Pro-neurogenesis and anti-dementia properties of tetradecyl 2,3-dihydroxybenzoate through TrkA receptor-mediated signalling pathways.
Tetradecyl 2,3-dihydroxybenzoate, termed ABG001, has been reported to enhance neurite outgrowth of PC12 cells. Herein, we report that oral administration of ABG001 for five days to adult male mice could dose-dependently enhance survival and neurite growth of newborn cells in hippocampal dentate gyrus (DG) without changes in cell proliferation and differentiation of progenitor cells. The ABG001 administration (0.5 mg/kg) enhanced the phosphorylation of tyrosine kinase A (TrkA) receptor, which induced increases in the levels of ERK, Akt and mTOR phosphorylation in hippocampus. The pro-neurogenesis of ABG001 was blocked by the TrkA receptor inhibitor K252a. By contrast, the ERK inhibitor U0126 attenuated only the ABG001-increased number of newborn cells, while the PI3K inhibitor LY294002 prevented mainly the ABG001-enhanced neurite growth. In comparison with control mice, the mice treated with ABG001 showed a more preferential spatial cognitive function as assessed by Morris water maze and Y maze tests, which was sensitive to the blockade of TrkA receptor. In addition, a single injection (i.c.v.) of 'aggregated' Aβ 25-35 in adult male mice (Aβ 25-35-mice) impaired spatial memory, survival and neurite growth of newborn cells in the DG with reduced phosphorylation of Akt and mTOR. The treatment of Aβ 25-35-mice with ABG001 could protect the survival and neurite growth of newborn cells through increasing TrkA receptor-induced phosphorylation of Akt and mTOR, which was accompanied by the improvement of spatial cognitive performance.
Department of Physiology,Nanjing Medical University,Nanjing,PR China.
Libin
L
Zhou
Department of Physiology,Nanjing Medical University,Nanjing,PR China.
Zihong
Z
Lu
Department of Physiology,Nanjing Medical University,Nanjing,PR China.
Lin
L
Li
Department of Physiology,Nanjing Medical University,Nanjing,PR China.
Lei
L
Chen
College of Pharmaceutical Sciences, Zhejiang University,Hangzhou,PR China.
Jianhua
J
Qi
Department of Physiology,Nanjing Medical University,Nanjing,PR China.
Ling
L
Chen
D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D003704:Dementia / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects; D062385:Hydroxybenzoates / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D016229:Amyloid beta-Peptides; D000089622:Doublecortin Domain Proteins; D005904:Glial Fibrillary Acidic Protein; D062385:Hydroxybenzoates; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D010446:Peptide Fragments; D012333:RNA, Messenger; C074636:amyloid beta-protein (25-35); C571109:tetradecyl-2,3-dihydroxybenzoate; C546843:mTOR protein, mouse; D020917:Receptor, trkA; D058570:TOR Serine-Threonine Kinases; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine