Alcohol-induced apoptosis of oligodendrocytes in the fetal macaque brain

BACKGROUND: In utero exposure of the fetal non-human primate (NHP) brain to alcohol on a single occasion during early or late third-trimester gestation triggers widespread acute apoptotic death of cells in both gray and white matter (WM) regions of the fetal brain. In a prior publication, we documented that the dying gray matter cells are neurons, and described the regional distribution and magnitude of this cell death response. Here, we present new findings regarding the magnitude, identity and maturational status of the dying WM cells in these alcohol-exposed fetal NHP brains. RESULTS: Our findings document that the dying WM cells belong to the oligodendrocyte (OL) lineage. OLs become vulnerable when they are just beginning to generate myelin basic protein in preparation for myelinating axons, and they remain vulnerable throughout later stages of myelination. We found no evidence linking astrocytes, microglia or OL progenitors to this WM cell death response. The mean density (profiles per mm(3)) of dying WM cells in alcohol-exposed brains was 12.7 times higher than the mean density of WM cells dying by natural apoptosis in drug-naive control brains. CONCLUSIONS: In utero exposure of the fetal NHP brain to alcohol on a single occasion triggers widespread acute apoptotic death of neurons (previous study) and of OLs (present study) throughout WM regions of the developing brain. The rate of OL apoptosis in alcohol-exposed brains was 12.7 times higher than the natural OL apoptosis rate. OLs become sensitive to the apoptogenic action of alcohol when they are just beginning to generate constituents of myelin in their cytoplasm, and they remain vulnerable throughout later stages of myelination. There is growing evidence for a similar apoptotic response of both neurons and OLs following exposure of the developing brain to anesthetic and anticonvulsant drugs. Collectively, this body of evidence raises important questions regarding the role that neuro and oligo apoptosis may play in the human condition known as fetal alcohol spectrum disorder (FASD), and also poses a question whether other apoptogenic drugs, although long considered safe for pediatric/obstetric use, may have the potential to cause iatrogenic FASD-like developmental disability syndromes

Behavioral Consequences of NMDA Antagonist-Induced Neuroapoptosis in the Infant Mouse Brain

Background: Exposure to NMDA glutamate antagonists during the brain growth spurt period causes widespread neuroapoptosis in the rodent brain. This period in rodents occurs during the first two weeks after birth, and corresponds to the third trimester of pregnancy and several years after birth in humans. The developing human brain may be exposed to NMDA antagonists through drug-abusing mothers or through anesthesia. Methodology/Principal Findings: We evaluated the long-term neurobehavioral effects of mice exposed to a single dose of the NMDA antagonist, phencyclidine (PCP), or saline, on postnatal day 2 (P2) or P7, or on both P2 and P7. PCP treatment on P2 + P7 caused more severe cognitive impairments than either single treatment. Histological examination of acute neuroapoptosis resulting from exposure to PCP indicated that the regional pattern of degeneration induced by PCP in P2 pups was different from that in P7 pups. The extent of damage when evaluated quantitatively on P7 was greater for pups previously treated on P2 compared to pups treated only on P7. Conclusions: These findings signify that PCP induces different patterns of neuroapoptosis depending on the developmental age at the time of exposure, and that exposure at two separate developmental ages causes more severe neuropathologica

From Drug-Induced Developmental Neuroapoptosis to Pediatric Anesthetic Neurotoxicity—Where Are We Now?

The fetal and neonatal periods are critical and sensitive periods for neurodevelopment, and involve rapid brain growth in addition to natural programmed cell death (i.e., apoptosis) and synaptic pruning. Apoptosis is an important process for neurodevelopment, preventing redundant, faulty, or unused neurons from cluttering the developing brain. However, animal studies have shown massive neuronal cell death by apoptosis can also be caused by exposure to several classes of drugs, namely gamma-aminobutyric acid (GABA) agonists and N-methyl-d-aspartate (NMDA) antagonists that are commonly used in pediatric anesthesia. This form of neurotoxic insult could cause a major disruption in brain development with the potential to permanently shape behavior and cognitive ability. Evidence does suggest that psychoactive drugs alter neurodevelopment and synaptic plasticity in the animal brain, which, in the human brain, may translate to permanent neurodevelopmental changes associated with long-term intellectual disability. This paper reviews the seminal animal research on drug-induced developmental apoptosis and the subsequent clinical studies that have been conducted thus far. In humans, there is growing evidence that suggests anesthetics have the potential to harm the developing brain, but the long-term outcome is not definitive and causality has not been determined. The consensus is that there is more work to be done using both animal models and human clinical studies

Use of Prescribed Psychotropics during Pregnancy: A Systematic Review of Pregnancy, Neonatal, and Childhood Outcomes

