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Abstract
Traumatic brain injury (TBI) precedes the onset of epilepsy in up to 15–20% of symptomatic epilepsies and up to 5% of all epilepsy. Treatment of acquired epilepsies, including post-traumatic epilepsy (PTE), presents clinical challenges, including frequent resistance to anti-epileptic therapies. Considering that over 1.6 million Americans present with a TBI each year, PTE is an urgent clinical problem. Neuroinflammation is thought to play a major causative role in many of the post-traumatic syndromes, including PTE. Increasing evidence suggests that neuroinflammation facilitates and potentially contributes to seizure induction and propagation. The inflammatory cytokine, macrophage migration inhibitory factor (MIF), is elevated after TBI and higher levels of MIF correlate with worse post-traumatic outcomes. MIF was recently demonstrated to directly alter the firing dynamics of CA1 pyramidal neurons in the hippocampus, a structure critically involved in many types of seizures. We hypothesized that antagonizing MIF after TBI would be anti-inflammatory, anti-neuroinflammatory and neuroprotective. The results show that administering the MIF antagonist ISO1 at 30 min after TBI prevented astrocytosis but was not neuroprotective in the peri-lesion cortex. The results also show that ISO1 inhibited the TBI-induced increase in γδT cells in the gut, and the percent of B cells infiltrating into the brain. The ISO1 treatment also increased this population of B cells in the spleen. These findings are discussed with an eye towards their therapeutic potential for post-traumatic syndromes, including PTE.
Highlights
Traumatic brain injury (TBI) precedes approximately 15–20% of symptomatic epilepsies and ~5% of all epilepsy cases [1,2]
A major impetus for this study was based on three of our previous observations: first, we reported that migration inhibitory factor (MIF) can directly alter the firing properties of hippocampal neurons [24]; second, we demonstrated that there is a peripheral expansion of B cells following TBI; and third, we demonstrated that CD74 contributes to neurodegeneration resulting from TBI [16]
We have demonstrated, for the first time, a strong case implicating MIF/CD74 signaling in the astrocytic response to fluid percussion injury (FPI)
Summary
Traumatic brain injury (TBI) precedes approximately 15–20% of symptomatic epilepsies and ~5% of all epilepsy cases [1,2]. Post-traumatic epilepsy (PTE) is a frequent consequence of TBI in civilian and military populations, and epidemiological studies have shown that a prior incidence of TBI is a leading cause in the development of delayed symptomatic epilepsy [3,4,5]. Treatment of acquired epilepsies such as PTE presents unique clinical challenges. These patients are often resistant to typical first and second line anti-epileptic drugs, and treatment options are lacking [6,7]. Despite ongoing intensive investigations into the mechanisms of injury and the resulting pathology, treatment options are lacking for both initial and chronic post-TBI syndromes. The initial symptoms may include early post-traumatic seizures. Chronic symptoms can include cognitive and affective disorders, as well as the increased susceptibility to developing chronic spontaneous seizures, the hallmark of PTE
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