nitroarginine and Amyotrophic-Lateral-Sclerosis

The development of new therapeutics for the treatment of neurodegenerative pathophysiologies currently stands at a crossroads. This presents an opportunity to transition future drug discovery efforts to target disease modification, an area in which much still remains unknown. In this Perspective we examine recent progress in the areas of neurodegenerative drug discovery, focusing on some of the most common targets and mechanisms: N-methyl-d-aspartic acid (NMDA) receptors, voltage gated calcium channels (VGCCs), neuronal nitric oxide synthase (nNOS), oxidative stress from reactive oxygen species, and protein aggregation. These represent the key players identified in neurodegeneration and are part of a complex, intertwined signaling cascade. The synergistic delivery of two or more compounds directed against these targets, along with the design of small molecules with multiple modes of action, should be explored in pursuit of more effective clinical treatments for neurodegenerative diseases.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Antioxidants; Calcium Channels; Drug Combinations; Drug Design; Humans; Huntington Disease; Neurodegenerative Diseases; Nitric Oxide Synthase Type I; Oxidative Stress; Parkinson Disease; Protein Folding; Protein Structure, Quaternary; Proteostasis Deficiencies; Receptors, N-Methyl-D-Aspartate

Autoradiography with [3H]nitro-L-arginine (3HL-NNA) was used to quantify nitric oxide synthase (NOS), and immunocytochemistry to identify NOS isoforms, in spinal cord in amyotrophic lateral sclerosis (ALS) and controls.. In controls NOS binding was marked only in the superficial dorsal horn, but in ALS tissue it was intense throughout the grey and white matter. A single population of binding sites was indicated in controls, but two populations in ALS. In the controls intense neuronal NOS (nNOS) immunoreactivity was present in numerous cells in the dorsal horn, and faint immunoreactivity in small and medium-sized cells in the ventral horn. Only weak immunoreactivity for inducible NOS (iNOS) and endothelial NOS (eNOS) was detectable in control tissue. In ALS, the pattern was broadly similar in the grey matter, but immunoreactivity for both nNOS and iNOS was present in white matter.. Expression of abnormal variants of nNOS or increased expression of iNOS may have a role in motoneuron death in ALS.

Topics: Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Autoradiography; Cell Count; Enzyme Inhibitors; Female; Humans; Immunohistochemistry; Male; Middle Aged; Motor Neurons; Nerve Degeneration; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroarginine; Spinal Cord; Tritium

The expression of nitric oxide synthase was studied in human postmortem cervical spinal cord from four individuals with amyotrophic lateral sclerosis (ALS) and four individuals who had died from non-neurological causes. A novel autoradiographic method employing [3H]nitro-L-arginine, a potent inhibitor of the enzyme, as the binding ligand, was used. The expression was quantified in four discrete subregions of the grey matter, and in the dorsal and ventral white matter. The maximum density of binding in the superficial dorsal, deeper dorsal horn, and intermediate subregions of the grey matter was similar in ALS and control tissue, but it was higher in the ALS tissue, in the ventral horn, and in the dorsal and ventral white matter, compared to the corresponding regions in the control tissue. Saturation analysis of the binding indicated a single population of high affinity binding sites in all subregions in the control tissue. However, in the ALS tissue, in all subregions, the presence of two populations of binding sites with different ligand binding affinities were indicated. It is possible therefore that the expression of an inducible isotype of nitric oxide synthase may contribute to the neuropathic changes seen in ALS.

Topics: Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Autoradiography; Cell Count; Female; Humans; Male; Middle Aged; Motor Neurons; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitroarginine; Spinal Cord; Tritium