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Traumatic Brain Injury: Low Dose Naltrexone and Microglial Modification


Sarah Zielsdorf, MD, MS


Traumatic Brain Injury (TBI) is defined as an alteration of brain function or other evidence of brain pathology, which is attributed to an external mechanical force. This emerging epidemic targets the predominately male, able-bodied workforce, and will become one of the leading causes of death in the next decade. TBI affects every aspect of an individual. Leaky gut equals leaky brain. After brain injury, tight junctions connecting the mucosal epithelial cells become dysfunctional and allow large macromolecules (food antigens) to cross into the bloodstream, which activate the immune system. The mucosal lining often atrophies and dies with changes occurring within minutes after brain injury. Similarly, tight junctions of the blood-brain barrier (BBB) also break down, and neuroinflammatory chemicals enter and wreck havoc. Brain injury often contributes to over or under-activation of the immune system, which may lead to autoimmunity or immune compromise. TBI can trigger autonomic dysfunction, disorders of visceral sensing and processing, and impair gut motility. As the macrophages of the central nervous system (CNS), microglia are the first line of defense of the immune system. In response to TBI, microglia migrate to site of injury and eliminate cellular/molecular debris. Activated microglia release noxious chemicals including pro-inflammatory cytokines, reactive oxygen species (ROS) and nitrogen species, and cause persistent neuro-excitation via glutamate release, which exacerbates existing damage and precedes neurodegeneration. The role of microglia activation in TBI is more highly nuanced than previously described, in which microglia are activated in different phenotypes. These correspond to neurotoxic or neuroprotective priming states. Low Dose Naltrexone (LDN) is a powerful microglial modifier and use in TBI may help prevent neurodegeneration and immune dysfunction. The mechanism is LDN’s antagonist effect on non-opioid receptors (Toll-Like Receptor 4, TLR4), found on macrophages including microglial cells.

Session Learning Objective: 

Participants will understand the definition of traumatic brain injury (TBI), and current/future burden of disease, systemic effects of brain injury, and role of microglia. Low Dose Naltrexone (LDN) therapy has shown the ability to modulate microglia, which is potentially neuroprotective.

Session Outline: 

  • Definition of Traumatic Brain Injury (TBI)
  • Burden of disease: young and male
  • Leaky Gut = Leaky Brain
  • Pathophysiology of TBI
  • Role of microglia
  • Microglial activation in response to brain injury
  • Low Dose Naltrexone (LDN) as microglial modifiers
  • Brief outline of treatment approach to TBI