Radical scavenging compound J 811 inhibits hydrogen peroxide‐induced death of cerebellar granule cells

Abstract

Oxidative stress is considered to be an important pathophysiological condition to promote cell death in a broad variety of disorders, such as cardiovascular and neurodegenerative diseases. Scavestrogens, structurally derived from estradiol, are potent radical scavengers and inhibitors of iron-induced cell damage in vitro. In this study the potential cytoprotective effects of the so-called scavestrogen estra-1,3,5(10),8-tetraene-3,17alpha-diol, J 811, was tested using rat cerebellar granule cells (CGCs) exposed to 25 or 50 microM hydrogen peroxide (H2O2). H2O2-induced apoptotic cell death was detected by the appearance of high molecular weight DNA fragments and nuclear condensation. The addition of J 811 before or shortly after the exposure to H2O2 prevented CGC apoptosis in a dose-dependent manner. The estrogen receptor antagonist ICI 182.780 failed to prevent the protective effect of J 811, suggesting that the latter is not dependent on estrogen receptor activation. The lack of protection against apoptosis caused by colchicine suggests that J 811 is neither interfering with the activation of caspase-3, nor acting downstream of caspase-3. Therefore, the protective effect observed against H2O2 seems to be upstream caspases activation, pointing to a scavenging action of J 811. Thus the scavestrogen J 811 is a powerful antioxidant able to interfere with radical-mediated cell death and is potentially useful in diseases where reactive oxygen species are involved.

PACAP protects cerebellar granule neurons against oxidative stress‐induced apoptosis

“…It has been previously reported that oxidative stress induced by H 2 O 2 causes apoptosis of different types of nerve cells, including granule cells (Bhat & Zhang, 1999; Gotz et al ., 1999; Mailly et al ., 1999; Wei et al ., 2000). We have recently demonstrated that PACAP promotes the survival of immature granule cells (Gonzalez et al ., 1997) through inhibition of caspase‐3 activity (Vaudry et al ., 2000b).…”

Protective Effect Of Resveratrol On Oxidative Damage In Male And Female Stroke‐Prone Spontaneously Hypertensive Rats

“…Free radicals and other active compounds have been suggested to be involved in many biological processes, including ageing and various chronic diseases. Oxidative stress originates as the result of an imbalance between the generation of ROS, such as superoxide (O 2 • – ), hydroxy radicals (HO•) and hydrogen peroxide (H 2 O 2 ), and cellular anti‐oxidants 1,19 . These ROS, if not scavenged in a timely fashion, may cause oxidative damage to macromolecules, such as DNA 20 .…”

Prenatal exposure to high levels of glucocorticoids increases the susceptibility of cerebellar granule cells to oxidative stress-induced cell death

“…Both H 2 O 2 and MeHg cause an increase in intracellular reactive oxygen species and intracellular Ca 2ϩ (30,31). Instead, the toxic effects of colchicine are mainly at the cytoskeletal level and cannot be blocked by antioxidants (15) or Ca 2ϩ channel blockers (12).…”

“…On day 7, cell viability was analyzed by evaluating living cell permeability to impermeant DNA dies. Cells then were exposed for 24 h to 25 M H 2 O 2, 1 M MeHg, or 1 M colchicine, stimuli inducing chromatin condensation and appearance of high molecular weight DNA fragments (12)(13)(14)(15)(16). For biochemical analyses on unexposed cells, CGC were collected after 1 week in culture.…”

“…Cerebellar granule cells (CGC) prepared from 1-week-old rats exposed in utero to the synthetic glucocorticoid dexamethasone, which is poorly metabolized by 11 ␤-hydroxysteroid dehydrogenase, were exposed to stimuli that mimic conditions occurring in neurodegeneration and that we have previously shown to induce apoptosis in CGC (12)(13)(14)(15)(16). H 2 O 2 and methylmercury(MeHg) were used to induce oxidative stress, which is known to be involved in age-related disorders and the pathogenesis of a variety of neurological and neurodegenerative conditions, such as Alzheimer's disease (17), Parkinson's disease (18) and amyotrophic lateral sclerosis (19).…”