Alcohol and the Developing Brain : Prevention and Intervention

by National Institute of Health

(Page 4 of 4)

Recently, several studies have shown that complex motor training and pharmacological treatments are able to prevent or ameliorate developmental alcohol-induced alterations in specific anatomical structures. These studies are based on the assumption that restoring neuroanatomical integrity would result in subsequent functional recovery. Therefore, identifying the structural alterations associated with prenatal alcohol exposure and understanding the underlying mechanisms of these changes are critical steps in developing both prevention and intervention strategies.

Complex Motor Training

Using a paradigm that involves complex motor training, Klintsova and colleagues convincingly demonstrated structural reorganization in rat cerebellum following early postnatal alcohol exposure. The most striking and profound aspect of these studies was that, although the complex motor skill training was initiated during adulthood, it was able to successfully stimulate the creation of new connections between Purkinje cells and the long connecting fibers (parallel fibers) of other neurons in animals that were exposed to alcohol between postnatal days 4 and 9. Although the number of Purkinje cells was unchanged following the complex motor training, the increased volume of the paramedian lobule of the cerebellar cortex and the increased number of parallel fiber synapses per Purkinje cell were sufficient anatomical changes to result in improved motor skills. These findings have relevant clinical significance and important therapeutic implications. They suggest that complex rehabilitative motor training can improve motor performance of children, or even adults, with FAS. However, at present it is unclear whether recovery or reorganization of neural connections is possible in regions other than the cerebellum and motor cortex of the nervous system. Moreover, it remains to be seen whether the improvement in motor skills and anatomical alteration in synapses following complex motor training is permanent.

Pharmacological Treatments

Antioxidant therapy has been reported to be effective in reducing early postnatal alcohol-induced neurotoxicity in animal studies. Heaton and colleagues showed that vitamin E protects against early postnatal alcohol-induced cerebellar Purkinje cell loss in lobule I, a lobule that is most sensitive to alcohol during development. Although it has not yet been documented, researchers speculate that antioxidant treatment would protect the functions of the cerebellum from early postnatal alcohol exposure because the antioxidant prevents the formation of harmful free radicals. In contrast to complex motor training, which is an intervention, administering vitamin E during pregnancy is a preventive effort. Prevention in many ways is more effective and economical than intervention in attenuating the detrimental effects of alcohol exposure during development. Recent data show that melatonin, a known and effective antioxidant, when given to neonatal rat pups simultaneously with alcohol, does not prevent the early postnatal alcohol-induced Purkinje cell loss in either the part of the cerebellum known as the cerebellar vermis or in lobule I. Taken together, these data suggest that preserving the intact neural structures depends on the type of antioxidant used and possibly the timing of antioxidant administration.

Treatment with antioxidants before alcohol exposure may be critical for the antioxidant to be available in an amount that would most effectively inhibit alcohol-induced generation of free radicals. Recently, two peptides derived from growth factors that are associated with normal development have been shown to be effective in preventing prenatal alcohol-induced somatic and brain growth retardation in a mouse model. In addition, supporting evidence indicated that the levels of these peptides were reduced in mouse embryos which were exposed to alcohol prenatally. More recently, these peptides have been shown to reverse alcohol-induced inhibition of L1-mediated cell-to-cell adhesion in vitro. Despite the promising findings that these peptides prevent some aspects of fetal alcohol-induced damage, their ability to prevent damage to specific neural anatomical structures has not been examined.

Recent data suggest that administering MK-801, a compound that blocks receptors for the brain chemical glutamate, during alcohol withdrawal reduces the loss of hippocampal pyramidal cells in the CA1 region in a neonatal rat model. However, the most profound effect of this pharmacological treatment is its ability to reverse the behavioral impairment in a specific learning task that was induced by early postnatal alcohol exposure. These findings demonstrate that preserving the integrity of neural structures is important for upholding function.

Further evidence for the effectiveness of certain pharmacological treatments involves the ability of the eight-carbon long-chain alcohol known as 1-octanol to attenuate alcohol-induced damage. Recent data show that a low dose of 1-octanol interacts with the L1CAM to block an alcohol-induced mechanism of abnormal physical development in a mouse embryo model. As shown in figure 2, it appears that l-octanol significantly reduces the severity of alcohol's effects. Although it is unclear whether treatment with 1-octanol in vivo would be just as effective as in vitro, or whether 1-octanol protects against alcohol-induced brain damage, this treatment holds promise for developing pharmacological agents to prevent alcohol-induced injury during development. In sum, these anatomical studies of developmental alcohol effects provide opportunities to assess the effectiveness of prevention and intervention methods.

Conclusion

Identifying specific neuroanatomical anomalies as adverse effects of heavy alcohol exposure during development has been a significant contribution to the fetal alcohol field. Animal studies have been important in the following ways: they have demonstrated that alcohol exposure during development, even without polydrug use or undernourishment, can induce significant structural changes to the developing brain.

They have demonstrated that various regions of the developing brain are not uniformly vulnerable, and that the brain is not equally vulnerable throughout its developmental period. Demonstrating so-called regional and temporal vulnerability, as well as other potential risk factors, has helped researchers to understand the considerable variability observed in children prenatally exposed to alcohol.

The quantifiable nature of specific neuroanatomical anomalies offers a direct measure for future studies to use in assessing the efficacy of putative neuroprotective agents.

Similarly, important advances also have been made in human studies. Noninvasive MRI studies in children exposed to alcohol in utero have been much more instructive than autopsy studies. They allow neuroanatomical deficits to be correlated with functional deficits. MRI, fMRI, PET, and other neuroimaging techniques offer the potential to help direct future research into pharmacological intervention and treatment strategies with fetal alcohol-exposed patients.

Taken together, human and animal neuroanatomical studies have provided both an experimental foundation for a better understanding of the behavioral impairments associated with heavy maternal drinking, and an important means of evaluating potential neuroprotective and therapeutic interventions.

About the Author

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