title: Tripchlorolide improves age-associated cognitive deficits by reversing hippocampal synaptic plasticity impairment and NMDA receptor dysfunction in SAMP8 mice.
abstract: Deficits in cognition and performance accompanying age-related neurodegenerative diseases such as Alzheimer's disease (AD) are closely associated with the impairment of synaptic plasticity. Here, using a mouse model of senescence-accelerated P8 (SAMP8), we reported the role of tripchlorolide (T4), an extract of the natural herb Tripterygium wilfordii Hook F, in improving cognitive deficits and promoting the long-term potentiation (LTP) of hippocampal slices via the N-methyl-D-aspartate receptor (NMDAR)-dependent signaling pathway. Our results demonstrated that chronic administration of T4 at low doses (0.25, 1.0, or 4.0 μg/kg per day, injected intraperitoneally for 75 days) significantly improved learning and memory function in aged SAMP8 mice, as indicated by a chain of behavioral tests including the Y-maze and Morris water maze. Additionally, T4 reversed the impaired LTP in hippocampal CA1 regions of SAMP8 mice in a dose-dependent manner. Moreover, it upregulated the levels of phospho-NMDAR1, postsynaptic density-95 (PSD-95), phospho-calcium-calmodulin dependent kinase II (CaMKII), phospho-CREB and brain derived neurotrophic factor (BDNF) in the hippocampus. This indicates that T4 prevents the impairment of NMDAR-mediated synaptic plasticity-related signal molecules. At optimal doses, T4 did not show significant side-effects on blood counts, blood biochemical measures, or survival of the mice. This novel mechanism in reversing age-related synaptic dysfunction and NMDAR functional deficits suggests that T4 can halt the manifestation of a key early-stage event in AD. With the consideration of SAMP8 mice as a model to develop therapeutic interventions for AD, our findings provide new insight into the clinical application of tripchlorolide in AD treatment.
authors.affiliation: Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, China; Key Laboratory of Brain Aging and Neurodegenerative Disease, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou 350001, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Lin
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Pan
authors.forename: Ai-qin
authors.initials: AQ
authors.lastname: Chen
authors.forename: Yuan-gui
authors.initials: YG
authors.lastname: Zhu
authors.forename: Ming
authors.initials: M
authors.lastname: Wu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiao-chun
authors.initials: XC
authors.lastname: Chen
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004224:Diterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D010616:Phenanthrenes / Q000494:pharmacology* / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology
chemical_list: D004224:Diterpenes; D010616:Phenanthrenes; D016194:Receptors, N-Methyl-D-Aspartate; C068051:tripchlorolide
keywords: AD; Aging; Alzheimer's Disease; BDNF; CREB; CaMKII; Cognition; EPSPs; LTP; Long-term potentiation; MWM; Morris water maze; N-methyl-d-aspartate receptor; NMDA receptor; NMDAR; PSD-95; SAMP8; Synaptic plasticity; T(4); Tripchlorolide; brain-derived neurotrophic factor; calcium/calmodulin-dependent protein kinase II; cyclic AMP-response element binding protein; excitatory postsynaptic potentials; long-term potentiation; postsynaptic density-95; senescence-accelerated mouse Prone 8 SAMR1; tripchlorolide