Cannabidiol as a Novel Therapeutic for Gulf War Illness
Abstract
Nearly one-third of the 700,000 U.S. Veterans of the 1991 Persian Gulf War (GW) returned from duty with a chronic multi-symptom disorder, termed Gulf War Illness (GWI). Veterans with GWI experience fatigue, chronic pain, cognitive dysfunction, and headaches among many physical and mental symptoms. Among many problems associated with GWI, impairment in brain function is of particular concern. Scientists used animal models to study the disease and found that overt exposures to toxic chemicals during the war, including pesticides, nerve agents, oil well fire smoke, and prophylactic drugs, along with a stressful environment may have caused chronic neuroinflammation to the GW Veterans, that is, a prolonged but uncontrolled inflammation in the brain. We hypothesized that this serious problem may have been initiated from the exposure to GW chemicals and stress that produced lasting deficits in the endocannabinoid (ECB) system, which is an anti-inflammatory neuroprotective mechanism of the brain. The loss of normal ECB system function may have caused changes in a type of brain cell called microglia, that normally plays an essential role in the bodily immune system, and made them hyperactive and uncontrollable for a long term. Therefore, we propose that rescue of ECB deficits may serve as an effective therapeutic strategy for inflammatory central nervous system (CNS) diseases, such as the GWI, and aging-associated neuroinflammation. Importantly, chronic neuroinflammation and microglial alterations are changes associated with aging and neurodegeneration. The intersection in neuroinflammation between GWI and the consequence of aging makes it even more important to tackle both processes simultaneously as the GW Veterans are moving into their 60s. Accordingly, an ideal therapeutic strategy should address the progress of GWI with aging, and include treatments targeting neuroinflammation and its accompanying neuronal dysfunction. Cannabidiol (CBD) is a promising intervention for GWI because it displays an ability to act as anti-inflammatory, anti-pain, anxiolytic, anti-depression and neuroprotective compounds. In contrast to the psychoactive phytocannabinoid delta9-tetrahydrocannabinol (THC), CBD is a non-addictive cannabinoid that does not produce psychotropic side effect but may increase ECB tone by inhibiting an enzyme that catalyzes degradation of ECB molecules. The favorable safety profile and the non-psychotropic pharmacology list CBD as an appealing therapeutic candidate for select conditions. CBD is currently a Food and Drug Administration (FDA)-approved prescription drug for treatment-resistant seizures. As of today, 335 clinical trials for CBD have been completed, or are in progress, to treat various forms of pain, drug addiction, and autism. Here, we hypothesized that GW chemical-induced deficits in the ECB system may cause a persistent change in the microglia, which leads to a dysregulated microglial activation and contributes to GWI pathogenesis. The primary objective of this study is to determine whether pharmacological enhancement of ECB signaling with CBD alleviates GWI pathology in rodent models. We have two aims: First, in Specific Aim 1, we will assess the efficacy of CBD in GWI model mice. With GW Veterans getting older, there will be likely an additive effect between age-related and GWI-related symptoms. Using two mice models that express symptoms of human GWI, we will determine whether a 28-day treatment with CBD reverses various molecular and behavioral abnormalities of the GWI mice at three different ages, including a cohort of very old mice. We anticipate that CBD will increase the neuroprotective effects of the endocannabinoid system, dampen neuroinflammation, and alleviate the behavioral and molecular pathology of GWI. In Specific Aim 2, we will elucidate the mechanism underlying beneficial effects of CBD for GWI. Both GWI and aging may cause dysregulation of the microglial activation that contributes to neuroin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210172
Entities
People
- Kwang-Mook Jung
Organizations
- United States Army
- University of California, Irvine