Calcium‐sensing receptor (CaSR) as a novel target for ischemic neuroprotection. (3rd October 2014)

• Record Type: Journal Article
• Authors: Kim, Jong Youl; Ho, Hanson; Kim, Nuri; Liu, Jialing; Tu, Chia‐Ling; Yenari, Midori A.; Chang, Wenhan
• Is Part Of: Annals of clinical and translational neurology. Volume 1:Number 11(2014)
• Page Start: 851
• Page End: 866
• Publication Date: 2014-10-03
• Subjects: Nervous system -- Diseases -- Periodicals; Neurology -- Periodicals; 616.8005
• DOI: 10.1002/acn3.118
• Languages: English
• ISSNs: 2328-9503

Abstract

<abstract abstract-type="main" id="acn3118-abs-0001"> <title>Abstract</title> <sec id="acn3118-sec-0001" sec-type="section"> <title>Object</title> <p>Ischemic brain injury is the leading cause for death and long‐term disability in patients who suffer cardiac arrest and embolic stroke. Excitotoxicity and subsequent Ca<sup>2+</sup>‐overload lead to ischemic neuron death. We explore a novel mechanism concerning the role of the excitatory extracellular calcium‐sensing receptor (CaSR) in the induction of ischemic brain injury.</p> </sec> <sec id="acn3118-sec-0002" sec-type="section"> <title>Method</title> <p>Mice were exposed to forebrain ischemia and the actions of CaSR were determined after its genes were ablated specifically in hippocampal neurons or its activities were inhibited pharmacologically. Since the CaSR forms a heteromeric complex with the inhibitory type B <italic>γ</italic>‐aminobutyric acid receptor 1 (GABA<sub>B</sub>R1), we compared neuronal responses to ischemia in mice deficient in CaSR, GABA<sub>B</sub>R1, or both, and in mice injected locally or systemically with a specific CaSR antagonist (or calcilytic) in the presence or absence of a GABA<sub>B</sub>R1 agonist (baclofen).</p> </sec> <sec id="acn3118-sec-0003" sec-type="section"> <title>Results</title> <p>Both global and focal brain ischemia led to CaSR overexpression and GABA<sub>B</sub>R1 downregulation in injured neurons. Genetic ablation of <italic>Casr</italic> genes or blocking CaSR activities by calcilytics rendered robust neuroprotection and preserved learning and memory functions in ischemic mice, partly by restoring GABA<sub>B</sub>R1 expression. Concurrent ablation of <italic>Gabbr1</italic> gene blocked the neuroprotection caused by the <italic>Casr</italic> gene knockout. Coinjection of calcilytics with baclofen synergistically enhanced neuroprotection. This combined therapy remained robust when given 6 h after ischemia.</p> </sec> <sec id="acn3118-sec-0004" sec-type="section"> <title>Interpretation</title> <p>Our study demonstrates a novel receptor interaction, which contributes to ischemic neuron death through CaSR upregulation and GABA<sub>B</sub>R1 downregulation, and feasibility of neuroprotection by concurrently targeting these two receptors.</p> </sec> </abstract>