The literature primarily investigates Maltol's pharmacological effects in the context of diabetic peripheral neuropathy (DPN). It describes antioxidative activity and effects on Na+-K+-ATPase. The mechanisms explored involve modulation of oxidative stress markers and apoptosis-related proteins.[1]

In RSC96 rat Schwann cells injured by H2O2 (0.6 mM), co-incubation with Maltol at concentrations of 0.1 and 0.5 mM significantly increased cell viability. It also elevated the expression of the anti-apoptotic protein Bcl-XL in a dose-dependent manner and decreased the expression of pro-apoptotic genes BAX and caspase-3.[1]

In streptozotocin (STZ)-induced diabetic rats, daily oral administration of Maltol at doses of 50, 100, and 200 mg/kg for 12 weeks significantly improved motor nerve conduction velocity (MNCV) by up to 58.2% at 200 mg/kg. It ameliorated thermal and mechanical hyperalgesia, increasing withdrawal thresholds and latencies. Maltol treatment elevated the activity of Na+-K+-ATPase in erythrocytes and sciatic nerves, increased serum levels of total antioxidant capacity (TAOC), glutathione (GSH), and superoxide dismutase (SOD), while decreasing malondialdehyde (MDA). It also modulated apoptosis-related proteins in the sciatic nerve (decreasing BAX and caspase-3, increasing BAG4 and Bcl-XL) and produced a decreasing trend (though not statistically significant) in caspase-3 activity in dorsal root ganglia. Maltol did not significantly affect fasting blood glucose levels or body weight.[1]

The cell viability assay (CCK-8) was performed on RSC96 cells. Cells were seeded in a 96-well plate and cultured overnight. After treatment with Maltol and/or H2O2 for 6 hours, CCK-8 reagent was added and incubated for another 3 hours. Absorbance was measured at 450 nm to determine cell viability.[1]
The expression of apoptosis-related proteins (Bcl-XL) and genes (BAX, caspase-3) in RSC96 cells was assessed. For Western blot, total protein was extracted from cells, quantified, separated by SDS-PAGE, transferred to a PVDF membrane, blocked, and incubated with primary antibodies (e.g., Bcl-XL) and HRP-conjugated secondary antibodies.[1]
For quantitative real-time PCR, total RNA was extracted from cells using TRIzol reagent, cDNA was synthesized, and PCR was performed using SYBR Green Master Mix and specific primers for BAX and caspase-3, with GAPDH as an internal standard.[1]

Diabetic peripheral neuropathy was induced in male Sprague-Dawley rats by a single intraperitoneal injection of STZ (65 mg/kg) dissolved in citrate buffer (0.1 mol/L, pH 4.5). Diabetic rats (fasting blood glucose ≥ 11.1 mmol/L) were selected 4 weeks post-induction and randomly divided into groups (n=12). Treatment began 4 weeks after diabetes confirmation and lasted for 12 weeks. Maltol was dissolved in 0.5% carboxymethyl cellulose sodium (CMC-Na) solution and administered daily by oral gavage at doses of 50, 100, and 200 mg/kg. Normal and diabetic control groups received the 0.5% CMC-Na vehicle. Body weight and fasting blood glucose were monitored periodically. At the end of the 12-week treatment, assessments included motor nerve conduction velocity (MNCV), thermal and mechanical pain thresholds, collection of blood and tissues (sciatic nerve, dorsal root ganglia) for biochemical (Na+-K+-ATPase, oxidative stress markers), molecular (Western blot, qPCR), and enzymatic (caspase-3 activity) analyses.[1]

Absorption, Distribution and Excretion
Two male and two female beagle dogs were placed in two separate groups and administered a single intravenous injection of 10 mg/kg body weight of maltol. Urine samples were collected over 72 hours. An average of 58.5% of the administered dose was excreted as a mixture of maltol sulfate and glucuronic acid conjugates. Approximately 98% of the conjugates were excreted within the first 24 hours, with males and females excreting an average of 42% and 73% of the administered dose, respectively. Metabolism/Metabolites Maltol and its derivatives contain a γ-pyranone ring system. γ-pyranones are basic, and this basicity is partly attributed to their aromaticity and the relative stability of the conjugated acids. Due to the presence of a 3-hydroxy substituent on the γ-pyranone ring, maltol and its derivatives are expected to readily conjugate with glucuronic acid or sulfate. Furthermore, maltol may form complexes with metal ions (e.g., Fe²⁺) like phenolic compounds.

