Leveraging Innate Immunity to Prevent Post-Traumatic Epilepsy
Abstract
Innate immune system serves to protect the organism against foreign substances by identifying, neutralizing, and removing them from the body. While innate immunity is largely associated with the response to and the protection against infections, its role is far broader, to include, for example removal of cells and tissues, which are either injured or died under a variety of pathological conditions. One of such conditions is traumatic brain injury (TBI), when brain cells undergo irreversible injury and death. After TBI, innate immune response engages to dispose of these dead cells, to clear the way for reparative processes. The first and the main component of innate immune system in the brain are microglial cells (or microglia). After TBI, microglia is activated quickly and persistently in and around the area of the injury. However, innate immune response is often imperfect, so that events that are purposed as biologically useful, may become harmful. Thus, when microglia is activated after TBI, it releases a variety of molecules, some of which predispose and contribute to the development of post-traumatic epilepsy (PTE). Indeed, based on the molecules that are predominantly produced and released, microglial cells can be divided into two types. On the one hand, there are cells that are mostly detrimental, and in the context of this project, are pro-epileptic; these cells are known as M1 type. On the other hand, there are cells that are mostly protective, and in the context of this project, antiepileptic; these cells are known as M2 type. Importantly, the dichotomy of microglia is not absolute: all cells release molecules of both types, and there are interventions that can modify microglia towards one type or another. Intriguingly, it was established that a bacterial toxin, called lipopolysaccharide (LPS, a.k.a. endotoxin), when administered in very low doses, stimulates the M2-type microglia. Under experimental conditions, involving animal models, it has been shown that such purposefully induced low-grade endotoxemia may have beneficial effects in a variety of brain diseases, such as macular degeneration, stroke, Alzheimer’s disease, TBI and epilepsy. Despite these findings, the dominating point of view in the TBI and epilepsy research remains that microglia is indiscriminately harmful, maladaptive, and proepileptic, with little or no explorations of its antiepileptic potential. In this project, we propose using a low-dose LPS to prevent PTE through effectively and safely leveraging innate immune response to TBI. The study involves a rat model of the TBI-PTE continuum – the lateral fluid percussion injury (LFPI) paradigm, which produces PTE in approximately one-half of the animals between 7 and 12 months after the injury. The project consists of three progressive aims. Under Aim 1, rats will undergo LFPI, followed by 1-week long subcutaneous administration of LPS in a low dose, to introduce a transient controlled low-grade endotoxemia. Seven to nine months later, the animals will be examined for the presence and the severity of PTE, with the expectation that early post-TBI endotoxemia reduces the risk of PTE, so that PTE develops in fewer animals, and that in affected subjected PTE is less severe, than in controls treated with placebo instead of LPS. Under Aim 2, we will examine the expression of specific markers of M1 and M2 microglia after LFPI with and without LPS treatment, with the expectation that LPS will stimulated M2 microglia at the expense of M1 microglia. Under Aim 3, we will examine whether LPS at the levels that protect against PTE produces any undesirable side effects, with the expectations that there will be none. Despite ongoing multiple efforts, the progress in treatment, and even less in prevention of PTE is meek, with the proportion of TBI patients who develop PTE remaining stable at alarmingly high rate (as high as 50%). It is clear that novel, paradigm-shifting approaches are necessary for a tangible
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210210
Entities
People
- Andréy Mazarati
Organizations
- United States Army
- University of California, Los Angeles