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Ischemic stroke has long been a significant global health concern, causing a range of symptoms including dizziness, limb numbness, paralysis, and even death. According to the World Health Organization (WHO), there are approximately 15 million new cases of stroke worldwide each year, with ischemic strokes accounting for about 85% of these cases. Stroke has become the second leading cause of death and the third leading cause of disability globally.

On July 10, 2024, a groundbreaking study titled "Glutamate acts on acid-sensing ion channels to worsen ischemic brain injury" was published in Nature, revealing the primary cause of brain damage in ischemic stroke and elucidating its underlying mechanism. This research, conducted by the team of Professors Shankai Yin and Bohai Shi from the Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, offers new directions for drug treatments of ischemic stroke-induced brain damage. The study highlights the potential of ASICs (acid-sensing ion channels) as novel therapeutic targets for ischemic stroke.

What are ASICs?

Acid-sensing ion channels (ASICs) are a type of protein complex that allows the passage of cations across cell membranes. They belong to the epithelial sodium channel/degenerin (ENaC/DEG) superfamily and play crucial roles in sensing extracellular pH changes and regulating various physiological functions such as pain sensation and taste. Inflammation can induce the transcription of ASICs and post-transcriptional regulation, affecting neuronal excitability and contributing to pain sensitization. ASIC3, mainly found in peripheral nociceptors, is closely related to pain hypersensitivity due to its ability to quickly activate and mediate sustained currents. In the neurons of the brain, ASICs are involved in multiple physiological processes and are linked to conditions such as stroke and chronic pain.

Glutamate's Action on ASICs

Previously, glutamate was recognized as the primary messenger in activating NMDA receptor (NMDAR)-dependent cell death pathways during stroke. However, the study found that glutamate increases the affinity of ASICs for protons and their open probability, exacerbating ischemic neurotoxicity in both in vitro and in vivo models. This novel discovery contrasts with earlier research that predominantly focused on NMDAR antagonists, which often have psychiatric side effects and fail to significantly improve neurological function in stroke patients. Therefore, targeting the glutamate binding sites on ASICs presents a promising alternative to NMDAR-based therapies.

Glutamate aggravates neurotoxicity in vitro and in vivo.

a–c, Examples and summary of changes in [Ca2+]i levels and time-course imaging in primary cultured cortical neurons from Asic1a (n = 18 and 18 cells from 3 cultures per group) and Asic1a+/+−/− (n = 16 and 18 cells from 3 cultures per group) mice with and without addition of 200 μM glutamate to the pH 7.0 solution. AUC, area under the curve. d, IASICs evoked at pH 7.0 from cultured cortical neurons for 30 s with and without glutamate. e, The peak amplitude and integral area of IASICs from d were pooled from n = 10 cells from 3 replicated cultures. 50 μM D-AP5, 10 μM NBQX and 10 μM LY341495 were applied. f, Schematic of the cell death experiment. DIV, days in vitro; P0, postnatal day 0. The diagram was created using BioRender (https://biorender.com). g, Calcein–propidium iodide (PI) staining of cultured neurons from Asic1a and Asic1a+/+−/− mice under different conditions: pH 7.4 or 7.0 with or without 100 ng ml−1 PcTX-1 or GluR-B; glutamate receptor blockers consisted of 50 μM D-AP5, 10 μM NBQX and 10 μM LY341495. h, Summary of the percentage of cell death calculated by calcein (live cells) and propidium iodide (dead cells) counting. n = 10–13 images from 3 replicated cultures for each group. i, LDH release from cultured neurons. n = 8 cultures for each group. j, The relative glutamate release with or without 1 h OGD. n = 5 cultures per group. k, Histology images of brain slices from mice subjected to MCAO. l, Quantification of the infarct volume after MCAO mice were injected with physiological saline and memantine (mem; 1 mg per kg). n = 3, 11, 8 and 9 mice for each group. Data are mean ± s.e.m. Statistical analysis was performed using two-tailed paired t-tests (e), and two-way (c,h,i) and one-way ANOVA (j,l) with Tukey post hoc correction.

Credit:Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury

Research Insights

In the study led by Professors Yin and Shi, researchers utilized various experimental techniques, including gene transfection and cellular electrophysiology, to comprehensively analyze the effects of glutamate on ASIC activation dynamics. The study unveiled a new molecular basis linking glutamate to ischemic stroke-induced brain damage.

Remarkably, the research also demonstrated that traditional NMDAR agonists and even NMDAR antagonists enhance ASIC-mediated currents and promote ASIC activation, indicating that these drugs might not protect neurons as previously thought, but rather exacerbate neural damage. This finding partially explains why NMDAR antagonists have failed to yield therapeutic benefits in stroke treatment.

Future Directions

The medical community has long sought direct ion channel-targeting therapies for ischemic stroke, but no such neuroprotective drugs have been marketed to date. The research team has identified related small-molecule compounds, potentially paving the way for new targeted therapies for ischemic stroke. This discovery offers a conceptual paradigm for understanding the mechanisms of ischemic neurotoxicity and developing new stroke treatment strategies independent of NMDAR.

Ischemic stroke remains a major public health challenge globally. Despite significant progress in prevention and treatment, continuous efforts in global cooperation and innovation are necessary to further reduce the burden of stroke.

By shedding light on the critical role of ASICs in ischemic brain injury, this study provides a promising avenue for the development of novel therapeutic interventions, potentially revolutionizing the treatment landscape for ischemic stroke patients worldwide.

Reference:

1. Lai, K., Pritišanac, I., Liu, ZQ. et al. Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury. Nature (2024). https://doi.org/10.1038/s41586-024-07684-7

2. https://www.who.int/srilanka/news/detail/29-10-2022-world-stroke-day-2022