Blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) prevents posttraumatic epileptogenesis in mice.

Abstract

Effective treatment for the prevention of posttraumatic epilepsy is still not available. Here, we sought to determine whether blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) signaling pathways would prevent posttraumatic epileptogenesis. In a mouse undercut model of posttraumatic epilepsy, daily injections of saline, RAGE monoclonal antibody (mAb), or TAK242, a TLR4 inhibitor, were made for 1week. Their effects on seizure susceptibility and spontaneous epileptic seizures were evaluated with a pentylenetetrazol (PTZ) test in 2weeks and with continuous video and wireless electroencephalography (EEG) monitoring between 2 and 6weeks after injury, respectively. Seizure susceptibility after undercut in RAGE knockout mice was also evaluated with the PTZ test. The lesioned cortex was analyzed with immunohistology. Undercut animals treated with RAGE mAb or TAK242showed significantly higher seizure threshold than saline-treated undercut mice. Consistently, undercut injury in RAGE knockout mice did not cause a reduction in seizure threshold in the PTZ test. EEG and video recordings revealed a significant decrease in the cumulative spontaneous seizure events in the RAGE mAb- or TAK242-treated group (p<0.001, when the RAGE mAb or TAK242group is compared with the saline group). The lesioned cortical tissues of RAGE mAb- or TAK242-treated undercut group showed higher neuronal densities of Nissl staining and higher densities of glutamic acid decarboxylase 67-immunoreactive interneurons than the saline-treated undercut group. Immunostaining to GFAP and Iba-1 revealed lower densities of astrocytes and microglia in the cortex of the treatment groups, suggesting reduced glia activation. RAGE and TLR4signaling are critically involved in posttraumatic epileptogenesis. Blocking these pathways early after traumatic brain injury is a promising strategy for preventing posttraumatic epilepsy.