Basal Ganglia Degeneration, Myelin Alterations, and Enzyme Inhibition Induced in Mice by the Plant Toxin 3‐nitropropanoic Acid

Abstract

The plant toxin, 3-nitropropanoic acid, produced topographically and morphologically distinctive lesions in mice after daily intraperitoneal injections. In the lateral caudate-putamen there were bilateral and symmetrical lesions consisting of marked swelling and pyknosis of individual cells and processes in otherwise unaffected tissue. The appearance of transitional forms and the usual post-synaptic location of the swollen processes indicated that affected cells were neurons. A few mice exhibited a more diffuse spongy change in the lateral caudate-putamen that caused major architectural changes. In the globus pallidus, entopeduncular nucleus, and anterior substantia nigra pars reticulata there was fine spongy change of the neuropil that spared cell bodies, and was primarily due to swelling of dendrites. A third lesion pattern in myelinated tracts of the midbrain, medulla, and spinal cord consisted of adaxonal, intramyelinic cleft formation. Succinate dehydrogenase activities assayed in frozen brain sections and in isolated mitochondria were markedly reduced in intoxicated mice.

Excitotoxicity is Required for Induction of Oxidative Stress and Apoptosis in Mouse Striatum by the Mitochondrial Toxin, 3-Nitropropionic Acid

“…Be cause mitochondrial energy toxins cause histotoxic hyp oxia, it is of interest that lesions with mitochondrial tox ins share several attributes with ischemic brain damage, such as excitotoxicity. 3-NP may also produce neuro pathologic changes similar to those induced by hypoxic and ischemic diseases (Gould and Gustine, 1982). It has also been reported that oxidative stress plays a substan tial role in the neurotoxicity of 3-NP-induced neuronal injury.…”

Mitochondrial Toxin 3-Nitropropionic Acid Induces Cardiac and Neurotoxicity Differentially in Mice

“…3NPA induces neurodegeneration in the caudate putamen in humans and experimental animals, resembling Huntington's disease. [3][4][5][6][7][8] Consequently, 3NPA poisoning is used primarily as an animal model of selective neurodegeneration. The mechanism of toxicity is thought to be because of the irreversible, covalent binding of 3NPA with subsequent inhibition of succinate dehydrogenase (SDH), an enzyme of the citric acid cycle that transfers electrons to the electron transport chain via its complex II function.…”

A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia.

“…The most common LHON mutations occur in complex I genes and include a G-to-A transition at nucleotide pair (np) 3460 in ND1 (6, 7); a G-to-A transition at np 11778 in ND4 (8); and a T-to-C transition at np 14484 in ND6 (9-13). Leigh syndrome is a rapidly progressive, childhood neurodegenerative disease associated with symmetric basal ganglia lesions that has been shown to result in a number of cases from mutations at np 8993 within the mitochondrial ATPase 6 gene (14)(15)(16)(17) (24), and chronic treatment of mammals with the complex IV inhibitor sodium azide (25) or the complex II inhibitor 3-nitropropanoic acid (26,27) produces basal ganglia lesions in primates and rodents similar to those seen on computerized tomography (CT) and magnetic resonance imaging analysis of severely affected LHON and dystonia patients (1,5).…”