Date of Award

2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

Abstract

Prenatal exposure to ethanol can cause serious damage to the developing central nervous system. Both in vivo and in vitro studies demonstrate the vulnerability of the developing serotonergic system to the damaging effects of ethanol. However, treatment with a serotonin-1A (5-HT1A) agonist prevents the ethanol-associated apoptosis in developing 5-HT neurons. One mechanism by which 5-HT1A agonists exert their neuroprotective effects appears to involve activation of the phosphatidylinositol 3'kinase (PI-3K) pro-survival pathway and activation of NF-κB dependent anti-apoptotic genes. Additional NF-κB dependent genes might also be involved with the neuroprotective effects of ipsapirone.

There is also considerable evidence that ethanol augments apoptosis by increasing the levels of reactive oxygen species (ROS). In light of the neuroprotective effects of ipsapirone and their ability to increase expression of NF-κB dependent genes, it was hypothesized that ipsapirone increases the expression of additional NF-κB dependent genes that encode specific antioxidant enzymes. This dissertation investigated the effects of ethanol and ipsapirone on ROS levels and on the expression/enzyme activities of endogenous antioxidants Cu/Zn-superoxide dismutase (SOD1), Mn-superoxide dismutase (SOD2), and catalase.

The results of these studies demonstrate that ethanol induces an increase in ROS and that ipsapirone pre-treatment prevents this increase. Time-course studies of the expression and enzyme activity of SOD1, SOD2, and catalase showed that ipsapirone mediates regulation of these enzymes. Ethanol treatment resulted in an early and transient increase in the expression of the three genes. However, expression levels returned to those in unstressed control neurons after prolonged ethanol exposure. Ipsapirone, on the other hand, prevented the latter fall in the expression of the antioxidant enzyme genes. Moreover, addition of EUK-134, which mimics SOD and catalase activities, attenuates ethanol-associated apoptosis. Interestingly, inhibitor studies suggested that both the PI-3K and MAPK pro-survival pathways might be involved with the effects of ethanol and ipsapirone on the expression of the antioxidant genes. In summary, it appears that some of the neuroprotective effects of 5-HT1A agonists such as ipsapirone are likely to involve the expression of antioxidant enzyme genes.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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