Fetal Alcohol Syndrome Treatment: The Role of Pioglitazone in Preventing Ethanol’s Effects on Glial Cell Development

Jey Thiruma

Introduction. Alcohol use during pregnancy causes Fetal Alcohol Syndrome (FAS), the most severe and visibly identifiable form of the fetal alcohol spectrum disorder. Alcohol is a teratogen, which means that it can easily cross the placenta, and affect the brain and other vital organs of the fetus (1). FAS can lead to secondary disabilities, leading to lifelong implications. One of the main causes of FAS is abnormal glial cell development and proliferation (2). The function of glial cells is affected dramatically by ethanol, including neuronal development, survival, and function, which leads to altered brain architecture (2). There is no cure or specific treatment for FAS. Methods. One study attempted to determine the abnormalities found in neocortical development and how they relate to the microglial properties and neuro-inflammation in mouse models of FASD (3). Microglial are activated by many various inflammatory factors. M1 “pro-inflammatory” microglial cells play a role in pathogen defense by producing pro-inflammatory cytokines. M2 “anti-inflammatory” microglial activation promotes tissue remodeling and repair. After exposure to EtOH, there was a significant increase in active microglia, and a decrease in nonactive microglia (3). Additionally, there was also an increase in M1 microglia, and a decrease in M2 microglia. The study also examined the effect of Pioglitazone. Pioglitazone is commonly used to treat Type II Diabetes (4). However, the receptor they work on, PPAR-gamma, has been found to modulate inflammatory responses in the CNS, suppressing the activation of microglia and preventing neuroinflammation and neurodegeneration (4). Results. The results of this study show that prenatal EtOH exposure affect both active microglial number and morphology and promotes M1 differentiation (3). The study stated that increased M1 activation in addition to reduced M2 activation is a main contributor to neocortical synaptogenesis and neurotransmission (3). It also stated that Pioglitazone caused attenuation of microglia developmental abnormalities and reduction in M1:M2 ratio of mice exposed to EtOH (3). Conclusions. PPAR-gamma agonists are already commonly used in treating Type II Diabetes, so they should have good safety profiles, and can be quickly facilitated to treat neuroinflammatory and neurodegenerative disorders, including EtOH mediated disease (5). Additional basic research is still required to determine the exact mechanism of PPAR-gamma agonists and how they protect neuronal cells from the toxic effects of ethanol. This would facilitate a rational approach to treatment of ethanol induced neuropathology (5).

 

  1. Popova, S., Lange, S., Probst, C., Gmel, G. and Rehm, J. (2019). Estimation of national, regional, and global prevalence of alcohol use during pregnancy and fetal alcohol syndrome: a systematic review and meta-analysis. [online] The Lancet. Available at: https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(17)30021-9/fulltext [Accessed 28 Feb. 2019].
  2. Guizzetti, M., Zhang, X., Goeke, C. and Gavin, D. (2019). Glia and Neurodevelopment: Focus on Fetal Alcohol Spectrum Disorders. [online] Glia and neurodevelopment: focus on fetal alcohol spectrum disorders. Available at: https://www.frontiersin.org/articles/10.3389/fped.2014.00123/full [Accessed 28 Feb. 2019].
  3. Komada, M., Hara, N., Kawachi, S., Kawachi, K., Kagawa, N., Nagao, T. and Ikeda, Y. (2017). Mechanisms underlying neuro-inflammation and neurodevelopmental toxicity in the mouse neocortex following prenatal exposure to ethanol. Scientific Reports, 7(1).
  4. Drew, P., Johnson, J., Douglas, J., Phelan, K. and Kane, C. (2015). Pioglitazone Blocks Ethanol Induction of Microglial Activation and Immune Responses in the Hippocampus, Cerebellum, and Cerebral Cortex in a Mouse Model of Fetal Alcohol Spectrum Disorders. Alcoholism: Clinical and Experimental Research, 39(3), pp.445-454.
  5. Kane, C., Phelan, K., Han, L., Smith, R., Xie, J., Douglas, J. and Drew, P. (2011). Protection of neurons and microglia against ethanol in a mouse model of fetal alcohol spectrum disorders by peroxisome proliferator-activated receptor-γ agonists. Brain, Behavior, and Immunity, 25, pp.S137-S145.