Toxicity Summary
Identification and Uses: Maltol is a white crystalline powder. It is used as a flavoring agent to give bread and cakes a "freshly baked" aroma and flavor. It is also used as a pharmaceutical. Human Exposure and Toxicity: Maltol at concentrations of 0.1 to 1.5 μmol/mL can induce sister chromatid exchange in human lymphocytes. Studies have shown that these results are due to the indirect effects of maltol, rather than its direct reaction with DNA. Animal Studies: Eight female mice were fed a diet containing 0.5% (w/w) maltol for 21 weeks, resulting in a calculated average daily intake of 750 mg/kg body weight. At the end of the experiment, no differences were found in the mice's general health, behavior, weight gain, or relative liver weight. Macroscopic and microscopic examination revealed no histological abnormalities in the livers of the treated mice compared to the control group. A three-generation reproductive toxicity study fed 20 male and 20 female rats with diets containing maltol at concentrations of 100, 200, or 400 mg/kg body weight/day. On day 134, the F1 generation animals developed salivary gland inflammation symptoms caused by an infectious virus. There were no deaths, and symptoms resolved within 10 days. Maltol had no effect on mating rate, mating vitality index, lactation, offspring sex ratio, or 21-day-old pups' survival rate. Maltol at concentrations of 0.1–1.5 μmol/mL induced sister chromatid exchange in Chinese hamster ovarian cells. The study suggests that these results may be due to the indirect effects of maltol, rather than a direct reaction with DNA. At concentrations of 1–3 mg/plate, maltol exhibited weak mutagenicity against Salmonella Typhimurium TA100 (increasing the number of reversion mutants by 2–3 times), effective both alone and in combination with metabolic activators. No activity against TA98 was detected. At concentrations of 0.1–10.0 mg/plate, maltol increased the number of reversion mutants in TA97 strain at a concentration of 1 mg/plate by approximately 2-fold. No increase in the number of reversion mutants was observed in the presence of an activation system, or when used alone or in combination with an activator. In other studies targeting Salmonella typhimurium, the mutagenicity of maltol was not stable at concentrations up to 10,000 μg/plate, whether used alone or in the presence of an activation system.

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Interactions
Pyranone compounds, 3-hydroxy-2-methyl-4-pyranone (maltol) and 3-hydroxy-2-ethyl-4-pyranone (ethyl maltol), can chelate iron with high affinity and selectivity. The resulting 1:3 (metal-ligand) complex is neutral and can easily cross the cell membrane, thus potentially promoting iron transport across the intestinal wall. This study investigated the absorption of radioactive iron (⁵⁹Fe) by pyranone compounds at 1, 2, 4, and 6 hours after intraduodenal administration of 7 micrograms of radioactive iron (⁵⁹Fe), and compared it with the absorption of ⁵⁹Fe in the form of ferric sulfate, ferric gluconate, ferric fumarate, or EDTA complex. Systemic absorption and distribution were calculated by measuring the ⁵⁹Fe content in different tissue samples. All iron preparations reached peak plasma concentrations at 1 hour post-injection, while the ⁵⁹Fe content in the primary deposition site (i.e., bone marrow) continued to rise over 6 hours. ⁵⁹Fe was not detected in urine. The systemic absorption of ⁵⁹Fe by pyranone compounds was significantly higher than that of the other four preparations. Within a dose range of 0.7–700 μg, the absorption rates of 59Fe by both maltol iron and ferric sulfate decreased with increasing dose. At doses of 0.7–70 μg, maltol significantly enhanced the absorption of 59Fe, but this was not observed at a dose of 700 μg, indicating that the use of these pyranone compounds does not lead to iron overload. Intragastric administration of 59Fe resulted in a slower onset of absorption but a longer duration, likely due to the stable transport of gastric-stored iron to the duodenum. In cultured rat hemispheric neurons, both aluminum and maltol induced neurofilament tangles. Quantitative analysis showed a significantly higher proportion of tangled neurons when using an aluminum-maltol mixture compared to aluminum alone. Neurofilament tangles were consistently stained by monoclonal antibodies against neurofilament proteins but did not react with polyclonal antibodies against microtubule-associated proteins 1, 2, and tau. Aluminum (Al) has been observed to cause the accumulation of neurofilament proteins in laboratory animals and cultured cells. Impaired axonal transport is considered one of the mechanisms of aluminum toxicity. However, inhibition of neurofilament protein degradation, leading to the accumulation of these proteins, may be another mechanism of aluminum toxicity. This study investigated the effect of calcium (Ca) on the hydrolysis of neurofilament triplet proteins by calcium-activated neutral protease (CANP) in isolated sciatic nerve explants. The results showed that the degree of degradation was correlated with calcium concentration. This study also examined the effects of aluminum chloride, aluminum citrate, and aluminum maltol on calcium-induced degradation. The results showed that these aluminum compounds had no effect, suggesting that aluminum may exert its neurotoxic effects through mechanisms other than inhibiting neurofilament protein hydrolysis. The study found that maltol itself can enhance the effect of calcium on neurofilament protein degradation, possibly by promoting calcium transneuronal membrane transport. In vivo aluminum deposition is a cause of dialysis-related diseases in patients with renal insufficiency and may play a role in the development of certain neurodegenerative diseases. Although citrate is known to significantly promote the absorption of aluminum in the gastrointestinal tract, its effect on aluminum distribution and accumulation remains unclear. Maltol has been shown to enhance the neurotoxicity of aluminum, but its effects on aluminum deposition in vivo are poorly understood. To elucidate the roles of citrate and maltol in aluminum accumulation and toxicity, researchers administered different doses of aluminum chloride intraperitoneally over 7 days, with or without citrate or maltol, and then analyzed aluminum levels in serum, brain, bone, and urine. Compared to aluminum and the aluminum-maltol combination, the citrate combination resulted in a relative decrease in serum aluminum levels. This can be attributed to the dual effect of enhanced tissue and renal clearance. …The study showed that maltol significantly promotes aluminum accumulation in serum, brain, and bone. The increase in aluminum levels in these target tissues was positively correlated with dose.
For more complete data on interactions with maltol (7 in total), please visit the HSDB record page.

