Biomedical subjects

Krikor Dikranian

Publications and source records attributed to Krikor Dikranian.

10 recordsLinked to original sources

PubMed2005

Role of caspase-3 in ethanol-induced developmental neurodegeneration.

Acute, transient exposure to ethanol causes a widespread pattern of caspase-3 activation and neuroapoptosis in the developing rodent brain. To determine whether caspase-3 activation is an essential step in ethanol-induced developmental neuroapoptosis, we treated homozygous caspase-3 knockout mice or wild-type mice on postnatal day 7 with an apoptosis-inducing dose of ethanol and examined the brains at appropriate survival times for evidence of apoptotic neurodegeneration. In caspase-3 knockout mice, the cell death process evolved more slowly than in wild-type mice, and morphological changes observed were not those typically associated with apoptosis. However, neuronal cell counts performed 2 weeks post-treatment revealed that the extent of neuron loss was similar in wild-type and caspase-3-deficient mice. We conclude that absence of functional caspase-3 alters the time course and morphological characteristics of the neurodegenerative process but does not prevent ethanol-induced neuron death.

Alcohol-Induced Disorders, Nervous System↗

PubMed2005

Ethanol-induced neuroapoptosis in the developing rodent cerebellum and related brain stem structures.

For three decades since the fetal alcohol syndrome (FAS) was first described, researchers have been keenly interested in understanding the mechanism(s) by which ethanol damages or disrupts development of the human fetal brain. It has been reported repeatedly that exposure of infant rats to ethanol causes a reduction in brain mass and loss of cerebellar Purkinje cells, but the mechanisms underlying these effects have remained elusive. In a recent series of studies, we have demonstrated that exposure of infant rats or mice to ethanol on a single occasion during the synaptogenesis period of development causes neurons in many regions of the developing central nervous system to commit suicide (die by apoptosis), but the cerebellum was not among the brain regions focused upon in these studies. Here we show in infant rats and mice that one-time exposure to ethanol triggers acute neurodegeneration of Purkinje cells and other neurons in the cerebellar cortex, deep cerebellar nuclei, and two related brainstem nuclei (nucleus pontis, inferior olivary complex). We also describe the time course of neurodegeneration and window of vulnerability for each of these neuronal cell types and demonstrate that the cell death process in each case is unequivocally apoptotic. We conclude that exposure of infant rats or mice to ethanol on a single occasion during synaptogenesis can kill Purkinje cells, and many other neuronal populations at all levels of the developing neuraxis, and in each case the mechanism of cell death is apoptosis.

Alcohol-Induced Disorders, Nervous System↗

PubMed2004

Excitotoxic versus apoptotic mechanisms of neuronal cell death in perinatal hypoxia/ischemia.

Hypoxic/ischemic (H/I) neuronal degeneration in the developing central nervous system (CNS) is mediated by an excitotoxic mechanism, and it has also been reported that an apoptosis mechanism is involved. However, there is much disagreement regarding how excitotoxic and apoptotic cell death processes relate to one another. Some authors believe that an excitotoxic stimulus directly triggers apoptotic cell death, but this interpretation is largely speculative at the present time. Our findings support the interpretation that excitotoxic and apoptotic neurodegeneration are two separate and distinct cell death processes that can be distinguished from one another by ultrastructural evaluation. Here we review evidence supporting this interpretation, including evidence that H/I in the developing CNS triggers two separate waves of neurodegeneration, the first being excitotoxic and the second being apoptotic. The first (excitotoxic) wave destroys neurons that would normally provide synaptic inputs or synaptic targets for the neurons that die in the second (apoptotic) wave. Since neurons, during the developmental period of synaptogenesis, are programmed to commit suicide if they fail to achieve normal connectivity, this explains why neuroapoptosis occurs following H/I in the developing CNS. However, it does not support the interpretation that H/I directly triggers apoptotic neurodegeneration. Rather, it documents that H/I directly triggers excitotoxic neurodegeneration, and apoptotic neurodegeneration ensues subsequently as the natural response of developing neurons to a specific kind of deprivation - loss of the ability to form normal synaptic connections.

