The alpha2-adrenoceptor agonist clonidine protects against hypoxic-ischemic brain damage in neonatal mice through the Nrf2/NF-κB signaling pathway

Daojing Su; Huan Gao; Min He; Hu Hao; Heng Liao; Su Zheng

doi:10.1016/j.imlet.2024.106928

The alpha2-adrenoceptor agonist clonidine protects against hypoxic-ischemic brain damage in neonatal mice through the Nrf2/NF-κB signaling pathway

Immunol Lett. 2024 Sep 17:270:106928. doi: 10.1016/j.imlet.2024.106928. Online ahead of print.

Authors

Daojing Su¹, Huan Gao², Min He³, Hu Hao⁴, Heng Liao⁵, Su Zheng⁶

Affiliations

¹ Department of Orthopedic Rehabilitation, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China.
² Department of Sleep and Psychosomatic Medicine Center, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China. Electronic address: huangao12356@sina.com.
³ Department of Gynecology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China.
⁴ Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China.
⁵ Department of Sleep and Psychosomatic Medicine Center, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China.
⁶ Second Department of Orthopedic Rehabilitation, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China.

PMID: 39299652
DOI: 10.1016/j.imlet.2024.106928

Abstract

Neonatal hypoxic-ischemic brain damage (HIBD) is a severe condition closely associated with neuroinflammation and oxidative stress. Clonidine, a selective α2-adrenergic receptor agonist, is known for its anti-inflammatory and antioxidant properties. Despite these recognized therapeutic benefits, the exact mechanisms by which clonidine exerts its effects in the context of HIBD are not fully understood. This study was designed to thoroughly investigate the impact of clonidine on HIBD-induced neuronal injury and to clarify its underlying mechanism of action. We employed a neonatal mouse model of HIBD to meticulously assess the effects of clonidine on neuronal injury, apoptosis, inflammation, and oxidative stress markers. In addition, we conducted extensive in vitro studies to evaluate the neuroprotective effects of clonidine on primary hippocampal neuronal cells, utilizing advanced techniques such as the Cell Counting Kit-8 (CCK-8), flow cytometry, enzyme-linked immunosorbent assay (ELISA), immunofluorescence assay, and western blotting. Furthermore, we explored the regulatory effects of clonidine on the nuclear factor erythroid 2-related factor (Nrf2)/nuclear factor-κB (NF-κB) signaling pathway through a combination of in vivo and in vitro experiments. The results showed that clonidine significantly reduced cerebral infarction, neuronal damage, and apoptosis in HIBD mice. It also alleviated neuroinflammation and oxidative stress, improved cell viability, and reduced neuronal injury following oxygen-glucose deprivation/reoxygenation (OGD/R). The neuroprotective effects of clonidine were linked to the activation of the Nrf2/heme oxygenase-1 (HO-1) pathway and the inhibition of the NF-κB pathway. Overall, clonidine exhibited neuroprotective properties in HIBD by reducing neuroinflammation and oxidative stress, likely through the modulation of the Nrf2/NF-κB signaling pathway.

Keywords: Clonidine; Hypoxic-ischemic brain damage; NF-κB; Neuroinflammation; Nrf2; Oxidative stress.