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Published on: August 17, 2021
Blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) prevents posttraumatic
Xingjie Ping1,2, Zhi Chai3, Weiping Wang4
1Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Objective:
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.
Methods:
In a mouse undercut model of posttraumatic epilepsy, daily injections of saline, RAGE monoclonal antibody (mAb), or TAK242, a TLR4 inhibitor, were made for 1 week. Their effects on seizure susceptibility and spontaneous epileptic seizures were evaluated with a pentylenetetrazol (PTZ) test in 2 weeks and with continuous video and wireless electroencephalography (EEG) monitoring between 2 and 6 weeks 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.
Results:
Undercut animals treated with RAGE mAb or TAK242 showed 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 TAK242 group 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.
Significance:
RAGE and TLR4 signaling are critically involved in posttraumatic epileptogenesis. Blocking these pathways early after traumatic brain injury is a promising strategy for preventing posttraumatic epilepsy.
Insights
Blocking receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) pathways effectively prevents posttraumatic epilepsy. This early intervention in traumatic brain injury models reduces seizure susceptibility and spontaneous seizures.
Area of Science:
- Neuroscience
- Immunology
- Epileptology
Background:
- Posttraumatic epilepsy (PTE) remains a significant challenge with no effective preventative treatments.
- Traumatic brain injury (TBI) can initiate complex molecular cascades leading to epileptogenesis.
- Receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) pathways are implicated in neuroinflammation and neuronal damage following TBI.
Purpose of the Study:
- To investigate the potential of blocking RAGE and TLR4 signaling pathways to prevent posttraumatic epileptogenesis.
- To evaluate the efficacy of RAGE monoclonal antibody (mAb) and a TLR4 inhibitor (TAK242) in a mouse model of PTE.
Main Methods:
- A mouse undercut model was used to induce TBI.
- Mice received daily injections of saline, RAGE mAb, or TAK242 for one week.
- Seizure susceptibility was assessed using the pentylenetetrazol (PTZ) test, and spontaneous seizures were monitored via electroencephalography (EEG) and video recordings.
Main Results:
- Treatment with RAGE mAb or TAK242 significantly increased seizure threshold compared to saline controls.
- RAGE knockout mice showed no reduction in seizure threshold after injury.
- EEG and video monitoring revealed a significant reduction in spontaneous seizure events in treated groups.
- Histological analysis showed increased neuronal density, higher interneuron counts, and reduced glial activation (astrocytes and microglia) in treated animals.
Conclusions:
- RAGE and TLR4 signaling pathways play critical roles in the development of posttraumatic epilepsy.
- Early blockade of these pathways following TBI represents a promising therapeutic strategy for preventing PTE.
- Targeting RAGE and TLR4 may offer a novel approach to mitigate the long-term consequences of brain injury.
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