Targeting TLR4-dependent inflammation in post-hemorrhagic brain injury.
Jason K KarimyBenjamin C ReevesKristopher T KahlePublished in: Expert opinion on therapeutic targets (2020)
Recent data have implicated inflammation of the cerebrospinal fluid spaces after subarachnoid, intraventricular, and intracerebral hemorrhage to be a critical driver of multiple secondary brain injuries such as hydrocephalus, cerebral edema, and vasospasm. While TLR4-dependent reparative inflammation is an important protective response that can eliminate physical irritants and damaged cells, sustained or inappropriately triggered inflammation can initiate or propagate disease.Areas covered: We review recent advances in our understanding of how TLR4, including its upstream damage-associated molecular patterns and its downstream MyD88-dependent and independent signaling pathways, contributes to hemorrhage-induced inflammation in numerous brain diseases. We discuss prospects for the pharmacotherapeutic targeting of TLR4 in these disorders, including the use of repurposed FDA-approved agents.Expert opinion: TLR4 inhibitors with good blood-brain-barrier (BBB) penetration could be useful adjuncts in post-hemorrhagic hydrocephalus and multiple other diseases associated with brain hemorrhage and inflammation.
Keyphrases
- brain injury
- subarachnoid hemorrhage
- oxidative stress
- cerebral ischemia
- blood brain barrier
- toll like receptor
- inflammatory response
- cerebrospinal fluid
- immune response
- induced apoptosis
- white matter
- physical activity
- nuclear factor
- signaling pathway
- diabetic rats
- resting state
- mental health
- cancer therapy
- drug delivery
- deep learning
- endoplasmic reticulum stress
- stress induced