Format

Send to

Choose Destination
Behav Brain Res. 2014 Jan 1;258:8-18. doi: 10.1016/j.bbr.2013.10.010. Epub 2013 Oct 17.

Tripchlorolide improves age-associated cognitive deficits by reversing hippocampal synaptic plasticity impairment and NMDA receptor dysfunction in SAMP8 mice.

Author information

1
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.

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.

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

PMID:
24140565
DOI:
10.1016/j.bbr.2013.10.010
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center