Suppression of DAPK1 reduces ischemic brain injury through inhibiting cell death signaling and promoting neural remodeling

Jinyoung Won; Seunghoon Lee; Zeeshan Ahmad Khan; Jeonghyun Choi; Tae Ho Lee; Yonggeun Hong

doi:10.1016/j.brainres.2023.148588

Suppression of DAPK1 reduces ischemic brain injury through inhibiting cell death signaling and promoting neural remodeling

Brain Res. 2023 Dec 1:1820:148588. doi: 10.1016/j.brainres.2023.148588. Epub 2023 Sep 23.

Authors

Jinyoung Won¹, Seunghoon Lee², Zeeshan Ahmad Khan², Jeonghyun Choi¹, Tae Ho Lee³, Yonggeun Hong⁴

Affiliations

¹ Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, South Korea; Biohealth Products Research Center (BPRC), Inje University, Gimhae, South Korea; Research Center for Aged-life Redesign (RCAR), Inje University, Gimhae, South Korea.
² Biohealth Products Research Center (BPRC), Inje University, Gimhae, South Korea; Research Center for Aged-life Redesign (RCAR), Inje University, Gimhae, South Korea; Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Inje University, Gimhae, South Korea.
³ Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Science, Fujian Medical University, Fuzhou, China.
⁴ Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, South Korea; Biohealth Products Research Center (BPRC), Inje University, Gimhae, South Korea; Research Center for Aged-life Redesign (RCAR), Inje University, Gimhae, South Korea; Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Inje University, Gimhae, South Korea. Electronic address: yonghong@inje.ac.kr.

PMID: 37742938
DOI: 10.1016/j.brainres.2023.148588

Abstract

The role of death-associated protein kinase1 (DAPK1) in post-stroke functional recovery is controversial, as is its mechanism of action and any neural remodeling effect after ischemia. To assess the debatable role of DAPK1, we established the middle cerebral artery occlusion (MCAo) model in DAPK1 knockout mice and Sprague-Dawley (SD) rats. We identified that the genetic deletion of the DAPK1 as well as pharmacological inhibition of DAPK1 showed reduced brain infarct volume and neurological deficit. We report that DAPK1 inhibition (DI) reduces post-stroke neuronal death by inhibiting BAX/BCL2 and LC3/Beclin1 mediated apoptosis and autophagy, respectively. Histological analysis displayed a reduction in nuclear condensation, neuronal dissociation, and degraded cytoplasm in the DI group. The DI treatment showed enhanced dendrite spine density and neurite outgrowth, upregulated neural proliferation marker proteins like brain-derived neurotrophic factor, and reduced structural abnormalities of the cortical pyramidal neurons. This research shows that DAPK1 drives cell death, its activation exacerbates functional recovery after cerebral ischemia and shows that oxazolone-based DI could be an excellent candidate for stroke and ischemic injury intervention.

Keywords: Cerebral ischemia; Death-associated protein kinase; Functional recovery; Neural remodeling; Stroke.