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Updated: May 10, 2026
Sex Stratified Neuronal Cultures to Study Ischemic Cell Death Pathways
Published on: December 9, 2013
Androgen and PARP-1 regulation of TRPM2 channels after ischemic injury
Takeru Shimizu1, Tara A Macey, Nidia Quillinan
1Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
Abstract:
The calcium-permeable transient receptor potential M2 (TRPM2) ion channel was recently demonstrated to have a sexually dimorphic contribution to ischemic brain injury, with inhibition or knockdown of the channel protecting male brain preferentially. We tested the hypothesis that androgen signaling is required for this male-specific cell-death pathway. Additionally, we tested the hypothesis that differential activation of the enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is responsible for male-specific TRPM2 channel activation and neuronal injury. We observed that administration of the TRPM2 inhibitor clotrimazole (CTZ) 2 hours after onset of ischemia reduced infarct volume in male mice and that protection from ischemic damage by CTZ was abolished by removal of testicular androgens (castration; CAST) and rescued by androgen replacement. Male PARP-1 knockout mice had reduced ischemic damage compared with WT mice and inhibition of TRPM2 with CTZ failed to reduce infarct size. Lastly, we observed that ischemia increased PARP activity in the peri-infarct region of male mice to a greater extent than female mice and the difference was abolished in CAST male mice. Data presented in the current study indicate that TRPM2-mediated neuronal death in the male brain requires intact androgen signaling and PARP-1 activity.
Insights
Androgen signaling and poly (ADP-ribose) polymerase-1 (PARP-1) activity are essential for male-specific TRPM2 ion channel-mediated brain injury after stroke. Inhibiting TRPM2 protects males, but only when androgens and PARP-1 are active.
Area of Science:
- Neuroscience
- Ion Channel Physiology
- Endocrinology
Background:
- Transient receptor potential M2 (TRPM2) ion channels play a sexually dimorphic role in ischemic brain injury.
- Androgen signaling and poly (ADP-ribose) polymerase-1 (PARP-1) are potential mediators of this male-specific pathway.
Purpose of the Study:
- To investigate the role of androgen signaling in male-specific TRPM2-mediated neuronal death.
- To determine if differential PARP-1 activation underlies male-specific TRPM2 channel activation and injury.
Main Methods:
- Administration of TRPM2 inhibitor clotrimazole (CTZ) in male mice with varying androgen levels (intact, castrated, androgen-replaced).
- Assessment of ischemic brain injury in male poly (ADP-ribose) polymerase-1 (PARP-1) knockout mice compared to wild-type (WT) mice.
- Measurement of PARP activity in the peri-infarct region of male and female mice after ischemia.
Main Results:
- TRPM2 inhibition by CTZ reduced infarct volume in male mice, an effect abolished by castration and restored by androgen replacement.
- Male PARP-1 knockout mice exhibited reduced ischemic damage, and CTZ failed to protect them.
- Ischemia elevated PARP activity more in males than females, with this difference disappearing after castration.
Conclusions:
- TRPM2-mediated neuronal death in the male brain following ischemia is dependent on intact androgen signaling.
- PARP-1 activity is crucial for male-specific TRPM2 channel activation and subsequent neuronal injury during stroke.
