Dimethyl Malonate: Protective Potential of Acute Kidney Injury and Toxic Summary

General Description

Dimethyl malonate shows promise as a therapeutic agent for acute kidney injury (AKI) by improving renal function and preserving mitochondrial integrity. It inhibits succinate dehydrogenase, attenuating renal injury and reducing oxidative stress. Studies demonstrate its efficacy in enhancing glomerular filtration rate, reducing blood urea nitrogen levels, and minimizing tubular injuries and apoptosis post-ischemia-reperfusion. Additionally, Dimethyl malonate preserves mitochondrial function, crucial in AKI pathogenesis. With a low toxicity profile and no evidence of reproductive or developmental harm, Dimethyl malonate presents potential for mitigating AKI and its complications in high-risk patients, warranting further clinical exploration.

Figure 1. Dimethyl malonate

Protective Potential of Acute Kidney Injury

Dimethyl malonate has garnered attention as a potential therapeutic agent for acute kidney injury (AKI), a prevalent condition in intensive care units often triggered by ischemia-reperfusion injury. Ischemia leads to succinate accumulation, exacerbating reactive oxygen species production during reperfusion and significantly contributing to renal damage. While succinate dehydrogenase inhibition has demonstrated protective effects in cardiac models of ischemia-reperfusion injury, its impact on renal and mitochondrial functions remains relatively unexplored.

Renal Function Improvement with Dimethyl malonate Treatment

Studies utilizing a mouse model of AKI induced by bilateral renal ischemia have highlighted the efficacy of Dimethyl malonate in improving renal function parameters. Pre-treatment with Dimethyl malonate resulted in a significant enhancement in glomerular filtration rate (GFR), assessed through FITC-inulin clearance, compared to controls. Additionally, Dimethyl malonate treatment markedly reduced blood urea nitrogen levels, a crucial marker of renal dysfunction. Histopathological analysis revealed substantial reductions in ischemia-reperfusion-induced tubular injuries and apoptosis in Dimethyl malonate-treated animals, underscoring its protective role against renal damage.

Mitochondrial Function Preservation by Dimethyl malonate

Dimethyl malonate treatment also demonstrated a pivotal role in preserving mitochondrial function post-ischemia-reperfusion injury. Evaluation using high-resolution respirometry indicated improvements in both mass-specific and intrinsic mitochondrial functions. This preservation is critical given that mitochondrial dysfunction significantly contributes to AKI pathogenesis. Moreover, Dimethyl malonate treatment mitigated NADPH oxidase activity in the kidneys, further supporting its ability to reduce oxidative stress—a hallmark of AKI progression. These findings collectively highlight Dimethyl malonate 's potential as a therapeutic candidate for protecting against acute kidney injury by improving renal function and preserving mitochondrial integrity.

In conclusion, inhibition of succinate dehydrogenase with Dimethyl malonate significantly attenuates renal injury and preserves mitochondrial function during the critical ischemia-reperfusion phase. These findings suggest that Dimethyl malonate holds promise as a therapeutic strategy to mitigate AKI and its associated complications in high-risk hospitalized patients. Further clinical studies are warranted to validate these preclinical findings and explore the translational potential of Dimethyl malonate in clinical practice. ¹

Toxic Summary

Toxicity Overview

Dimethyl malonate is considered to have a low toxicity profile based on experimental data and modeled predictions. This chemical compound does not cause skin irritation, as evidenced by testing on rabbits, indicating its mild nature when in contact with the skin. Additionally, oral and dermal lethal-dose studies conducted on rats have shown no adverse effects, with LD50 values exceeding 2,000 mg/kg. These findings suggest that Dimethyl malonate is relatively safe in acute exposure scenarios, posing minimal risk to human health under normal handling conditions.

Liver Effects and Systemic Responses

In studies involving repeated oral doses, Dimethyl malonate has been shown to cause reversible hepatocellular hypertrophy in rats at the highest tested dose of 1,000 mg/kg/day. This condition, characterized by an increase in liver cell size, is indicative of liver metabolism rather than a sign of systemic toxicity. The reversibility of this effect highlights Dimethyl malonate's limited long-term risk to liver health. However, it underscores the necessity for careful monitoring in industrial or laboratory settings where long-term exposure might occur.

Reproductive and Developmental Safety

Dimethyl malonate has been thoroughly investigated for potential reproductive or developmental toxicity. Studies indicate no evidence of harm in these areas, nor any mutagenic effects, making it a safer chemical in terms of genetic impact. While it may cause mild to moderate eye irritation, as noted in animal tests, these effects are not severe and are considered manageable with standard safety precautions. The comprehensive safety profile of Dimethyl malonate supports its continued use in various applications, provided that proper handling guidelines are followed to avoid unnecessary exposure. ²

Reference

1. Carlström M, Rannier Ribeiro Antonino Carvalho L, Guimaraes D, Boeder A, Schiffer TA. Dimethyl malonate preserves renal and mitochondrial functions following ischemia-reperfusion via inhibition of succinate dehydrogenase. Redox Biol. 2024; 69: 102984.

2. National Center for Biotechnology Information (2024). PubChem Compound Summary for CID 7943, Dimethyl malonate.