Review: Oxidant—antioxidant imbalance in asthma: scientific evidence, epidemiological data and possible therapeutic options

Prevalence of asthma has increased considerably in recent decades throughout the world especially in developed countries. Airway inflammation is thought to be prime cause for repeated episodes of airway obstruction in asthmatics. Several studies have shown that reactive oxygen species (ROS) play a key role in initiation as well as amplification of inflammation in asthmatic airways. Excessive ROS production in asthma leads to alteration in key enzymatic as well as nonenzymatic antioxidants such as glutathione, vitamins C and E, beta-carotene, uric acid, thioredoxin, superoxide dismutases, catalase, and glutathione peroxidases leading to oxidant—antioxidant imbalance in airways. Oxidant—antioxidant imbalance leads to pathophysiological effects associated with asthma such as vascular permeability, mucus hypersecretion, smooth muscle contraction, and epithelial shedding. Epidemiological data also support the scientific evidence of oxidant—antioxidant imbalance in asthmatics. Therefore, the supplementation of antioxidants to boost the endogenous antioxidants or scavenge excessive ROS production could be utilized to dampen/prevent the inflammatory response in asthma by restoring oxidant—antioxidant balance. This review summarizes the scientific and epidemiological evidence linking asthma with oxidant—antioxidant imbalance and possible antioxidant strategies that can be used therapeutically for better management of asthma

Involvement of nitric oxide (NO) in the regulation of stress susceptibility and adaptation in rats

809-815The present study evaluated the regulatory role of nitric oxide (NO) in stress susceptibility and adaptation in rats. Acute restraint stress (RS ×1) reduced the number of entries and time spent in the open arms in the elevated plus maze (EPM) test and raised plasma corticosterone levels. RS (×1)-induced neurobehavioral suppression and raised corticosterone levels were attenuated by pretreatment with the NO precursor, L-arginine (500 and 1000 mg/kg)and unaffected or further aggravated by NO synthase inhibitor, L-NAME or 7-nitroindazole (10 and 50 mg/kg). Biochemical assay of plasma and brain homogenates showed that these RS – induced behavioral and neuroendocrinal changes were associated with lowered levels of plasma and brain total nitrates/nitrites (NOx). L-Arginine attenuated the RS-induced suppression of NOx levels in plasma and brain, whereas, the NO synthase inhibitors tended to produce reverse effects. In the experiments involving repeated stress i.e. RS (×5), exposure resulted in attenuation/reversal of (a) neurobehavioral suppression in the EPM test and (b) lowered brain NOx, that was seen after RS (×1). The RS (×5)-induced changes in EPM parameters and brain Nox were further potentiated after L-arginine pretreatment, whereas, the NO synthase inhibitors were less effective. Rats were screened as high and low emotional in the open-field test, and high emotional rats showed greater(a) behavioral suppression in the EPM, (b) corticosterone responses (c) brain NOx suppression, and (d) cold-restraint stress (CRS) induced gastric mucosal lesions as compared to their low emotional counterparts. L-Arginine pretreatment was more effective in modulating the above RS induced stress responses/markers in the high emotional group of rats. Our data suggest that NO plays a differential role during exposure to acute and repeated stress situations, and that the relationship between stress and emotionality status may be under the regulatory influence of NO

Anxiolytic Effects of Phosphodiesterase-2 Inhibitors Associated with Increased cGMP Signaling

Phosphodiesterase (PDE)-2 is a component of the nitric-oxide synthase (NOS)/guanylyl cyclase signaling pathway in the brain. Given recent evidence that pharmacologically induced changes in NO-cGMP signaling can affect anxiety-related behaviors, the effects of the PDE2 inhibitors (2-(3,4-dimethoxybenzyl)-7-det-5-methylimidazo-[5,1-f][1,2,4]triazin-4(3H)-one) (Bay 60-7550) and 3-(8-methoxy-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)benzamide (ND7001), as well as modulators of NO, were assessed on cGMP signaling in neurons and on the behavior of mice in the elevated plus-maze, hole-board, and open-field tests, well established procedures for the evaluation of anxiolytics. Bay 60-7550 (1 μM) and ND7001 (10 μM) increased basal and N-methyl-d-aspartate- or detanonoate-stimulated cGMP in primary cultures of rat cerebral cortical neurons; Bay 60-7550, but not ND7001, also increased cAMP. Increased cGMP signaling, either by administration of the PDE2 inhibitors Bay 60-7550 (0.5, 1, and 3 mg/kg) or ND7001 (1 mg/kg), or the NO donor detanonoate (0.5 mg/kg), antagonized the anxiogenic effects of restraint stress on behavior in the three tests. These drugs also produced anxiolytic effects on behavior in nonstressed mice in the elevated plus-maze and hole-board tests; these effects were antagonized by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (20 mg/kg). By contrast, the NOS inhibitor Nω-nitro-l-arginine methyl ester (50 mg/kg), which reduces cGMP signaling, produced anxiogenic effects similar to restraint stress. Overall, the present behavioral and neurochemical data suggest that PDE2 may be a novel pharmacological target for the development of drugs for the treatment of anxiety disorders