Ketogenic diet and β-Hydroxybutyrate alleviate ischemic brain injury in mice via an IRAKM-dependent pathway

Chuman Lin; Shengnan Wang; Jiaxin Xie; Juan Zhu; Jiawei Xu; Kewei Liu; Jiancong Chen; Mingjia Yu; Hengren Zhong; Kaibin Huang; Suyue Pan

doi:10.1016/j.ejphar.2023.175933

Ketogenic diet and β-Hydroxybutyrate alleviate ischemic brain injury in mice via an IRAKM-dependent pathway

Eur J Pharmacol. 2023 Sep 15:955:175933. doi: 10.1016/j.ejphar.2023.175933. Epub 2023 Jul 20.

Authors

Chuman Lin¹, Shengnan Wang², Jiaxin Xie¹, Juan Zhu¹, Jiawei Xu¹, Kewei Liu¹, Jiancong Chen¹, Mingjia Yu¹, Hengren Zhong³, Kaibin Huang⁴, Suyue Pan⁵

Affiliations

¹ Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
² Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Department of Critical Care Medicine, Baiyun Branch, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510420, China.
³ Department of Clinical Research Center, Hainan Provincial Hospital of Chinese Medicine, Haikou, Hainan, 570203, China.
⁴ Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China. Electronic address: hkb@smu.edu.cn.
⁵ Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China. Electronic address: pansuyue@smu.edu.cn.

PMID: 37481199
DOI: 10.1016/j.ejphar.2023.175933

Abstract

Ketogenic diet (KD) is a classical nonpharmacological therapy that has recently been shown to benefit cerebral ischemia, but the mechanism remains unclear. This study investigated the neuroprotective effects of KD pretreatment and β-hydroxybutyrate (BHB, bioactive product of KD) post-treatment in a mouse model of temporary middle cerebral artery occlusion (tMCAO). Neurological function, infarct volume, as well as inflammatory reactions are evaluated 24 h after ischemia. Results showed that both KD pretreatment or BHB post-treatment improved the Bederson score and Grip test score, reduced infarct volume and the extravasation of IgG, suppressed the over-activation of microglia, and modulated the expression of cytokines. Mechanically, we found that both KD pretreatment or BHB post-treatment significantly stimulated the expression of interleukin-1 receptor-associated kinase M (IRAKM) and then inhibited the nuclear translocation of NF-κB. IRAKM deletion (Irakm^-/-) exacerbated tMCAO-induced neurovascular injuries, and aggravated neuroinflammatory response. Moreover, KD pretreatment or BHB post-treatment lost their neuroprotection in the tMCAO-treated Irakm^-/- mice. Our results support that KD pretreatment and BHB post-treatment alleviate ischemic brain injury in mice, possibly via an IRAKM-dependent way.

Keywords: IRAKM; Ischemic brain injury; Ketogenic diet; Proinflammatory cytokines; β-Hydroxybutyrate.