Biomedical subjects

Vesna Jevtovic-Todorovic

Publications and source records attributed to Vesna Jevtovic-Todorovic.

22 records · Page 2Linked to original sources

PubMed2002

Mechanical and thermal antinociception in rats following systemic administration of mibefradil, a T-type calcium channel blocker.

Voltage-gated Ca(2+) channels play a crucial role in pain perception. We studied the antinociceptive potential of systemically administered mibefradil, a peripherally acting antihypertensive agent and preferential T-type Ca(2+) channel blocker. Systemic injections of mibefradil, in clinically relevant doses, induced mechanical and thermal antinociception in adult rats without compromising their sensorimotor abilities. This suggests that peripherally acting T-type Ca(2+) channel blockers can be useful antinociceptive agents.

Analgesics↗

PubMed2002

The enigma of fetal alcohol neurotoxicity.

The neurotoxic effects of ethanol on the human fetal brain (fetal alcohol syndrome, FAS) have been recognized for three decades, but the underlying mechanisms have remained elusive. Recently, we discovered that a single episode of ethanol intoxication lasting for several hours can trigger a massive wave of apoptotic neurodegeneration in the developing rat or mouse brain. The window of vulnerability coincides with the developmental period of synaptogenesis, also known as the brain growth-spurt period, which in rodents is a postnatal event, but in humans extends from the sixth month of gestation to several years after birth. We propose that the N-methyl-D-aspartate (NMDA) antagonist and gamma-aminobutyric (GABA)mimetic properties of ethanol are responsible for its apoptogenic action, in that we have found that other drugs that block NMDA glutamate receptors or mimic GABA at GABA(A) receptors also trigger apoptotic neurodegeneration in the developing brain. Our findings have clinical significance, not only because they can explain the reduced brain mass and neurobehavioral disturbances associated with the human FAS, but because many agents in the human environment, other than ethanol, have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers [phencyclidine (angel dust), ketamine (Special K), nitrous oxide (laughing gas), barbiturates, benzodiazepines], and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).

Alcohol-Induced Disorders, Nervous System↗

PubMed2002

Glutamate and GABA receptor dysfunction in the fetal alcohol syndrome.

The brain damaging effects of ethanol, as the most disabling component of the fetal alcohol syndrome FAS), have been recognized for 3 decades, but the mechanism underlying these effects has remained elusive. Recently, we discovered that ethanol triggers widespread apoptotic neurodegeneration throughout the developing brain when administered to infant rodents during the period of synaptogenesis, also known as the brain growth spurt period. These findings provide a more likely explanation than has heretofore been available for the reduced brain mass and lifelong neurobehavioral disturbances associated with the human FAS. We propose that a dual mechanism - blockade of NMDA glutamate receptors and hyperactivation of GABA(A) receptors - mediates ethanol's apoptogenic action, based on established evidence that ethanol has both NMDA antagonist and GABAmimetic properties, and our recent finding that other drugs with either NMDA antagonist or GABAmimetic properties robustly trigger apoptotic neurodegeneration in the developing brain. The brain growth spurt occurs in different species at different times relative to birth. In rats and mice it is a postnatal event, but in humans it extends from the sixth month of gestation to several years after birth. Thus, there is a period in pre and postnatal human development, lasting for several years, during which immature CNS neurons are prone to commit suicide if exposed to intoxicating concentrations of drugs with NMDA antagonist or GABAmimetic properties. These findings are important, not only because of their relevance to the FAS, but because there are many agents in the human environment, other than ethanol, that have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers [ethanol, phencyclidine (angel dust), ketamine (Special K), nitrous oxide (laughing gas), barbiturates, benzodiazepines], and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).

Journal Article↗

PubMed2002

Drug-induced apoptotic neurodegeneration in the developing brain.

Physiological cell death (PCD), a process by which redundant or unsuccessful neurons are deleted by apoptosis (cell suicide) from the developing central nervous system, has been recognized as a natural phenomenon for many years. Whether environmental factors can interact with PCD mechanisms to increase the number of neurons undergoing PCD, thereby converting this natural phenomenon into a pathological process, is an interesting question for which new answers are just now becoming available. In a series of recent studies we have shown that 2 major classes of drugs (those that block NMDA glutamate receptors and those that promote GABAA receptor activation), when administered to immature rodents during the period of synaptogenesis, trigger widespread apoptotic neurodegeneration throughout the developing brain. In addition, we have found that ethanol, which has both NMDA antagonist and GABAmimetic properties, triggers a robust pattern of apoptotic neurodegeneration, thereby deleting large numbers of neurons from many different regions of the developing brain. These findings provide a more likely explanation than has heretofore been available for the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). The period of synaptogenesis, also known as the brain growth spurt period, occurs in different species at different times relative to birth. In rats and mice it is a postnatal event, but in humans it extends from the sixth month of gestation to several years after birth. Thus, there is a period in pre- and postnatal human development, lasting for several years, during which immature CNS neurons are prone to commit suicide if exposed to intoxicating concentrations of drugs with NMDA antagonist or GABAmimetic properties. These findings are important, not only because of their relevance to the FAS, but because there are many agents in the human environment, other than ethanol, that have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers (ethanol, phencyclidine [angel dust], ketamine [Special K], nitrous oxide [laughing gas], barbiturates, benzodiazepines), and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).

Animals↗