Disrupted Ionic Homeostasis in Ischemic Stroke and New Therapeutic Targets

Oct 22, 2017Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association

Disrupted Ion Balance in Stroke and Possible New Treatments

AI simplified

Abstract

Dysfunction of ionic transporters and disrupted ionic homeostasis are the earliest changes associated with ischemic brain injury.

Ionic transporters and channels play a critical role in ischemia-induced cellular degeneration, contributing to cytotoxic edema, excitotoxicity, necrosis, apoptosis, and autophagic cell death.
Specific ionic transporters, including Na/K-ATPase, Na/CaExchanger, and acid-sensing ion channels, are involved in these degenerative processes.
Glutamate-mediated excitotoxicity needs to be addressed within 2 hours after a stroke for effective treatment.
Certain channels, such as SUR1-regulated NCchannels and TRP channels, have a longer therapeutic window, suggesting potential new targets for acute ischemic stroke therapy.
Future stroke therapies may benefit from a polypharmacology approach, targeting multiple ion transporters and their interactions with neurotoxic signaling pathways.

AI simplified

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/CaExchanger, ionotropic glutamate receptor, acid-sensing ion channels (ASICs), sulfonylurea receptor isoform 1 (SUR1)-regulated NCchannels, 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 NCchannels, 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. + + + 2+ + + Ca-ATP Ca-ATP

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.

Full Text

Full text is available at the source.

View full text (XML) ↗View full text ↗

Abstract

Full Text

Related papers

what lands in your inbox each week: