On February 9, a research article entitled ‘Extracellular spermine exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis’ was published in the Journal of Neuroscience. This work was carried out by Dr. Bo Duan and Ph.D candidate Yi-Zhi Wang, under the supervision of Dr. Tian-Le Xu.

Ischemic brain injury is a major problem associated with stroke. It has been increasingly recognized that acid-sensing ion channels (ASICs) contribute significantly to ischemic neuronal damage, but the underlying mechanism has remained elusive. Bo Duan and Yi-Zhi Wang showed that extracellular spermine, one of the endogenous polyamines, exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. Pharmacological blockade of ASIC1a or deletion of the ASIC1 gene greatly reduces the enhancing effect of spermine in ischemic neuronal damage both in cultures of dissociated neurons and in a mouse model of focal ischemia. Mechanistically, spermine profoundly reduces desensitization of ASIC1a by slowing down desensitization in the open state, shifting steady-state desensitization to more acidic pH, and accelerating recovery between repeated periods of acid stimulation. Spermine-mediated potentiation of ASIC1a activity is occluded by PcTX1, a specific ASIC1a inhibitor binding to its extracellular domain. Functionally, the enhanced channel activity is accompanied by increased acid-induced neuronal membrane depolarization and cytoplasmic Ca²⁺ overload, which may partially explain the exacerbated neuronal damage caused by spermine. More importantly, blocking endogenous spermine synthesis significantly attenuates ischemic brain injury mediated by ASIC1a but not that by N-methyl-D-aspartate receptors. Thus, extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. This paper suggests potential neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine-ASIC interaction.

This study was supported by grants from the National Natural Science Foundation of China, the National Basic Research Program of China, and the Shanghai Municipal Government. B. Duan is a postdoctoral fellow supported by the K. C. Wong Education Foundation (Hong Kong).

In a severe ischemia model (60 min MCAO), PcTX1 (1 μM) and DFMO (75 μg/μl) injection reduced the infarct volume in brains from WT mice in an additive manner compared to aCSF group from WT mice. Co-injection of SPM (2.5 mM) with DFMO reversed the neuroprotective effect of DFMO. ASIC1 deletion also reduced the infarct volume but DFMO was ineffective in ASIC1^-/- mice. Top images show examples of TTC-stained brain sections and infarct areas for the different treatment groups.