ATP-sensitive Potassium Channel Subunits in Neuroinflammation: Novel Drug Targets in Neurodegenerative Disorders
| Autor: | Domenico Tricarico, Rosa Scala, Fatima Maqoud, Bruno Zappacosta, Malvina Hoxha |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
0301 basic medicine
Agonist endocrine system ATP-sensitive potassium channel medicine.drug_class Pharmacology Sulfonylurea Receptors Glibenclamide 03 medical and health sciences Adenosine Triphosphate 0302 clinical medicine KATP Channels medicine Animals Hypoglycemic Agents Potassium Channels Inwardly Rectifying Receptor Neuroinflammation Ion channel Chemistry General Neuroscience Neurodegeneration Neurodegenerative Diseases medicine.disease Potassium channel 030104 developmental biology Neuroinflammatory Diseases 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | CNS & Neurological Disorders - Drug Targets. 21:130-149 |
| ISSN: | 1871-5273 |
| DOI: | 10.2174/1871527320666210119095626 |
| Popis: | Arachidonic acids and its metabolites modulate plenty of ligand-gated, voltage-dependent ion channels, and metabolically regulated potassium channels including ATP-sensitive potassium channels (KATP). KATP channels are hetero-multimeric complexes of sulfonylureas receptors (SUR1, SUR2A or SUR2B) and the pore-forming subunits (Kir6.1 and Kir6.2) likewise expressed in the pre-post synapsis of neurons and inflammatory cells, thereby affecting their proliferation and activity. KATP channels are involved in amyloid-β (Aβ)-induced pathology, therefore emerging as therapeutic targets against Alzheimer’s and related diseases. The modulation of these channels can represent an innovative strategy for the treatment of neurodegenerative disorders; nevertheless, the currently available drugs are not selective for brain KATP channels and show contrasting effects. This phenomenon can be a consequence of the multiple physiological roles of the different varieties of KATP channels. Openings of cardiac and muscular KATP channel subunits, are protective against caspase-dependent atrophy in these tissues and some neurodegenerative disorders, whereas in some neuroinflammatory diseases, benefits can be obtained through the inhibition of neuronal KATP channel subunits. For example, glibenclamide exerts an anti-inflammatory effect in respiratory, digestive, urological, and central nervous system (CNS) diseases, as well as in ischemia-reperfusion injury associated with abnormal SUR1-Trpm4/TNF-α or SUR1-Trpm4/ Nos2/ROS signaling. Despite this strategy being promising, glibenclamide may have limited clinical efficacy due to its unselective blocking action of SUR2A/B subunits also expressed in cardiovascular apparatus with pro-arrhythmic effects and SUR1 expressed in pancreatic beta cells with hypoglycemic risk. Alternatively, neuronal selective dual modulators showing agonist/antagonist actions on KATP channels can be an option. |
| Databáze: | OpenAIRE |
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