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Non-human toxicity values
Chicken oral LD50: 3720 mg/kg
Guinea pig oral LD50: 1410 mg/kg
Rabbit oral LD50: 1620 mg/kg
Mouse subcutaneous injection LD50: 820 mg/kg
For more non-human toxicity values (complete) for maltol (6 in total), please visit the HSDB record page.

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In vivo studies reported no significant effect on body weight after 12 weeks of continuous oral administration, indicating that no significant systemic toxicity was observed at the test doses (50-200 mg/kg) in this model. In vitro studies indicated that maltol at concentrations of 0.1 and 0.5 mM protected RSC96 cells from H2O2-induced damage, but the literature (in the discussion section) also mentions that other studies have reported cytotoxic/apoptotic effects of maltol at higher concentrations (e.g., 1.2 mM) or in different cell types, suggesting that its effects may be concentration- and cell type-dependent. [1]

[1]. Maltol, a food flavor enhancer, attenuates diabetic peripheral neuropathy in streptozotocin-induceddiabetic rats. Food Funct. 2018 Dec 13;9(12):6287-6297.

Maltol is a white crystalline powder with a caramel-cream flavor. Its pH (5% aqueous solution) is 5.3. (NTP, 1992)
3-Hydroxy-2-methyl-4-pyranone belongs to the 4-pyranone class of compounds and is a metabolite.
Maltol has been reported in Bolbostemma paniculatum, Streptomyces, and other organisms with relevant data.
3-Hydroxy-2-methyl-4-pyranone is a metabolite found or produced in Saccharomyces cerevisiae.
Mechanism of Action

Maltol (3-hydroxy-2-methyl-4-pyranone) forms complexes with transition metals, producing reactive oxygen species. The maltol/iron complex inactivates aconitase, an enzyme most sensitive to oxidative stress. Aconitase inactivation is iron-dependent and inhibited by the reactive oxygen species scavenger TEMPOL, suggesting that maltol/iron-mediated superoxide anion generation is the cause of aconitase inactivation. Maltol addition effectively enhances ascorbic acid/copper-mediated generation of 8-hydroxy-2'-deoxyguanosine in DNA. Maltol addition effectively promotes CuSO₄ oxidation of ascorbic acid, while the addition of catalase and superoxide dismutase significantly inhibits this enhanced oxidation rate. These results indicate that maltol promotes the coupling of copper reduction and ascorbic acid oxidation, leading to the generation of superoxide radicals, which are then converted into hydrogen peroxide and hydroxyl radicals. The cytotoxic effect of maltol can be attributed to its pro-oxidative properties: the maltol/transition metal complex generates reactive oxygen species, leading to aconitase inactivation and the generation of hydroxyl radicals, which in turn form DNA base adducts. We investigated the ability of maltol to induce cytochrome P450 1a1 (Cyp1a1), an enzyme known to play a crucial role in the chemical activation of xenobiotics into carcinogenic derivatives. Our results showed that treatment of Hepa 1c1c7 cells with maltol significantly induced Cyp1a1 mRNA, protein, and activity levels in a concentration-dependent manner. The RNA synthesis inhibitor actinomycin D completely blocked the induction of Cyp1a1 mRNA by maltol, indicating that de novo RNA synthesis requires transcriptional activation. Furthermore, maltol induced the expression of an aryl hydrocarbon receptor (AhR)-dependent luciferase reporter gene in stably transfected H1L1.1c2 cells, suggesting that its mechanism of action is AhR-dependent. This is the first time that the food flavoring agent maltol has been demonstrated to directly induce Cyp1a1 gene expression in an AhR-dependent manner, revealing a novel mechanism by which maltol promotes carcinogenicity and toxicity. Maltol possesses antioxidant properties, likely due to its ability to complex with metal ions such as Fe²⁺ and promote the formation of reduced glutathione (GSH). At a concentration of 130 μmol/L, maltol inhibits iron-mediated lipid peroxidation and enhances reactive oxygen species scavenging by increasing the NADPH supply required for GSH regeneration. In the presence of Fe²⁺ and ascorbic acid, maltol incubation with rat liver microsomes inhibits the formation of thiobarbituric acid reactants. Maltol at concentrations of 130–140 μmol/L also effectively inhibits the inactivation of NADP-isocitrate dehydrogenase (the main NADPH-generating enzyme) by Fe++. Maltol significantly promotes the oxidation of Fe++, while dimethylpyranone does not. The latter result suggests that the 3-hydroxy substituent in maltol is essential for promoting Fe++ oxidation.

