA (AD-related), MPP + (PD-related), and IL-12 p40 2 (MS-related) (Figure 2) ^[45]. Factors such as BDNF and neurotrophin-3 (NT-3) have protective functions for neurons and play an important role in alleviating neuronal loss in neurodegeneration ^[73]. Sodium benzoate increased the expression of BDNF and NT-3 in an in vitro study (cell culture), as well as in vivo in mouse brain cells. Researchers assume that this compound acts on these factors through the PKA CREB pathway. It is also significant that the compound easily penetrates the BBB.

/media/item_content/202206/62bbb439a7c78nutrients-14-01497-g002.png

Figure 2. Summary the of beneficial effects of sodium benzoate on neurodegenerative disease.

Additionally, benzoate inhibited ROS production in microglia cells induced by MPP+ (toxin in PD), LPS, and Aβ1-42 (AD etiological factor) ^[47]. This mechanism probably occurs through p21^rac inhibition, which was also confirmed in vivo (5XFAD Tg mice). The compound also reduced oxidative stress and gliosis in the hippocampus in animals. Moreover, the compound inhibited neurodegeneration in a mouse model of AD and reduced tau protein phosphorylation and βA levels. In addition, it affected learning and memory in mice. Moreover, depletion of the intermediates of the mevalonate pathway was shown to be responsible for the antioxidant effects of benzoate, as speculated in a previously mentioned study ^[45]. A reduction in homocysteine levels after sodium benzoate administration was reported in animals, as well ^[47]. The lowering of homocysteine levels by benzoate may be a beneficial feature for the treatment of other neurodegenerative diseases, as well, due to the fact that hyperhomocysteinemia is an independent risk factor for their occurrence ^[74]^[75].

Sodium benzoate (250–1500 mg/day) was tested on patients with mild cognitive impairment, as well ^[76]. By assessing regional homogeneity (ReHo), how it affects brain activity, and more specifically local functional connectivity (FC), was examined. In the sodium benzoate-treated group, a positive correlation was noted between the change in non-verbal (spatial) working memory and ReHo in the right precentral gyrus and right middle occipital gyrus. In addition, in this group, a positive correlation was observed between memory and verbal learning and ReHo in the left precuneus.

Furthermore, some studies have undertaken evaluation of the therapeutic properties of benzoate in PD. Mutations in the DJ-1 protein are presumed to be associated with the pathogenesis and occurrence of PD ^[77]. It was mentioned previously that sodium benzoate in a mouse model of intracerebral hemorrhage had a beneficial effect on DJ-1 levels ^[78]. In another study, it increased the levels of this protein by modulating the mevalonate pathway in primary mouse and human astocytes, as well as in human neuronal cells ^[79]. Additionally, the compound increased the expression of other PD-related genes, such as Parkin, PINK1, LRRK2 and HtrA2, while suppressing the expression of α-synuclein. The researchers suggest that this compound could alleviate nigrostriatal damage in PD. In an animal model of PD (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model), sodium benzoate was also shown to affect levels of glial cell-derived neurotrophic factor (GDNF) ^[80]. It stimulated the increase in GDNF expression in mouse and human astocytes via CREB, but in vivo also had a beneficial effect on the levels of this factor in the substantia nigra pars compacta (SNpc). Thus, the compound improved locomotor activity in mice and also had a neuroprotective effect restoring the innervation of the striatum. It should be noted that the mouse model of MPTP PD has limitations ^[81].

Shifting the balance of Th1 to Th2 is one of the therapeutic strategies in MS ^[82], and it was previously mentioned that sodium benzoate acted on both populations of these lymphophytes ^[53]. This was also confirmed by in vitro studies on peripheral blood mononuclear cells (PBMCs) in MS patients ^[83]. Mice with experimental allergic encephalomyelitis (EAE), a model in MS, were treated with sodium benzoate (2.5–10 mg/mL, and also, the mice drank water containing sodium benzoate-5 mg/mL) ^[84]. This compound inhibited the symptoms of the disease in both the acute and chronic phase. In addition, it reduced inflammation, thereby decreasing inflammatory infiltration, and it reduced demyelination and slowed disease progression.

3.5. Sodium Benzoate in Pain Relief

Sodium benzoate (400 mg/kg b.w.) is proved to relieve the pain in especially those associated with chronic pain ^[85]. It did not exhibit an effect in the acute phase of pain in an in vivo study in mice. Intraperitoneal as well as systemic administration of benzoate (400 mg/kg b.w.) to rats had analgesic effects in these animals ^[86]. Sodium benzoate reduced mechanical allodynia in rats with neuropathy and formalin-induced hyperalgesia. As before, no effect of the compound on acute pain was demonstrated. This effect was also confirmed in another study where benzoate prevented formalin-induced tonic pain in an in vivo model, yet had no effect on acute pain ^[87]. It also had a beneficial effect alleviating hypersensitivity to pain caused by sleep deprivation ^[88]. This effect was dose-dependent, and the maximum effect was observed 60 min after administration to rats.On the other hand, benzoic acid derivatives showed analgesic effects. These derivatives are believed to act as antagonists of prostaglandin E2 receptor subtype 4 ^[89]. Moreover, they acted specifically on adrenergic but also dopaminergic and GABAergic transmission ^[90].

3.6. Sodium Benzoate in Autism Spectrum Disorder

As mentioned above, sodium benzoate attenuates microglia activation (Figure 3) ^[45]^[47]^[73] and has a beneficial effect in shifting the balance towards Th2 ^[53]^[83]^[84]. Furthermore, it beneficially effects the Treg/Th17 ratio ^[91]^[92]. Therefore, these properties may support the potential use of sodium benzoate in the treatment of ASD patients. Another study administered sodium benzoate (for children with body weight ≥ 15 kg, the dose was 500 mg/day, for children with body weight < 15 kg, the dose was 250 mg/day) to non-communicative children with ASD for 12 weeks ^[93]. Half of the children demonstrated improvement in communication, and an activation effect was observed in three of the six children. However, the activation effect was not strong enough to require medical intervention or discontinuation of the study. In one case report, a girl with symptoms similar to ASD, but also with a urea cycle disorder, was administered thioridazine and also sodium benzoate (1.5–1.75 mmol/kg/day) ^[94]. Her condition improved after one year, and autistic symptoms were not noticeable. Perhaps the resolution of ASD symptoms was not only related to the use of thioridazine but in part to benzoate.

/media/item_content/202206/62bbb45244b7anutrients-14-01497-g003.png

Figure 3. Summary of the beneficial effects of sodium benzoate on ASD.

The beneficial effect of benzoate on patients with ASD may also be due to its effect on p21 expression, as previously reported ^[45]^[47]. Activated p21 kinase has been shown to be associated with severe ASD ^[95]. In addition, benzoate affects homocysteine levels ^[47]. Similar to the disorders described above, high levels are also observed in ASD ^[96]^[97]. It was mentioned earlier that sodium benzoate affects the inhibition of neopterin production and tryptophan degradation ^[53]. It should be noted that elevated levels are observed in individuals with ASD ^[98]^[99]. Abnormal tryptophan metabolism is also observed in these patients ^[100]^[101]. Given the effects of sodium benzoate in alleviating ASD as described above and other potential mechanisms of its action, more research in this direction would be warranted.

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