Toxicity Summary
3-Nitropropionic acid is a suicide inhibitor of succinate dehydrogenase, an enzyme required for the activity of the tricarboxylic acid (TCA) cycle as well as mitochondrial respiratory complex II of the electron transport chain. It forms a covalent adduct with the side chain of Arg297, inactivating the succinate dehydrogenase. This affects neurons by leading to NMDA-receptor activation, excessive calcium influx, and formation of reactive oxygen species, eventually causing neuronal cell death. (A2967, A2968)

---

Interactions
Systemic administration of 3-nitropropionic acid (3-NPA, a mycotoxin) induces brain damage accompanied by disturbance in the blood-brain barrier (BBB). Since the endothelial cells are important components of the BBB and the first target of a systemic intoxication, in the present study, the effect of 3-NPA on primary cultured rat brain endothelial cells (rBECs) was examined by studying intracellular Ca2+ ([Ca2+]i) response using imaging techniques. Data indicate that a medium to high concentration of 3-NPA induces damage on rBECs as revealed by an accumulation of [Ca2+]i, but the damage was protected by cotreatment with 17 beta-estradiol or tamoxifen, suggesting that estrogen may be protective for the brain vascular damage via estrogen receptor.
The role of impaired mitochondrial function in processes leading to the generation of seizures was studied in mice. An inhibitor of mitochondrial complex III, 3-nitropropionic acid, which is known to evoke convulsions per se, and was used here in subthreshold dose, enhanced seizures generated by electric current and application of 4-aminopyridine. In contrast, 3-nitropropionic acid did not affect convulsions induced by gamma-aminobutyric acid (GABA) receptor antagonists - bicuculline, pentylenetetrazol and picrotoxin, glycine antagonist - strychnine, cholinomimetic drug-pilocarpine, and kynurenine aminotransferase inhibitor - aminooxyacetic acid. It is hypothesised that deranged mitochondrial metabolism renders the central nervous system more susceptible to factors inducing seizures via direct depolarization.
There is currently no effective treatment for Huntington's disease (HD), a progressive, fatal, neurodegenerative disorder characterized by motor & cognitive deterioration. It is well established that Huntington's disease is associated with perturbation of mitochondrial energy metab. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile acid, can stabilize the mitochondrial membrane, inhibit the mitochondrial permeability transition, decrease free radical formation, & derail apoptotic pathways. Here we report that tauroursodeoxycholic acid significantly reduced 3-nitropropionic acid (3-NPA) mediated striatal neuronal cell death in cell culture, In addition, rats treated with tauroursodeoxycholic acid exhibited an 80% reduction in apoptosis & in lesion volumes associated with 3-nitropropionic acid admin. Moreover, rats which received a combination of tauroursodeoxycholic acid + 3-nitropropionic acid exhibited sensor/motor & cognitive task performance that was indistinguishable from that of controls, & this effect persisted at least 6 months. Bile acids have traditionally been used as therapeutic agents for certain liver diseases. This is the first demonstration, however, that a bile acid can be delivered to the brain & function as a neuroprotectant & thus may offer potential therapeutic benefit in the treatment of certain neurodegenerative diseases.

---

Non-Human Toxicity Values
LD50 Rat ip 67 mg/kg
LD50 Mouse iv 50 mg/kg

[1]. 3-nitropropionic acid is a suicide inhibitor of mitochondrial respiration that, upon oxidation by complex II, forms a covalent adduct with a catalytic base arginine in the active site of the enzyme. J Biol Chem. 2006 Mar 3;281(9):5965-72.

[2]. 3-Nitropropionic acid (3-NPA), a potent antimycobacterial agent from endophytic fungi: is 3-NPA in some plants produced by endophytes? J Nat Prod. 2005 Jul;68(7):1103-5.

[3]. 3-Nitropropionic acid induces autophagy by forming mitochondrial permeability transition pores rather than activating the mitochondrial fission pathway. Br J Pharmacol. 2013 Jan;168(1):63-75.

[4]. Effect of 3-nitropropionic acid inducing oxidative stress and apoptosis of granulosa cells in geese. Biosci Rep. 2018 Sep 12;38(5):BSR20180274.

[5]. Pang Z, Geddes JW. Mechanisms of cell death induced by the mitochondrial toxin 3-nitropropionic acid: acute excitotoxic necrosis and delayed apoptosis. J Neurosci. 1997 May 1;17(9):3064-73.

[6]. Protective effect of melatonin on 3-nitropropionic acid-induced oxidative stress in synaptosomes in an animal model of Huntington's disease. J Pineal Res. 2004 Nov;37(4):252-6.

