The effect of 3-hydroxybutyrate methyl ester on learning and memory in mice.
Learning and memory requires energy-demanding cellular processes and can be enhanced when the brain is supplemented with metabolic substrates. In this study, we found that neuroglial cell metabolic activity was significantly elevated when cultured in the presence of polyhydroxybutyrate (PHB) degradation product 3-hydroxybutyrate (3-HB) and derivatives. We demonstrated that the receptor for 3-HB, namely, protein upregulated in macrophages by IFN-gamma (PUMA-G), was expressed in brain and upregulated in mice treated with 3-hydroxybutyrate methyl ester (3-HBME). We also affirmed increased expression of connexin 36 protein and phosphorylated ERK2 (extracellular signal-regulated kinase 2) in brain tissues following 3-HBME treatment, although these differences were not statistically significant. Mice treated with 3-HBME performed significantly (p<0.05) better in the Morris water maze than either the negative controls (no treatment) or positive controls (acetyl-l-carnitine treatment). Moreover, we found that 3-HBME enhanced gap junctional intercellular communication between neurons. Thus, 3-HB and derivatives enhance learning and memory, possibly through a signaling pathway requiring PUMA-G that increases protein synthesis and gap junctional intercellular communication.
Zou
Xiang-Hui
XH
Multidisciplinary Research Center, Shantou University, Shantou, Guangdong, China.
Li
Hong-Ming
HM
Wang
Sheng
S
Leski
Michael
M
Yao
Yong-Chao
YC
Yang
Xiao-Di
XD
Huang
Qing-Jun
QJ
Chen
Guo-Qiang
GQ
D000108:Acetylcarnitine / Q000494:pharmacology; D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D017630:Connexins / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D006885:Hydroxybutyrates / Q000494:pharmacology*; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D000097004:Gap Junction delta-2 Protein
D000108:Acetylcarnitine; D017630:Connexins; D006885:Hydroxybutyrates; D019950:Mitogen-Activated Protein Kinase 1; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D000097004:Gap Junction delta-2 Protein; C539306:3-hydroxybutyrate methyl ester; C473652:Hcar2 protein, mouse