Kirenol alleviates cerebral ischemic injury by promoting synaptic plasticity via HDAC2-mediated BDNF expression
Min Guo1, Yonghua Ye1, Xuezhen Li1
1Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
Background:
Ischemic stroke is an acute cerebrovascular disorder posing various public health challenges; however, the treatment is lacking. Kirenol (Kir), a natural diterpenoid compound with various bioactive properties, demonstrated potential neuroprotective effects on PC12 cells subjected to glutamic acid injury. However, the protective mechanism of Kir remains undefined.
Objective:
This study explored whether Kir could alleviate cerebral ischemic injury by protecting neurons and promoting synaptic plasticity. The molecular mechanisms involved were also elucidated.
Methods:
Kir was injected intraperitoneally into rats subjected to cerebral ischemic insult induced by middle cerebral artery occlusion-reperfusion (MCAO/R). Neurobiological changes, brain infarct size, apoptosis, neuroplasticity, and levels of target proteins were assessed. The mechanism of Kir in protecting neurons and promoting synaptic plasticity via histone deacetylase 2 (HDAC2)-mediated brain-derived neurotrophic factor (BDNF) expression was demonstrated using inhibitor of Tumorigenesis and Senescence Associated 1 (ITSA-1, an HDAC activator), suberoylanilide hydroxamic acid (SAHA, an HDAC inhibitor), and HDAC2 overexpression recombinant adenovirus.
Results:
Kir mitigated MCAO-induced cerebral infarct area, neurological deficits, histopathological damage, and neuronal apoptosis in rats. Kir effectively increased dendritic spine density, total dendritic length, and branching and upregulated the expression of key neuroplasticity proteins (GAP-43, PSD-95, Synapsin-I, and α-Synuclein). Mechanically, Kir significantly decreased HDAC2 expression and activity, facilitated an increase in H4 acetylation BDNF promoter II, enhancing BDNF expression, and activating the TrKB signaling pathway, thereby exerting neuroprotective effect in MCAO rats. The neuroprotection of Kir on neurons and synaptic plasticity were reversed by ITSA-1 and HDAC2 overexpression recombinant adenovirus.
Conclusion:
Kir exerted its protective effects through acetylation changes in histones and increased expression of BDNF-specific isoforms, thereby safeguarding neurons, promoting synaptic plasticity, and offering potential as a therapeutic agent for ischemic stroke.