Animals↗

PubMed2003

Muscimol prevents NMDA antagonist neurotoxicity by activating GABAA receptors in several brain regions.

N-Methyl-D-aspartate (NMDA) glutamate receptor antagonists are being developed as therapeutic agents for several clinical conditions. However, the ability of these agents to produce neurotoxicity and psychosis can compromise their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state may play a role in neurodegenerative and psychotic disorders. A better understanding of the mechanism underlying these adverse effects should allow for the safer use of these agents and might clarify mechanisms underlying certain clinical disorders. NRHypo neurotoxicity is mediated by a complex disinhibition mechanism in which NMDA antagonists abolish GABAergic inhibition, resulting in the simultaneous excessive release of acetylcholine and glutamate onto the vulnerable retrosplenial cortex (RSC) neurons. Systemically administered GABAergic agents are potent protectors against NRHypo neurotoxicity. To determine where in brain GABAergic agents could be acting to protect against NRHypo neurotoxicity, we injected the GABAergic agonist, muscimol, into different brain regions of rats treated systemically with a neurotoxic dose of the potent NMDA antagonist, MK-801. We report that muscimol injections into the anterior thalamus or diagonal band of Broca provide substantial protection, suggesting that disinhibition of neurons in these regions underlies NRHypo neurotoxicity. Muscimol injections into the RSC also provide substantial protection possibly by directly inhibiting the vulnerable RSC neuron. Injections of muscimol into other areas known to project to the RSC (ventral orbital cortex, anterior cingulate cortex and subiculum) provide only minimal protection. We conclude that GABAergic agents prevent NRHypo neurotoxicity mainly by activating GABA receptors in the anterior thalamus, diagonal band of Broca and RSC.

Animals↗

PubMed2003

Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits.

Recently it was demonstrated that exposure of the developing brain during the period of synaptogenesis to drugs that block NMDA glutamate receptors or drugs that potentiate GABA(A) receptors can trigger widespread apoptotic neurodegeneration. All currently used general anesthetic agents have either NMDA receptor-blocking or GABA(A) receptor-enhancing properties. To induce or maintain a surgical plane of anesthesia, it is common practice in pediatric or obstetrical medicine to use agents from these two classes in combination. Therefore, the question arises whether this practice entails significant risk of inducing apoptotic neurodegeneration in the developing human brain. To begin to address this problem, we have administered to 7-d-old infant rats a combination of drugs commonly used in pediatric anesthesia (midazolam, nitrous oxide, and isoflurane) in doses sufficient to maintain a surgical plane of anesthesia for 6 hr, and have observed that this causes widespread apoptotic neurodegeneration in the developing brain, deficits in hippocampal synaptic function, and persistent memory/learning impairments.

Anesthetics↗

PubMed2003

Nuclear translocation of nuclear transcription factor-kappa B by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors leads to transcription of p53 and cell death in dopaminergic neurons.

We describe a new molecular mechanism of cell death by excitotoxicity mediated through nuclear transcription factor kappa B (NF kappa B) in rat embryonic cultures of dopaminergic neurons. Treatment of mesencephalic cultures with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) resulted in a number of changes that occurred selectively in dopaminergic neurons, including persistent elevation in intracellular Ca(2+) monitored with Fura-2, and a significant increase in intramitochondrial oxidation of dihydrorhodamine 123, probably associated with transient increase of mitochondrial permeability, cytochrome c release, nuclear translocation of NF kappa B, and transcriptional activation of the oncogene p53. Interruption of any of these steps by specific antagonists prevented neurite pruning and programmed cell death. In contrast, cell death was not prevented by caspase antagonists and only partly prevented by nitric-oxide synthase inhibitors. This signal transduction pathway might be a contributing mechanism in ongoing neuronal death in Parkinson disease.

Active Transport, Cell Nucleus↗

PubMed2003

Ethanol-induced apoptosis in the developing visual system during synaptogenesis.

