stilbenes and 3-nitropropionic-acid

Currently, there is no effective treatment for neurological complications of infection with the human immunodeficiency virus that persists despite the use of combination antiretroviral therapy. A medium throughput assay was developed for screening neuroprotective compounds using primary mixed neuronal cells and mitochondrial toxin 3-nitropropionic acid. Using this assay, a library of 2,000 compounds was screened. Out of 256 compounds that showed variable degrees of neuroprotection, nine were related to epicatechin, a monomeric flavonoid found in cocoa and green tea leaves that readily crosses the blood-brain barrier. Hence, catechin, epicatechin, and the related compound, epigallocatechin gallate (EGCG) were further screened for their neuroprotective properties against HIV proteins Tat and gp120, and compared to those of resveratrol. Epicatechin and EGCG targets the brain-derived neurotrophic factor (BDNF) and its precursor proBDNF signaling pathways, normalizing both Tat-mediated increases in proapoptotic proBDNF and concomitant Tat-mediated decreases in the mature BDNF protein in hippocampal neurons. Epicatechin and epigallocatechin gallate were more potent than catechin or resveratrol as neuroprotectants. Due to its simpler structure and more efficient blood-brain barrier penetration properties, epicatechin might be the best therapeutic candidate for neurodegenerative diseases including HIV-associated neurocognitive disorders where oxidative stress is an important pathophysiological mechanism.

Topics: Animals; Anti-HIV Agents; Brain-Derived Neurotrophic Factor; Catechin; Embryo, Mammalian; Gene Expression Regulation; High-Throughput Screening Assays; Hippocampus; HIV Envelope Protein gp120; Humans; Mitochondria; Neurons; Neuroprotective Agents; Nitro Compounds; Oxidative Stress; Primary Cell Culture; Propionates; Protein Precursors; Rats; Resveratrol; Signal Transduction; Stereoisomerism; Stilbenes; tat Gene Products, Human Immunodeficiency Virus

Oxidative stress and secondary excitotoxicity, due to cellular energy deficit, are major factors playing roles in 3-nitropropionic acid (3-NPA) induced mitochondrial dysfunction. Acute or chronic exposure to 3-NPA also leads to neuronal degeneration in different brain regions. The present study quantitatively assessed peripheral neuropathy induced by chronic exposure to 3-NPA in rats. The neuroprotective abilities of two antioxidants, acetyl-l-carnitine and resveratrol, were investigated as well. Rats were exposed for up to four weeks to 3-NPA alone or 3-NPA combined with acetyl-l-carnitine or resveratrol, administered peripherally. The experimental outcome was evaluated by neurophysiological, histological, and morphometric analyses. Rats exposed to 3-NPA developed hind limb paresis. Furthermore, a significant decrease in motor nerve conduction velocity (MCV) was detected in tail nerves and axonal degeneration in sciatic nerves (p<0.05). Treatment with resveratrol prevented the functional effects of 3-NPA exposure, whereas treatment with acetyl-l-carnitine, preventing paresis, was not effective to MCV and morphological changes. These data suggest that resveratrol is a good candidate for treatment of metabolic neuropathy. The experimental outcome of this study shows that chronic treatment with 3-NPA in rats is relevant in development of an experimental model of toxic neuropathy.

Topics: Acetylcarnitine; Animals; Antioxidants; Axons; Environmental Pollutants; Male; Nerve Degeneration; Neural Conduction; Neuroprotective Agents; Nitro Compounds; Peripheral Nervous System Diseases; Propionates; Rats; Rats, Sprague-Dawley; Resveratrol; Sciatic Nerve; Stilbenes

Huntington's disease is a progressive, degenerative disease characterized by abnormal body movements called chorea, and a reduction of various mental abilities. 3-Nitropropionic acid, an inhibitor of complex II of the electron transport chain, causes Huntington's disease-like symptoms in rodents. Recently, it has been reported that oxidative stress, which is one of the pathological hallmarks of various neurodegenerative disorders, also plays an important role in the pathogenesis of Huntington's disease. The present study was designed to investigate effects of resveratrol, an antioxidant with cyclooxygenase I inhibitory activity, in the 3-nitropropionic acid-induced model of Huntington's disease. Intraperitoneal administration of 3-nitropropionic acid (20 mg/kg for 4 days) caused significant loss of body weight, a decline in motor function (locomotor activity, movement pattern and vacuous chewing movements) and poor retention of memory. Repeated treatment with resveratrol (5 and 10 mg/kg, orally), once daily for a period of 8 days beginning 4 days prior to 3-nitropropionic acid administration, significantly improved the 3-nitropropionic acid-induced motor and cognitive impairment. Biochemical analysis revealed that systemic 3-nitropropionic acid administration significantly increased lipid peroxidation, nitrite levels, and depleted reduced glutathione levels, and decreased succinate dehydrogenase activity in the brains of rats. The results of the present study indicate that resveratrol (5 and 10 mg/kg, orally) significantly reversed 3-nitropropionic acid-induced motor and cognitive impairment, and that the beneficial effects of resveratrol might be attributed to its antioxidant activity.

Topics: Animals; Antioxidants; Behavior, Animal; Brain; Cell Survival; Glutathione; Huntington Disease; Injections, Intraperitoneal; Lipid Peroxidation; Male; Motor Activity; Neurons; Neuroprotective Agents; Neurotoxins; Nitro Compounds; Propionates; Rats; Rats, Wistar; Resveratrol; Retention, Psychology; Stereotyped Behavior; Stilbenes; Succinate Dehydrogenase