This paper reviews the findings from preclinical animal and human clinical research investigating maternal/fetal, neonatal, and child neurodevelopmental outcomes following prenatal exposure to psychotropic drugs. Evidence for the risks associated with prenatal exposure was examined, including teratogenicity, neurodevelopmental effects, neonatal toxicity, and long-term neurobehavioral consequences (i.e., behavioral teratogenicity). We conducted a comprehensive review of the recent results and conclusions of original research and reviews, respectively, which have investigated the short- and long-term impact of drugs commonly prescribed to pregnant women for psychological disorders, including mood, anxiety, and sleep disorders. Because mental illness in the mother is not a benign event, and may itself pose significant risks to both mother and child, simply discontinuing or avoiding medication use during pregnancy may not be possible. Therefore, prenatal exposure to psychotropic drugs is a major public health concern. Decisions regarding drug choice, dose, and duration should be made carefully, by balancing severity, chronicity, and co-morbidity of the mental illness, disorder, or condition against the potential risk for adverse outcomes due to drug exposure. Globally, maternal mental health problems are considered as a major public health challenge, which requires a stronger focus on mental health services that will benefit both mother and child. More preclinical and clinical research is needed in order to make well-informed decisions, understanding the risks associated with the use of psychotropic medications during pregnancy

Developmental Neurotoxicity of Alcohol and Anesthetic Drugs Is Augmented by Co-Exposure to Caffeine

brain science

Repeated neonatal isoflurane exposures in the mouse induce apoptotic degenerative changes in the brain and relatively mild long-term behavioral deficits

Abstract Epidemiological studies suggest exposures to anesthetic agents and/or sedative drugs (AASDs) in children under three years old, or pregnant women during the third trimester, may adversely affect brain development. Evidence suggests lengthy or repeated AASD exposures are associated with increased risk of neurobehavioral deficits. Animal models have been valuable in determining the type of acute damage in the developing brain induced by AASD exposures, as well as in elucidating long-term functional consequences. Few studies examining very early exposure to AASDs suggest this may be a critical period for inducing long-term functional consequences, but the impact of repeated exposures at these ages has not yet been assessed. To address this, we exposed mouse pups to a prototypical general anesthetic, isoflurane (ISO, 1.5% for 3 hr), at three early postnatal ages (P3, P5 and P7). We quantified the acute neuroapoptotic response to a single versus repeated exposure, and found age- and brain region-specific effects. We also found that repeated early exposures to ISO induced subtle, sex-specific disruptions to activity levels, motor coordination, anxiety-related behavior and social preference. Our findings provide evidence that repeated ISO exposures may induce behavioral disturbances that are subtle in nature following early repeated exposures to a single AASD

Density of AC3-positive profiles is greater when PCP exposure occurs on P2 and P7 (P2+P7) compared to exposure on P7 alone.

<p>Density of AC3-positive cell profiles summed across forebrain regions most sensitive to PCP-induced neuroapoptosis on P7 (retrosplenial cortex, caudate putamen, anterior thalamic nuclei) is significantly (**<i>p</i> = 0.012) greater in mice that were exposed to PCP on P2 and P7 (P2+P7PCP group) compared to that observed in mice that were treated only on P7 (P7PCP). The P7PCP and P2+P7PCP groups each showed significantly greater densities of AC3-positive profiles compared to the saline controls (†<i>p</i> = 0.001; *<i>p</i><0.00005, respectively). Numbers in parentheses indicate sample sizes of each group.</p

P2+P7 PCP treatment impairs spatial learning and memory in the Morris water maze.

<p>(A) An effect of Group (**p = 0.015) and a Group by Gender by Blocks of Trials interaction (***p = 0.017), suggested group differences in path length over trials in the cued condition. However, PCP-treated mice did not differ significantly from control mice on any single block of trials suggesting differences were minimal, and additional contrasts did not indicate meaningful gender effects. (B) PCP-treated animals showed significant acquisition deficits at P30 (**p<0.0005) for blocks 1, 2, and 3, (*p<0.009) while large differences were found for blocks 4 (†p = 0.042) and 5 (†p = 0.011). (C) Swimming speeds of PCP-treated mice were slower than controls during place trials (**p = 0.031), although pairwise comparisons showed no significant difference in any given block of trials. (D) Control mice showed good retention at the end of training (**p<0.0005). Specifically, they showed spatial bias for the target quadrant (*p<0.0005). (E) PCP-treated mice showed acquisition deficits at P75 (**p = 0.008). Differences were greatest for blocks 3 (†p = 0.049), and 5 (†p = 0.033). (F) For the 1-h delay probe trial control mice exhibited spatial bias for the target quadrant, (**p<0.0005; *p<0.007 for target vs each of the other quadrants) (G) A Group by Blocks interaction (**p = 0.010) was observed for the cued trials at P170. Greatest differences occurred during the first block (†p = 0.023, not significant past Bonferroni correction p = 0.0125). (H) PCP-treated mice displayed acquisition deficits at P170 (**p = 0.003), specifically for blocks 1, 2, and 3 (*p<0.007) and for block 4 (†p = 0.018). (I) During the first 24-h delay probe trial control mice showed spatial bias for the target quadrant (**p<0.0005; *p<0.0005 for target vs each of the other quadrants), while PCP-treated mice did not.</p