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Therapeutic Use
/EXPL THER/ /The purpose of this study/ was to evaluate the neuroprotective and neurite growth effects of the natural aroma compound maltol on retinal ganglion cells (RGCs) under in vitro oxidative stress. Primary mouse RGCs were isolated using an immunopanning-magnetic separation method and exposed to H₂O₂ in the presence of maltol. Cell viability and apoptosis were assessed using an adenosine 5'-triphosphate (ATP) assay and a TdT-mediated deoxyuridine triphosphate (dUTP) nick-end labeling assay, respectively. Neuronal growth was assessed using α-tubulin immunofluorescence. Activation of nuclear factor-κB (NF-κB) was also assessed using immunofluorescence. After 16 hours of exposure to 20 μM H₂O₂, the viability of RGCs decreased to 40.3 ± 3.4%. However, maltol treatment restored cell viability in a dose-dependent manner. ATP assays showed that cell viability recovered to 73.9 ± 5.1% after treatment with 10 μM maltol, and even reached 175.1 ± 11.3% after treatment with 2 mM maltol. Oxidative stress significantly increased the number of TUNEL-positive retinal ganglion cells (RGCs), but maltol significantly reduced the proportion of these apoptotic cells. Oxidative stress inhibited neurite growth in RGCs, while maltol restored their ability to germinate neurites. Regarding NF-κB, the active form of phosphorylated NF-κB (pNF-κB) increased oxidative stress levels, but maltol treatment again reduced it to the level of no stress. Our data indicate that maltol alleviated oxidative stress-induced damage in primary mouse RGCs. Its neuroprotective and neurite-promoting effects appear to be related to the NF-κB signaling pathway. Maltol shows promise as a novel neuroprotective agent for the treatment of oxidative stress-related eye diseases, including glaucoma. Maltol (3-hydroxy-2-methyl-4-pyranone) is a food flavoring and preservative with known antioxidant properties. This study reports for the first time the protective effect of maltol in a streptozotocin (STZ)-induced diabetic peripheral neuropathy (DPN) rat model. Its mechanism of action may involve the antioxidant activity of maltol (scavenging free radicals and improving oxidative stress markers) and its anti-apoptotic effects (regulating Bcl-2 family proteins and caspase-3), which occur in peripheral nerves and Schwann cells. These benefits are independent of glycemic control. This study suggests that maltol may be a novel potential candidate for the treatment of DPN. [1]

C6H6O3

126.1100

126.031

118-71-8

8369

White to off-white solid powder

1.3±0.1 g/cm3

284.7±40.0 °C at 760 mmHg

160-164 °C(lit.)

127.3±20.8 °C

0.0±1.3 mmHg at 25°C

1.561

0.08

1

3

0

9

200

0

XPCTZQVDEJYUGT-UHFFFAOYSA-N

InChI=1S/C6H6O3/c1-4-6(8)5(7)2-3-9-4/h2-3,8H,1H3

3-hydroxy-2-methylpyran-4-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~792.96 mM)
H2O : ~1.82 mg/mL (~14.43 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (19.82 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (19.82 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (19.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 3.33 mg/mL (26.41 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)