Journal of Translational Neurosciences

Editorial

Fetal Alcohol Spectrum Disorders (FASD) result from ethanol exposure to the developing fetus and are the most common cause of mental retardation in the United States. These disorders are characterized by a variety of neurodevelopmental and neurodegenerative anomalies which result in significant lifetime disabilities. Thus, novel therapies are required to limit the devastating consequences of FASD. Neuropathology associated with FASD can occur throughout the Central Nervous System (CNS), but is particularly well characterized in the developing cerebellum. Rodent models of FASD have previously demonstrated that both Purkinje cells and granule cells, which are the two major types of neurons in the cerebellum, are highly susceptible to the toxic effects of ethanol. The current studies demonstrate that ethanol decreases the viability of cultured cerebellar granule cells and microglial cells. Interestingly, microglias have dual functionality in the CNS. They provide trophic and protective support to neurons. However, they may also become pathologically activated and produce inflammatory molecules toxic to parenchymal cells including neurons. The findings in this study demonstrate that the peroxisome proliferator-activated receptor-γ agonists 15-deoxy-Δ12,15 prostaglandin J2 and pioglitazone protect cultured granule cells and microglia from the toxic effects of ethanol.

Furthermore, investigations using a newly developed mouse model of FASD and stereological cell counting methods in the cerebellum elucidate that ethanol administration to neonates is toxic to both Purkinje cell neurons as well as microglia and that in vivo administration of PPAR-γ agonists protects these cells. In composite, these studies suggest that PPAR-γ agonists may be effective in limiting ethanol induced toxicity to the developing CNS. Fetal Alcohol Spectrum Disorders (FASD) and related disorders occur in approximately 1% of live births in the United States and represent the most common cause of mental retardation. FASD is caused by ethanol induced neuro degeneration in the developing Central Nervous System (CNS).

Pathology in the cerebellum, hippocampus, cerebrum, corpus callosum, basal forebrain and other brain regions persists throughout life and underlies the dysfunction associated with this disorder. FASD is commonly associated with significant lifetime disability and thus the prevention and treatment of this syndrome is greatly needed.

The effects of ethanol on the developing cerebellum have been extensively investigated. Brain imaging of children exposed to prenatal ethanol reveals defects throughout the cerebellum. Cerebellar maturation that occurs during the third trimester of human development has been well modeled in the neonatal rat with developmental equivalence during the first 2 postnatal weeks. In the neonatal rat, the cerebellum has been studied as a prototype for ethanol effects on neuronal development. The two major neuronal populations in the cerebellum, Purkinje cells and granule cells, are susceptible to ethanol with high vulnerability on postnatal days 4-6, with deficits in these neuronal populations persisting in the adult animal.

Ethanol toxicity in cerebellar granule cells has been particularly well studied in culture. Granule cells require trophic support which can be provided by neuro trophins or NMDA receptor activation in culture. Ethanol interferes with normal neuro trophic support resulting in death of granule cells. Under normal physiological conditions, microglias promote neuronal development and survival by secreting factors including neuro trophins and protective cytokines, as well as by sequestering neurotransmitters. However, upon CNS insult, microglia can become pathologically activated leading to neuropathology, neuro inflammation and/or neuro degeneration. Studies in adult animal models of alcohol abuse also provide clues to the effects of ethanol on microglia. In these models, ethanol administration induces an activated morphological phenotype and stimulates production of inflammatory and neurotoxic molecules. Collectively, these studies suggest that ethanol may stimulate neuron cell death, at least in part, through stimulation of neuro inflammatory and neurodegenerative processes in the CNS.