3-Nitropropionic acid's lethal triplet: cooperative pathways of neurodegeneration

3-Nitropropionic acid (3-NP) is a mitochondrial toxin which interferes with ATP synthesis. Accidental ingestion of 3-NP by humans as well as other mammals results in neuronal degeneration within the basal ganglia and movement dysfunction characterized by dystonia, chorea, and hypokinesia. The selective degeneration of structures of the basal ganglia occurs despite the non-selective impairment of energy metabolism throughout the brain and body. These effects of 3-NP are shared with the genetic disorder Huntington's disease (HD), which is characterized by progressive neurodegeneration of the basal ganglia and choreic motor dysfunction. These similarities have prompted further investigation of 3-NP as an animal model of HD. Metabolic compromise with 3-NP causes neurodegeneration that involves three interacting processes: energy impairment, excitotoxicity, and oxidative stress. This triplet of cooperative pathways of neurodegeneration helps to explain 3-NP's regional selectivity of neurotoxicity to the basal ganglia. This mini-review will focus on the actions of 3-NP and the related compound, malonic acid (MA), in the central nervous system, with an emphasis on the more current findings regarding their mechanisms of action.     

Computational model of obsessive-compulsive disorder: examination of etiologic hypothesis and treatment strategies

Research has shown that obsessive compulsive disorder (OCD) is related to structural and functional abnormalities in the brain, and several authors have organized these findings into theories of OCD neuropsychiatric dysfunction. In this paper, these theories were used to develop a neural network model of OCD. OCD symptoms were hypothesized to result from a hyperactive orbitofrontal-striato-thalamic-orbitofrontal neural loop. The network was constructed and trained with a backpropagation algorithm, and it was then used to assess etiologic theories of OCD (e.g., basal ganglia dysfunction, inadequate dopaminergic inhibitory influence on basal ganglia and excessive input from the limbic system). The network was also observed in analogues of the treatment of OCD with serotonergic medications and behavior therapy. Results show that a) the network behaved both normally and abnormally, depending on what combinations of perceptual, motivational, and neurochemical inputs were presented to it; b) several etiologic mechanisms produced changes in the networks' behaviors similar to patients' subjective experiences of OCD symptoms; and c) different treatment strategies, both those modeled as pharmacologic and behavioral therapies, produced reductions in simulated OCD symptoms.     

Interferon-induced upregulation and cytoplasmic localization of Myc-interacting protein Nmi

Production of toxins A and B by Clostridium difficile is enhanced in a defined medium with biotin-limited conditions. In the present study compounds inhibitory to enhanced toxin production by a C. difficile strain were examined. Increases in biotin concentration from 0.05 nM to 50 nM accelerated growth and inhibited enhanced toxin production. Asparagine, glutamic acid and glutamine (10 mM) showed an effect on growth and toxin production similar to that of biotin. Lysine (10 mM) suppressed growth and inhibited toxin production. Addition of these toxin-inhibitory compounds within an incubation period of 2 days inhibited the enhanced toxin production, but later addition showed only slight inhibition of toxin production. Amino acids contained in the defined medium under the biotin-limited conditions were actively utilised in the presence of the three toxin-inhibitory amino acids, but in the presence of lysine, amino-acid utilisation was suppressed. Different mechanisms of action of these toxin-inhibitory molecules, which may be divided into excess biotin, asparagine-glutamic acid-glutamine group, and lysine, are discussed.