Mild Hypothermia Suppresses Calcium-Sensing Receptor (CaSR) Induction Following Forebrain Ischemia While Increasing GABA-B Receptor 1 (GABA-B-R1) Expression

Abstract

Hypothermia improves neurological outcome from cardiac arrest. The mechanisms of protection are multifold, but identifying some may be useful in exploring potential therapeutic targets. The extracellular calcium-sensing receptor (CaSR) was originally found in parathyroid cells in which the receptor senses minute changes in extracellular [Ca2+] and promotes Ca2+ influx and intracellular Ca2+ release. The CaSR is broadly expressed in the CNS and colocalized with the inhibitory γ-aminobutyric acid-B receptor 1 (GABA-B-R1). In hippocampal neurons, GABA-B-R1 heterodimerizes with CaSR and suppresses CaSR expression. To study the interplay between these two receptors in the development of ischemic cell death and neuroprotection by hypothermia, we subjected C57/BL6 mice to global cerebral ischemia by performing bilateral carotid artery occlusion (10 min) followed by reperfusion for 1–3 days with or without therapeutic hypothermia (33°C for 3 h at the onset of reperfusion). Terminal deoxynucleotidyl transferase dUTP nick end labeling staining and immunohistochemistry showed that forebrain ischemia increased CaSR expression, decreased GABA-B-R1 expression, and promoted cell death. These changes were particularly evident in hippocampal neurons and could be reversed by mild hypothermia. The induction of CaSR, along with reciprocal decreases in GABA-B-R1 expression, may together potentiate ischemic neuronal death, suggesting a new therapeutic target for treatment of ischemic brain injury.

Triggering Receptor Expressed on Myeloid Cells-2 Correlates to Hypothermic Neuroprotection in Ischemic Stroke

“…We and others have shown that intraischemic and postischemic hypothermia can be neuroprotective partially by inhibiting the acute inflammatory response (Toyoda et al, 1996;Maier et al, 1998;Han et al, 2002;Deng et al, 2003;Kim et al, 2011). Nevertheless, the mechanisms underlying this protective effect are still not fully elucidated.…”

Ischemia-like Oxygen and Glucose Deprivation Mediates Down-regulation of Cell Surface γ-Aminobutyric AcidB Receptors via the Endoplasmic Reticulum (ER) Stress-induced Transcription Factor CCAAT/Enhancer-binding Protein (C/EBP)-homologous Protein (CHOP)

“…In vivo models of ischemia demonstrated a loss of GABA B receptors 1-4 days after the insult (7)(8)(9). Because considerable ischemia-induced neuronal death occurs during this time period, the loss of GABA B receptors might be due, at least in part, to a loss of GABA B receptorexpressing neurons.…”

“…Decreased GABAergic activity appears to contribute to neuronal overexcitation (6), and there are indications that GABA B receptors are down-regulated under ischemic conditions (7)(8)(9)(10). This suggests that impaired GABA B receptor signaling contributes to excitotoxicity.…”

Therapeutic benefits of mild hypothermia in patients successfully resuscitated from cardiac arrest:A meta-analysis

“…The possible mechanisms of therapeutic hypothermia for neuroprotection include: 1) Therapeutic hypothermia can inhibit the biosynthesis, release and uptake of several catecholamines and neurotransmitters especially glutamate and dopamine leading to brain damage; [16][17][18][19][20][21] 2) It can preserve the blood brain barrier and adenosine triphosphate stores, restitute cerebral microcirculation after ischemia, decrease intracranial pressure and increase cerebral brain blood flow; [22][23][24][25] 3) It also can reduce the amount of cell death in certain brain regions. [26][27][28][29][30] Although therapeutic mild hypothermia benefits CA patients, adverse events caused by mild hypothermia should not be neglected. Adverse events reported in all trials included pneumonia, pulmonary edema, bleeding, need for platelet transfusions, sepsis, arrhythmia, recurrence of CA, renal failure or oliguria, hemodialysis, pancreatitis, and seizures.…”