Free radicals and antioxidants in human health: current status and future prospects.

Free radicals and related species have attracted a great deal of attention in recent years. They are mainly derived from oxygen (reactive oxygen species/ROS) and nitrogen (reactive nitrogen species/RNS), and are generated in our body by various endogenous systems, exposure to different physicochemical conditions or pathophysiological states. Free radicals can adversely alter lipids, proteins and DNA and have been implicated in aging and a number of human diseases. Lipids are highly prone to free radical damage resulting in lipid peroxidation that can lead to adverse alterations. Free radical damage to protein can result in loss of enzyme activity. Damage caused to DNA, can result in mutagenesis and carcinogenesis. Redox signaling is a major area of free radical research that is attracting attention. Nature has endowed us with protective antioxidant mechanisms- superoxide dismutase (SOD), catalase, glutathione, glutathione peroxidases and reductase, vitamin E (tocopherols and tocotrienols), vitamin C etc., apart from many dietary components. There are epidemiological evidences correlating higher intake of components/ foods with antioxidant abilities to lower incidence of various human morbidities or mortalities. Current research reveals the different potential applications of antioxidant/free radical manipulations in prevention or control of disease. Natural products from dietary components such as Indian spices and medicinal plants are known to possess antioxidant activity. Newer and future approaches include gene therapy to produce more antioxidants in the body, genetically engineered plant products with higher level of antioxidants, synthetic antioxidant enzymes (SOD mimics), novel biomolecules and the use of functional foods enriched with antioxidants.

Effects of prenatal cocaine on hearing, vision, growth, and behavior.

The illicit use of cocaine has increased dramatically over the last 10-12 years. There has been a corresponding increase in cocaine abuse among obstetric patients and in the number of "cocaine babies." According to some estimates, these children make up more than half of the drug-associated births. This problem is therefore a major public health concern. Consequently, our laboratory investigated the effects of prenatal cocaine exposure on hearing, vision, growth, and exploratory/stress behavior. This chapter summarizes the literature on animals and humans on these topics and presents new observations from our laboratory. In terms of maternal toxicity, prenatal cocaine exposure causes hypertension, placental abruption, spontaneous abortion, poor pregnancy weight gain, and undernutrition secondary to appetite suppression. Some offspring effects include in utero growth retardation, cephalic hemorrhage, fetal edema, altered body composition, congenital malformations, and even pre- and postnatal death. The offspring can also exhibit a variety of behavioral, visual, hearing, and language disorders. Differential effects of animal strain and late gestational cocaine exposure are discussed. Comparisons are made between prenatal cocaine, the fetal alcohol syndrome, and the effects of prenatal undernutrition. Recommendations for clinical assessment and intervention are made.

Sulpiride-induced increases in serum prolactin levels in female rats exposed prenatally to alcohol.

We examined the impact of prenatal alcohol exposure on serum prolactin levels and on the ability of the D2 dopamine antagonist sulpiride to stimulate prolactin release in Long-Evans rats. Pregnant rats were intubated with alcohol (0, 3, or 5 g/kg/day) from gestational day 8 (GD8) to GD20. Adult female offspring were screened for estrous cycle stage. At diestrus, the rats were challenged with a single dose of sulpiride (0, 10, or 40 micrograms/kg) and trunk blood was collected 20 min later. After prenatal exposure to either dose of alcohol, mean basal serum levels of prolactin were about 65% less than the 0 g/kg group, and the 35-40% mean differences from an untreated control group were not significant. Sulpiride produced dramatic dose-dependent increases in serum prolactin levels in all prenatal treatment groups. Across all doses of sulpiride, the group given the higher dose of prenatal alcohol (5 g/kg/day) had significantly lower serum prolactin levels than all other groups. There was no significant interaction between prenatal treatment and sulpiride dose. Neither prenatal alcohol exposure nor sulpiride injections had significant effects on serum corticosterone levels in this study. Although the current results are unclear regarding a baseline decrease in prolactin levels after prenatal alcohol exposure, the overall results suggest that prenatal alcohol exposure decreases prolactin levels but there is no evidence that it does so by altering dopaminergic tone in hypothalamus of female rats.

Differential effects of prenatal cocaine and retinoic acid on activity level throughout day and night.

Prenatal cocaine exposure is associated with disrupted state control and lowered activity levels. Prenatal retinoic acid excess also influences activity levels in laboratory rats. Activity level is usually monitored during a brief period in young offspring. The effects of these drugs on pup activity levels throughout the day is unknown. There is also little information on the long-lasting effects of these teratogens in adult animals. We compared the daily activity of rats which were prenatally exposed to cocaine or retinoic acid (RA). Appropriate control groups were also used. The offspring were evaluated for activity levels in a neophobic situation and for a 22-h period in same-sex groups of 3 littermates. As both pups and adults, the cocaine groups were hypoactive while the RA group was hyperactive when first placed into the testing cage (neophobic situation). Similarly, during the remainder of the 22-h testing period, the pup and adult cocaine animals exhibited reduced activity levels while the RA animals exhibited elevated activity levels. Thus, prenatal cocaine and retinoic acid exposures affected offspring activity levels differently, both drugs have long-lasting neurobehavioral effects that persist into adulthood, and effects are influenced by time-of-day. Strain-dependent differences and mechanisms of action are discussed.

Interactive effects of prenatal alcohol and cocaine exposures on postnatal mortality, development and behavior in the Long-Evans rat.

Polydrug abuse has increased substantially in recent years amongst obstetric patients. One of the most common drug combinations is alcohol and cocaine. To better understand the adverse consequences of this drug combination on pregnancy and the offspring, alcohol (2 g/kg, b.i.d.) and cocaine HCl (30 mg/kg, b.i.d.) were administered individually and in combination to separate groups of pregnant Long-Evans rats from gestation days 7-20. The pregnant dams were evaluated for maternal weight gain, food and water consumption, mortality, and gestational length. The offspring were evaluated for physical maturation, mortality, and behavior. The drug combination was found to have greater effects regarding decreased birth weight, increased postnatal mortality, and delayed physical maturation than either drug alone. Drug treatments also influenced activity monitor behavior in that prenatal cocaine exposure was associated with hypoactivity while the alcohol and the alcohol-plus-cocaine treatments were associated with hyperactivity in periweanling pups. Drug treatments had no significant effects on passive or active avoidance behaviors. These results suggest that combining alcohol and cocaine increases the risk to the offspring.