Involvement of KCa3.1 channel activity in immediate perioperative cognitive and neuroinflammatory outcomes
Sarah Saxena1, Vincent Nuyens2, Christopher Rodts3
1Department of Anesthesia and Critical Care, AZ Sint-Jan Brugge Oostende AV, Bruges, Belgium. sarah.saxena@ulb.be.
Background:
Potassium channels (KCa3.1; Kv1.3; Kir2.1) are necessary for microglial activation, a pivotal requirement for the development of Perioperative Neurocognitive Disorders (PNDs). We previously reported on the role of microglial Kv1.3 for PNDs; the present study sought to determine whether inhibiting KCa3.1 channel activity affects neuroinflammation and prevents development of PND.
Methods:
Mice (wild-type [WT] and KCa3.1-/-) underwent aseptic tibial fracture trauma under isoflurane anesthesia or received anesthesia alone. WT mice received either TRAM34 (a specific KCa3.1 channel inhibitor) dissolved in its vehicle (miglyol) or miglyol alone. Spatial memory was assessed in the Y-maze paradigm 6 h post-surgery/anesthesia. Circulating interleukin-6 (IL-6) and high mobility group box-1 protein (HMGB1) were assessed by ELISA, and microglial activitation Iba-1 staining.
Results:
In WT mice surgery induced significant cognitive decline in the Y-maze test, p = 0.019), microgliosis (p = 0.001), and increases in plasma IL-6 (p = 0.002) and HMGB1 (p = 0.001) when compared to anesthesia alone. TRAM34 administration attenuated the surgery-induced changes in cognition, microglial activation, and HMGB1 but not circulating IL-6 levels. In KCa3.1-/- mice surgery neither affected cognition nor microgliosis, although circulating IL-6 levels did increase (p < 0.001).
Conclusion:
Similar to our earlier report with Kv1.3, perioperative microglial KCa3.1 blockade decreases immediate perioperative cognitive changes, microgliosis as well as the peripheral trauma marker HMGB1 although surgery-induced IL-6 elevation was unchanged. Future research should address whether a synergistic interaction exists between blockade of Kv1.3 and KCa3.1 for preventing PNDs.
Insights
Inhibiting the KCa3.1 potassium channel in microglia reduced cognitive decline and neuroinflammation after surgery. This suggests KCa3.1 channel blockade is a potential strategy for preventing Perioperative Neurocognitive Disorders (PNDs).
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglial activation is crucial for Perioperative Neurocognitive Disorders (PNDs).
- Potassium channels, including KCa3.1, Kv1.3, and Kir2.1, are essential for microglial activation.
- Previous research implicated microglial Kv1.3 in PND development.
Purpose of the Study:
- To investigate the effect of inhibiting the KCa3.1 channel on neuroinflammation and PND development.
- To determine if KCa3.1 channel blockade can prevent surgery-induced cognitive decline.
Main Methods:
- Wild-type (WT) and KCa3.1 knockout (KCa3.1-/-) mice underwent aseptic tibial fracture trauma under anesthesia.
- WT mice received either TRAM34 (a KCa3.1 inhibitor) or vehicle.
- Cognitive function (Y-maze), microglial activation (Iba-1 staining), and plasma biomarkers (IL-6, HMGB1) were assessed.
Main Results:
- Surgery induced cognitive decline, microgliosis, and elevated IL-6 and HMGB1 in WT mice.
- TRAM34 treatment attenuated surgery-induced cognitive decline, microgliosis, and HMGB1 increase, but not IL-6 levels.
- KCa3.1-/- mice showed no cognitive or microglial changes post-surgery, despite increased IL-6.
Conclusions:
- Perioperative blockade of microglial KCa3.1 channels reduces immediate cognitive impairment and microgliosis.
- KCa3.1 inhibition also lowers the peripheral trauma marker HMGB1.
- Further research is warranted to explore synergistic effects of blocking Kv1.3 and KCa3.1 channels for PND prevention.
