Mechanisms of Action of 3-Nitropropionic Acid

Abstract

Neurons in the CA1 hippocampus, striatum, or reticular nucleus of the thalamus are most often damaged during brain ischemia. An abundant glutamatergic innervation that drives excitotoxity and the vulnerability of γ-aminobutyric acid-ergic (GABAergic) neurons to such stress has been suggested for the neuronal cell death of these areas (1–4). Intoxication with 3-nitropropionic acid (3-NPA), a mycotoxin that inhibits succinate dehydrogenase irreversibly, leads to high-energy (ATP) deficiency (5–7) and production of free radicals (8, 9), thus results in cellular hypoxia and cellular damage. Systemic intoxication with 3-NPA induces striatum-selective lesions with motor symptoms, reminiscent of Huntington’s disease (10–13). Enhancement of excitotoxicity (5–7) and breakdown of the blood-brain barrier (14–17) have been suggested but mechanisms are not yet well understood. 3-NPA-induced striatal lesions are located in the lateral part of the striatum associated with dysfunction of the blood-brain barrier (17). This suggests that specific mechanisms are operating in this area of the brain. In this chapter, we propose that the dopamine (DA) toxicity due to DA overflow and the vulnerability of the lateral striatal (1STR) artery resulting from damage to endothelial cells and end-feet of astrocytes contribute to development of striatum-selective lesions following systemic 3-NPA intoxication. These characteristics may be major predisposing factors for neurodegenerative diseases, autoimmune diseases, or stroke that often affect the striatum.