The Impact of Ethanol Abuse on Cognitive Function in Adolescence due to Neuroinflammation from the Innate Immune System: The Role of Toll-Like Receptor 4

Peter Nguyen

Introduction. Alcohol Use Disorders (AUDs) are one of the main risk factors for disease that account for 6-9% of mental, neurological, and substance abuse disorders.1 It has been discovered that ethanol abuse can lead to sustained neuroinflammation due to the response of the innate immune system via Toll-Like Receptor 4 (TLR-4). In adolescence, a time that is essential for brain maturation, these effects can negatively impact neurocognitive development, particularly in the pre-frontal cortex.2 Studies have shown that mice treated intermittently with ethanol activates TLR-4 signaling pathways (NF-kB), leading to the upregulation of pro- inflammatory mediators. This causes synaptic alterations and myelin protein reduction, leading to long-lasting cognitive dysfunction as demonstrated with the object recognition and passive avoidance test. 3 Other studies found that binge-like ethanol exposure in mice impairs autophagy machinery by increasing inhibitory proteins (mTOR), further causing cognitive dysfunction. 4 These findings suggest that potential therapies that can block the TLR-4 response due to alcohol can prevent neurocognitive damage. Methods. Female wild-type (WT) and TLR4-knock out (TLR4-KO) mice were utilized. Western blot technique was performed in pre-frontal cortex (PFC) tissue lysates. 3,4 PFC-homogenized lysates were analyzed to determine levels of cytokines and chemokines using the Milliplex MAP kit. Behavioral test such as the object recognition test and the passive avoidance test were done to assess cognitive impairment. 3 Statistical significance was determined by the t- test, controlling for genetics and age. 3,4 Results. Intermittent ethanol treatment in WT mice up-regulated the levels of inflammatory cytokines such as COX-2, but TLR4-KO mice showed neither activation of different kinases nor the production of inflammatory cytokines. WT mice also showed a lower discrimination index in the object recognition test and less latency to leave the safe illuminated compartment in the passive avoidance test, suggesting cognitive impairment.3 Ethanol treatment reduced the expression of proteins involved in phagophore and autophagosome formation (LC3-II) in WT mice, while also showing an increase in proteins that are associated with inhibition of autophagy (ATG5).4 Conclusion. Studies have found that the impact of sustained inflammation due to the impact of the innate immune system can lead to neurocognitive dysfunction in adolescence due to long-term myelin dysfunction and autophagy impairment. Potential treatments, such as Nalmefene, has shown potential to block the TLR-4 response by interacting with co-adaptor protein MD2, preventing neuronal cell death and myelin alteration.5

  1. Pascual M, Montesinos J, Guerri C. Role of the innate immune system in the neuropathological consequences induced by adolescent binge drinking. Journal of Neuroscience Research. 2017;96(5):765-780. doi:10.1002/jnr.24203.
  2. Montesinos J, Alfonso-Loeches S, Guerri C. Impact of the Innate Immune Response in the Actions of Ethanol on the Central Nervous System. Alcoholism: Clinical and Experimental Research. 2016;40(11):2260-2270. doi:10.1111/acer.13208.
  3. Montesinos, Jorge, et al. TLR4 Elimination Prevents Synaptic and Myelin Alterations and Long-Term Cognitive Dysfunctions in Adolescent Mice with Intermittent Ethanol Treatment. Brain, Behavior, and Immunity, Academic Press, 5 Dec. 2014.
  4. Montesinos J, Pascual M, Millán-Esteban D, Guerri C. Binge-like ethanol treatment in adolescence impairs autophagy and hinders synaptic maturation: Role of TLR4. Neuroscience Letters. 2018;682:85-91. doi:10.1016/j.neulet.2018.05.049.
  5. Montesinos J, Gil A, Guerri C. Nalmefene Prevents Alcohol-Induced Neuroinflammation and Alcohol Drinking Preference in Adolescent Female Mice: Role of TLR4. Alcoholism: Clinical and Experimental Research. 2017;41(7):1257-1270. doi:10.1111/acer.13416.