arl-17477 and Brain-Injuries

Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features leading to neuronal death in cerebral ischemia, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nitric oxide (NO) alone or in cooperation with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of NO synthase (NOS) inhibitors and mutant mice lacking each NOS isoform have provided evidence for the injurious effects of NO derived from neuronal or inducible isoforms. New neuroprotective strategies have been proposed with selective NOS inhibitors for the neuronal (ARL17477) or the inducible (1400 W) isoforms or with compounds combining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in experimental ischemia-induced acute neuronal damage. The efficacy of these new strategies is well established in acute neuronal injury but remains to be determined in more chronic neurological diseases.

Topics: Alzheimer Disease; Amidines; Amyotrophic Lateral Sclerosis; Animals; Benzylamines; Brain Injuries; Brain Ischemia; Enzyme Induction; Humans; Huntington Disease; Mice; Mice, Neurologic Mutants; Mice, Transgenic; Nerve Degeneration; Nerve Tissue Proteins; Nervous System Diseases; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Organ Specificity; Polymethacrylic Acids; Pyrazines; Thiophenes

Prolonged hypothermic circulatory arrest (HCA) causes neurologic injury. However, the mechanism of this injury is unknown. We hypothesized that HCA causes nitric oxide production to result in neuronal necrosis. This study was undertaken to determine whether the neuronal nitric oxide synthase inhibitor 17477AR reduces necrosis after HCA.. Thirty-two dogs underwent 2 hours of HCA at 18 degrees C. Nitric oxide synthase catalytic assay and intracerebral microdialysis for nitric oxide production were performed in acute nonsurvival experiments (n = 16). Sixteen animals survived for 72 hours after HCA: Group 1 (n = 9) was treated with 17477AR (Astra Arcus), and group 2 (n = 7) received vehicle only. Animals were scored from 0 (normal) to 500 (coma) for neurologic function and from 0 (normal) to 100 (severe) for neuronal necrosis.. Administration of 17477AR reduced nitric oxide production in the striatum by 94% (HCA alone), 3.65+/-2.42 micromol/L; HCA and 17477AR, 0.20+/-0.14 micromol/L citrulline). Dogs treated with 17477AR after HCA had superior neurologic function (62.22+/-29.82 for group 1 versus 141.86+/-61.53 for group 2, p = 0.019) and significantly reduced neuronal necrosis (9.33+/-4.67 for group 1 versus 38.14+/-2.23 for group 2, p<0.00001) compared with untreated HCA dogs.. Our results provide evidence that neuronal nitric oxide synthase mediates neuronal necrosis after HCA and plays a significant role in HCA-induced neurotoxicity. Pharmacologic strategies to inhibit neuronal nitric oxide synthase after the ischemic period of HCA may be clinically beneficial.

Topics: Amidines; Animals; Brain Injuries; Dogs; Enzyme Inhibitors; Heart Arrest, Induced; Hypothermia, Induced; Male; Microdialysis; Necrosis; Neurons; Nitric Oxide Synthase