[7]. A. Mitochondrial toxin 3-nitropropionic acid evokes seizures in mice. Eur J Pharmacol. 1998 Oct 16;359(1):55-8.

3-nitropropionic acid appears as golden crystals (from chloroform). (NTP, 1992)
3-nitropropanoic acid is a C-nitro compound that is propanoic acid in which one of the methyl hydrogens has been replaced by a nitro group. It has a role as a neurotoxin, an EC 1.3.5.1 [succinate dehydrogenase (quinone)] inhibitor, an antimycobacterial drug and a mycotoxin. It is functionally related to a propionic acid. It is a conjugate acid of a 3-nitropropanoate. It is a tautomer of a 3-aci-nitropropanoic acid.
3-Nitropropionic acid has been reported in Phomopsis velata, Penicillium atrovenetum, and other organisms with data available.
Bovinocidin is isolated from Aspergillus sp. and moulds contaminating food

Bovinocidin belongs to the family of Beta Amino Acids and Derivatives. These are amino acids having a (-NH2) group attached to the beta carbon atom.

---

Mechanism of Action
3-Nitropropionic acid (3-NP), a naturally occurring mycotoxin, is an irreversible inhibitor of succinate dehydrogenase that produces adenosine triphosphate (ATP) depletion in cerebral cortical explants and is associated with motor disorders in livestock and humans that have ingested contaminated food.
Previous studies indicate that 3-nitropropionic acid (3-NPA) neurotoxicity involves the excitotoxic activation of N-methyl-D-aspartate (NMDA) receptors. Thus, ... the effect of orphenadrine ... on N-methyl-D-aspartate neurotoxicity in both cultured rat cerebellar granule cells (CGCs) & in rats /was studied/. Orphenadrine protected cerebellar granule cells from N-methyl-D-aspartate induced mortality, as assessed by both the neutral red viability assay & laser scanning cytometry, using propidium iodide staining. For rats, two indirect markers of neuronal damage were used: the binding of ((3)H)-PK 11195 to the peripheral type benzodiazepine receptor (PBR), a microglial marker, & expression of the 27 kD heat shock protein (HSP27), a marker of activated astroglia. Systemic admin of N-methyl-D-aspartate (30 mg/kg/day for 3 days) induced a 170% incr in ((3)H)-PK 11195 binding, & expression of 27 kD heat shock protein. Both the incr in ((3)H)-PK 11195 & HSP 27 expression were prevented by previous admin of 30 mg/kg/day of orphenadrine for 3 days. Lower doses (10 & 20 mg/kg) had no protective effect. Orphenadrine also reduced N-methyl-D-aspartate induced mortality in a dose dependent manner. ... Orphenadrine or orphenadrine like drugs could be used to treat neurodegenerative disorders mediated by overactivation of N-methyl-D-aspartate receptors.
The present study investigated the mechanism of cellular degeneration within the striatum following administration of the mitochondrial toxin, 3-nitropropionic (3-NP) acid. Internucleosomal fragmentation typical of apoptosis was present in the DNA of cells from the striatum of 3-NP-treated rats. DNA fragmentation was also evident in this region by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling. The data suggest that striatal cells die by apoptosis following administration of 3-NP.
3-nitropropionic acid blocks energy metabolism prior to exerting neurotoxic damage and the degree of energy depletion determines the detrimental effects of 3-nitropropionic acid. In the present study, we also demonstrate that glutamate and glutamine levels as well as astrocytic functions may play pivotal roles in 3-nitropropionic acid-induced striatal lesions.
For more Mechanism of Action (Complete) data for 3-NITROPROPIONIC ACID (15 total), please visit the HSDB record page.

C3H5NO4

119.0761

119.021

504-88-1

1678

White to yellow solid powder

1.4±0.1 g/cm3

303.0±25.0 °C at 760 mmHg

68-70ºC(lit.)

148.4±11.6 °C

0.0±1.4 mmHg at 25°C

1.463

-0.08

1

4

2

8

104

0

WBLZUCOIBUDNBV-UHFFFAOYSA-N

InChI=1S/C3H5NO4/c5-3(6)1-2-4(7)8/h1-2H2,(H,5,6)

3-nitropropanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

DMSO : ~125 mg/mL (~1049.71 mM)
H2O : ~100 mg/mL (~839.77 mM)

Solubility in Formulation 1: ≥ 2.17 mg/mL (18.22 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 21.7 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.

---

Solubility in Formulation 2: ≥ 2.08 mg/mL (17.47 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 20.8 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.

---

View More

Solubility in Formulation 3: ≥ 2.08 mg/mL (17.47 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

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