Disrupted ionic homeostasis in ischemic stroke and new therapeutic targets

HJ Hu, M Song - Journal of stroke and cerebrovascular diseases, 2017 - Elsevier
HJ Hu, M Song
Journal of stroke and cerebrovascular diseases, 2017Elsevier
Background Stroke is a leading cause of long-term disability. All neuroprotectants targeting
excitotoxicity have failed to become stroke medications. In order to explore and identify new
therapeutic targets for stroke, we here reviewed present studies of ionic transporters and
channels that are involved in ischemic brain damage. Method We surveyed recent literature
from animal experiments and clinical reports in the databases of PubMed and Elsevier
ScienceDirect to analyze ionic mechanisms underlying ischemic cell damage and suggest …
Background
Stroke is a leading cause of long-term disability. All neuroprotectants targeting excitotoxicity have failed to become stroke medications. In order to explore and identify new therapeutic targets for stroke, we here reviewed present studies of ionic transporters and channels that are involved in ischemic brain damage.
Method
We surveyed recent literature from animal experiments and clinical reports in the databases of PubMed and Elsevier ScienceDirect to analyze ionic mechanisms underlying ischemic cell damage and suggest promising ideas for stroke therapy.
Results
Dysfunction of ionic transporters and disrupted ionic homeostasis are most early changes that underlie ischemic brain injury, thus receiving sustained attention in translational stroke research. The Na+/K+-ATPase, Na+/Ca2+ Exchanger, ionotropic glutamate receptor, acid-sensing ion channels (ASICs), sulfonylurea receptor isoform 1 (SUR1)–regulated NCCa-ATP channels, and transient receptor potential (TRP) channels are critically involved in ischemia-induced cellular degenerating processes such as cytotoxic edema, excitotoxicity, necrosis, apoptosis, and autophagic cell death. Some ionic transporters/channels also act as signalosomes to regulate cell death signaling. For acute stroke treatment, glutamate-mediated excitotoxicity must be interfered within 2 hours after stroke. The SUR1-regulated NCCa-ATP channels, Na+/K+-ATPase, ASICs, and TRP channels have a much longer therapeutic window, providing new therapeutic targets for developing feasible pharmacological treatments toward acute ischemic stroke.
Conclusion
The next generation of stroke therapy can apply a polypharmacology strategy for which drugs are designed to target multiple ion transporters/channels or their interaction with neurotoxic signaling pathways. But a successful translation of neuroprotectants relies on in-depth analyses of cell death mechanisms and suitable animal models resembling human stroke.
Elsevier
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