Sirtuin-2 mediates male specific neuronal injury following experimental cardiac arrest through activation of TRPM2 ion channels

Abstract

Objective Sirtuins (Sirt) are a class of deacetylase enzymes that play an important role in cell proliferation. Sirt2 activation produces O-acetylated-ADPribose (OAADPr) which can act as a ligand for transient receptor potential cation channel, M2 (TRPM2). We tested the hypothesis that Sirt2 is activated following global cerebral ischemia and contributes to neuronal injury through activation of TRPM2. Methods Adult male and female mice (8–12 weeks old) C57Bl/6 and TRPM2 knock-out mice were subjected to 8 min of cardiac arrest followed by cardiopulmonary resuscitation (CA/CPR). The Sirt2 inhibitor AGK-2 was administered intravenously 30 min after resuscitation. Hippocampal CA1 injury was analyzed at 3 days after CA/CPR. Acute Sirt2 activity was analyzed at 3 and 24 h after CA/CPR. Long-term hippocampal function was assessed using slice electrophysiology 7 days after CA/CPR. Results AGK-2 significantly reduced CA1 injury in WT but not TRPM2 knock-out males and had no effect on CA1 injury in females. Elevated Sirt2 activity was observed in hippocampal tissue from males at 24 h after cardiac arrest and was reduced by AGK-2. In contrast, Sirt2 activity in females was increased at 3 but not 24 h. Finally, we observed long-term benefit of AGK-2 on hippocampal function, with a protection of long-term potentiation at CA1 synapses at 7 and 30 days after ischemia. Conclusions In summary, we observed a male specific activation of Sirt2 that contributes to neuronal injury and functional deficits after ischemia specifically in males. These results are consistent with a role of Sirt2 in activating TRPM2 following global ischemia in a sex specific manner. These results support the growing body of literature showing that oxidative stress mechanisms predominate in males and converge on TRPM2 activation as a mediator of cell death.

TRPM2 channel: A novel target for alleviating ischaemia‐reperfusion, chronic cerebral hypo‐perfusion and neonatal hypoxic‐ischaemic brain damage

“…It is known that ischaemia‐reperfusion brain damage exhibits strong sexual dimorphism in rodent models and stroke patients. Herson and colleagues studied, using in vitro and in vivo models, whether TRPM2‐dependent ischaemia‐reperfusion brain damage was also sexual dimorphic . The TRPM2 channel expression or activity level was similar in cortical and hippocampal neurons from male and female mice.…”

Extended therapeutic window of a novel peptide inhibitor of TRPM2 channels following focal cerebral ischemia

“…ADPr is generated by PARP-1 in response to oxidative stress and cerebral ischemia, which is particularly relevant in the setting of reperfusion injury after ischemia (Shimizu et al, 2013). Inhibition of TRPM2 ion channels with clotrimazole (CTZ) or genetic knockdown reduces ischemic injury in males, but not females (Jia et al, 2011; Verma et al, 2012; Shimizu et al, 2013; Quillinan et al, 2014; Shimizu et al, 2016). While we have previously shown that CTZ can be administered up to 2 h after onset of ischemia in stroke models (Shimizu et al, 2013), we have not previously investigated whether inhibiting TRPM2 at more extended time points provides neuroprotection.…”

The Current State of NAD+‐Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets

“…Several studies underline the function of the transacetylation product O AADPR as an important signaling molecule . In yeast, O AADPR was shown to be crucial for the chromatin binding of Sir2 .…”

“…In yeast, O AADPR was shown to be crucial for the chromatin binding of Sir2 . Furthermore, O AADPR is able to activate TRPM2 (transient receptor potential cation channel, subfamily M, member 2), a major regulator of cell survival under excessive exposure to oxidative stress . So‐called macrodomains have been identified as binding domains for O AADPR and other NAD + metabolites, such as ADP‐ribose (ADPR) or poly‐ADPR.…”

“…The potent and Sirt2‐selective α‐cyanopropenamide AGK2 ( 24 ) (Fig. ) is widely used to investigate the downstream effects of Sirt2 inhibition in cells and animals, despite its poor physicochemical properties and its poor water solubility.…”