Kirenol Alleviates Cerebral Ischemic Injury by Promoting Synaptic Plasticity Via Hdac2-Mediated Bdnf Expression

Abstract

BackgroundIschemic stroke is a devastating acute cerebrovascular disorder, leading to various public health challenges, but the treatment is still lacking. Kirenol (Kir), a natural diterpenoid compound with a variety of bioactive properties, has been preliminarily reported to have potential neuroprotective effects on PC12 cells subjected to glutamic acid injury. However, the protective mechanisms of Kir remains unknown.ObjectiveTo explore whether Kir can alleviate cerebral ischemic injury by protecting neurons and promoting synaptic plasticity, and to elucidate the molecular mechanisms involved.MethodsKir was administered by intraperitoneal injection on rats subjected to cerebral ischemic insult induced by middle cerebral artery occlusion-reperfusion (MCAO/R). Various neurobiological changes, brain infarct size, apoptosis, and neuroplasticity in the rats and levels of target proteins were subsequently assessed. The mechanism of Kir in protecting neurons and promoting synaptic plasticity through HDAC2-mediated BDNF expression was further confirmed by using ITSA-1 (an HDAC activator), SAHA (an HDAC inhibitor), and HDAC2 overexpression recombinant adenovirus.ResultsKir obviously mitigated MCAO-induced cerebral infarct area, neurological deficits, histopathological damage, and neuronal apoptosis in rats. Besides, Kir effectively increased dendritic spine density, total dendritic length, and branching, and upregulated the expression of key axonal proteins (MAP2, GAP43, and PSD-95). Moreover, Kir significantly decreased HDAC2 expression and it’s activity, facilitated an increase in H3 acetylation acetylation BDNF promoter II leads to an increase in the expression of BDNF. Mechanistically, the neuroprotection of Kir on neurons and synaptic plasticity were reversed by ITSA-1 and HDAC2 overexpression recombinant adenovirus.ConclusionsThese findings revealed that Kir exerts its profound protective effects through changes of acetylation on histones and increase BDNF specific isoforms expression, thereby safeguarding neurons, promoting synaptic plasticity, offering potential as a therapeutic agent for ischemic stroke.

Note:
Funding declaration: The study is supported by the National Natural Science Foundation of China (Grant No.81803768), the Natural Science Foundation of Fujian Province, China (Grant No. 2024J01127), “Select the best candidates to lead key research projects” of Fujian University of Traditional Chinese Medicine (XJB2023001), Foundation of Fujian University of Traditional Chinese Medicine (X2023001-Talent) and School Project of Fujian University of Traditional Chinese Medicine (Grant No. XJC2023013) for the support extended for the present work.

Conflict of Interests: The authors declare that they have no competing interests.

Ethical Approval: All experimental procedures were approved by the Animal Care and Use Committee of Fujian University of Traditional Chinese Medicine and conformed to the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health (Ethics approval number for animal use is FJTCM IACUC 2021087).

Keywords: ischemic stroke, Kirenol, Neuroprotection, Histone acetylation, Synaptic plasticity