Role of oxygen free radicals in cocaine‐induced vascular disruption in mice

Abstract

To test the hypothesis that cocaine-induced embryonic vascular disruption is mediated by oxygen free radicals, the antioxidants 2-oxothiazolidine-4-carboxylate (OTC) and alpha-phenyl-N-t-butyl nitrone (PBN) were employed. When cocaine (78 mg/kg) was administered on day 8 of gestation to ICR mice and embryos evaluated on day 10 (in vivo), 62.3% of cocaine-treated embryos showed increased vasodilation compared to 4.9% for controls, and 33.1% of the cocaine-exposed embryos showed marked hemorrhage compared to 3.3% for controls. In addition, cocaine increased the incidence of neural defects, in the form of open neural tube, hypoplastic prosencephalon, and microcephaly. Administration of OTC (0.25 and 0.5 mmol/kg) or PBN (300 mg/kg) prior to cocaine significantly reduced cocaine-induced vasodilation and hemorrhage, while not preventing neural defects. When cocaine (78 mg/kg) was administered in vivo on day 8 of gestation and embryos were dissected 15 min later and subsequently cultured for 48 hr in the absence of cocaine (in vivo-in vitro), marked vascular disruption was observed: normal yolk circulation/heartbeat was decreased to 26.6%, while edema/blisters and vasodilation/hemorrhage were increased to 45.6% and 59.6%, respectively. Administration of PBN (300 mg/kg) prior to cocaine completely prevented cocaine-induced vascular disruption. When cocaine was administered in vivo and PBN (300 micrograms/ml) was incubated with cultured embryos in vitro, the antioxidant only partially prevented cocaine-induced cardiovascular defects in this model. Neural defects produced by cocaine were not significantly affected by PBN, administered either in vivo or in vitro. Cocaine (78 mg/kg) administered in vivo stimulated lipid peroxidation maximally after 3 hr in both day 8 and day 9 embryos. When cocaine was incubated in vitro during embryo culture at 33 micrograms/ml, a concentration that produces nonspecific inhibition of growth and development, embryonic lipid peroxidation on day 9 was not affected. Finally, when PBN (300 mg/kg) was administered prior to cocaine (78 mg/kg) on day 8 of gestation, stimulation of lipid peroxidation by cocaine was prevented. These results suggest that cocaine-induced vascular disruption in early development is mediated by maternal production of oxygen free radicals.

Hypoxia and the Edema Syndrome: elucidation of a mechanism of teratogenesis

“…Ischemia reperfusion and free radical injury have been hypothesized to play a role in the etiology of cocaine-induced vascular disruption in the embryo (Fantel et al, 1992;Zimmerman et al, 1994). Cocaine administration to pregnant rats can also result in fetal edema (Church et al, 1988), further indicating effects on fluid balance.…”

Lipidomic profiling reveals protective function of fatty acid oxidation in cocaine-induced hepatotoxicity

“…Nitrogen was used as both cone gas (50 L/h) and desolvation gas (600 L/h), and argon as collision gas. For accurate mass measurement, the mass spectrometer was calibrated with sodium formate solution (range m/z 50-1,000) and monitored by the intermittent injection of the lock mass leucine enkephalin ( and survival leads to progressive necrosis and apoptosis of hepatocytes (18)(19)(20). Although previous studies have yielded multifaceted mechanistic information on cocaine-induced hepatotoxicity, our current understanding on this toxic event still remains insuffi cient.…”

The spatio-temporal expression pattern of cytoplasmic Cu/Zn superoxide dismutase (SOD1) mRNA during mouse embryogenesis

“…Female mice lacking SOD1 are characterized by an increase in embryo lethality (Ho et al 1998). Significantly, an increase in SOD activity can improve the development outcome of the embryos exposed to selective teratogenic agents (Zimmerman et al 1994;Kotch et al 1995;Karabulut et al 2000).…”