Abstract
BackgroundNeuroinflammation occurs following brain injury, including soman (GD) induced status epilepticus (SE), and may contribute to loss of neural tissue and declined behavioral function. However, little is known about this important pathological process following GD exposure. Limited transcriptional information on a small number of brain-expressed inflammatory mediators has been shown following GD-induced SE and even less information on protein upregulation has been elucidated. The purpose of this study is to further characterize the regional and temporal progression of the neuroinflammatory process following acute GD-induced SE.MethodsThe protein levels of 10 cytokines was quantified using bead multiplex immunoassays in damaged brain regions (i.e., piriform cortex, hippocampus and thalamus) up to 72 hours following seizure onset. Those factors showing significant changes were then localized to neural cells using fluorescent IHC.ResultsA significant concentration increase was observed in all injured brain regions for four acute phase response (APR) induction cytokines: interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor (TNF)-α. Increases in these APR cytokines corresponded both temporally and regionally to areas of known seizure damage and neuronal death. Neurotoxic cytokines IL-1α and IL-1β were primarily expressed by activated microglia whereas the potentially neuroprotective cytokine IL-6 was expressed by neurons and hypertrophic astrocytes.ConclusionsIncreases in neurotoxic cytokines likely play an active role in the progression of GD-induced SE neuropathology though the exact role that these and other cytokines play in this process require further study.
Highlights
Neuroinflammation occurs following brain injury, including soman (GD) induced status epilepticus (SE), and may contribute to loss of neural tissue and declined behavioral function
IL-1β significantly increased in the piriform cortex at 12 hours (41 ± 10 pg/ml v. 16 ± 10 pg/ml vehicle control) and in the thalamus at 12 hours (48 ± 28 pg/ml) and 24 hours (24 ± 12 pg/ml v. 5 ± 1 pg/ml vehicle control) (Figure 2)
No significant changes in IL-1β concentration were observed in the hippocampus though a definite trend was observed, with an approximate 3-fold increase were identified in each brain region using IHC at the 12hour time point, the peak of cytokine expression for the majority of these brain regions
Summary
Neuroinflammation occurs following brain injury, including soman (GD) induced status epilepticus (SE), and may contribute to loss of neural tissue and declined behavioral function. Following injury, infiltrating leukocytes and activated macrophages release many inflammatory proteins, including the acute phase response (APR) inducing cytokines IL-1, IL-6 and TNF-α [15]. Though pluripotent, cytokines such as IL-1 (α and β) and TNF-α are toxic to neural tissues in vitro [16,17,18] and can exacerbate experimental CNS injury in vivo [19,20,21]
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