PURPOSE: Ethanol is known to have deleterious effects on the human fetal nervous system (fetal alcohol syndrome), including components of the visual system, but only modest progress has been made in understanding these effects. The authors have recently demonstrated that, during the period of synaptogenesis, a single episode of ethanol intoxication lasting for several hours triggers a massive wave of apoptotic neurodegeneration in several regions of the developing rat or mouse forebrain. The present study was undertaken to determine to what extent the developing visual system is vulnerable to the apoptogenic effects of ethanol. METHODS: Infant rats and mice at ages from birth to 21 days were treated subcutaneously with a single dose of ethanol or with two doses, 2 hours apart, on a single day. Blood alcohol levels were determined, and the retinas and visual centers in the brain were examined by light and electronmicroscopy at various times from 4 to 24 hours after treatment. RESULTS: Retinal ganglion cells and neurons in the lateral geniculate nucleus, superior colliculus, and visual cortex were all highly susceptible to ethanol's apoptogenic action, the period of peak sensitivity being postnatal days 1 to 4 for ganglion cells and 4 to 7 for the other visual neurons. A transient elevation of blood alcohol to approximately 120 mg/dL was sufficient to activate the cell death program in visual neurons. CONCLUSIONS: During synaptogenesis, a single ethanol intoxication episode triggers apoptotic cell death of neurons at all levels of the visual system from retina to the visual cortex.

Alcohol-Induced Disorders, Nervous System↗

PubMed2002

Antiepileptic drugs and apoptotic neurodegeneration in the developing brain.

Epilepsy is the most common neurological disorder of young humans. Each year 150,000 children in the United States experience their first seizure. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects. The cause of unwanted effects of therapy with AEDs is unknown. Here we reveal that phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproate cause apoptotic neurodegeneration in the developing rat brain at plasma concentrations relevant for seizure control in humans. Neuronal death is associated with reduced expression of neurotrophins and decreased concentrations of survival-promoting proteins in the brain. beta-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorates AED-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with prenatal or postnatal exposure of humans to antiepileptic therapy.

Animals↗

PubMed2002

Ethanol-induced apoptotic neurodegeneration in the developing C57BL/6 mouse brain.

Recent studies have shown that administration of ethanol to infant rats during the synaptogenesis period (first 2 weeks after birth), triggers extensive apoptotic neurodegeneration throughout many regions of the developing brain. While synaptogenesis is largely a postnatal phenomenon in rats, it occurs prenatally (last trimester of pregnancy) in humans. Recent evidence strongly supports the interpretation that ethanol exerts its apoptogenic action by a dual mechanism--blockade of NMDA glutamate receptors and hyperactivation of GABA(A) receptors. These findings in immature rats represent a significant advance in the fetal alcohol research field, in that previous in vivo animal studies had not demonstrated an apoptogenic action of ethanol, had not documented ethanol-induced cell loss from more than a very few brain regions and had not provided penetrating insight into the mechanisms underlying ethanol's neurotoxic action. To add to the mechanistic insights recently gained, it would be desirable to examine gene-regulated aspects of ethanol-induced apoptotic neurodegeneration, using genetically altered strains of mice. The feasibility of such research must first be established by demonstrating that appropriate mouse strains are sensitive to this neurotoxic mechanism. In the present study, we demonstrate that mice of the C57BL/6 strain, a strain frequently used in transgenic and gene deletion research, are exquisitely sensitive to the mechanism by which ethanol induces apoptotic neurodegeneration during the synaptogenesis period of development.

Alcohol-Induced Disorders, Nervous System↗

PubMed2002

Ethanol-induced caspase-3 activation in the in vivo developing mouse brain.

Recently several methods have been described for triggering extensive apoptotic neurodegeneration in the developing in vivo mammalian brain. These methods include treatment with drugs that block NMDA glutamate receptors, drugs that promote GABA(A) neurotransmission, or treatment with ethanol, which has both NMDA antagonist and GABAmimetic properties. A single intoxication episode induced by any of these agents is sufficient to cause widespread neurodegeneration throughout many brain regions. The cell death process transpires rapidly from early to late stages within several hours. As the neurons die, they become TUNEL positive and show, by both light and electron microscopy, all of the classical morphological characteristics of apoptosis. In the present study, using immunocytochemical methods, we document that ethanol intoxication of 7-day-old infant mice causes a widespread pattern of caspase-3 activation corresponding to the pattern of apoptotic neurodegeneration that is occurring simultaneously.

Animals↗