Related Experiment Video
Updated: Feb 28, 2026
2-Vessel Occlusion/Hypotension: A Rat Model of Global Brain Ischemia
Published on: June 22, 2013
Blockade and knock-out of CALHM1 channels attenuate ischemic brain damage
Abraham Cisneros-Mejorado1,2, Miroslav Gottlieb1,3, Asier Ruiz1,2
11 Achucarro Basque Center for Neuroscience, Departamento de Neurociencias and CIBERNED, Universidad del País Vasco (UPV/EHU), Leioa, Spain.
Abstract:
Overactivation of purinergic receptors during cerebral ischemia results in a massive release of neurotransmitters, including adenosine triphosphate (ATP), to the extracellular space which leads to cell death. Some hypothetical pathways of ATP release are large ion channels, such as calcium homeostasis modulator 1 (CALHM1), a membrane ion channel that can permeate ATP. Since this transmitter contributes to postischemic brain damage, we hypothesized that CALHM1 activation may be a relevant target to attenuate stroke injury. Here, we analyzed the contribution of CALHM1 to postanoxic depolarization after ischemia in cultured neurons and in cortical slices. We observed that the onset of postanoxic currents in neurons in those preparations was delayed after its blockade with ruthenium red or silencing of Calhm1 gene by short hairpin RNA, as well as in slices from CALHM1 knockout mice. Subsequently, we used transient middle cerebral artery occlusion and found that ruthenium red, a blocker of CALHM1, or the lack of CALHM1, substantially attenuated the motor symptoms and reduced significantly the infarct volume. These results show that CALHM1 channels mediate postanoxic depolarization in neurons and brain damage after ischemia. Therefore, targeting CALHM1 may have a high therapeutic potential for treating brain damage after ischemia.
Insights
Calcium homeostasis modulator 1 (CALHM1) channels contribute to brain damage after stroke by mediating postanoxic depolarization. Blocking CALHM1 shows therapeutic potential for treating ischemic stroke injury.
Area of Science:
- Neuroscience
- Cell Biology
- Ischemic Stroke Research
Background:
- Cerebral ischemia triggers purinergic receptor overactivation, leading to massive extracellular adenosine triphosphate (ATP) release and cell death.
- Calcium homeostasis modulator 1 (CALHM1) is a potential ion channel involved in ATP release during ischemia.
Purpose of the Study:
- To investigate the role of CALHM1 in postanoxic depolarization and neuronal death following ischemic stroke.
- To evaluate CALHM1 as a therapeutic target for mitigating stroke-induced brain damage.
Main Methods:
- Analysis of postanoxic currents in cultured neurons and cortical slices after CALHM1 blockade (ruthenium red) or gene silencing (shRNA).
- Assessment of CALHM1 knockout mice in vitro.
- Evaluation of motor symptoms and infarct volume in a transient middle cerebral artery occlusion (tMCAO) stroke model using CALHM1 knockout mice and ruthenium red treatment.
Main Results:
- CALHM1 blockade or silencing delayed postanoxic current onset in neurons.
- CALHM1 knockout mice exhibited delayed postanoxic currents.
- Ruthenium red treatment and CALHM1 deficiency significantly reduced motor deficits and infarct volume in the tMCAO model.
Conclusions:
- CALHM1 channels are key mediators of postanoxic depolarization in neurons after ischemia.
- CALHM1 plays a significant role in neuronal death and brain damage following ischemic events.
- Targeting CALHM1 presents a promising therapeutic strategy for treating ischemic brain injury.
