phenanthrenes and Cognition-Disorders

We previously showed that activity of the large conductance calcium-activated potassium (Big-K; BK) channels is suppressed in 3xTg Alzheimer disease (AD) model mice. However, its behavioral significance is not known. In the present report, ventricular injection of the BK channel activator isopimaric acid (ISO) was conducted to examine whether BK channel activation ameliorates cognition in 3xTg mice. The novel object recognition (NOR) test revealed that chronic injection of ISO improved non-spatial memory in 3xTg mice. In the Morris water maze, the probe test demonstrated an improved spatial memory after ISO injection. Electrophysiological underpinnings of the ISO effect were then examined in slices obtained from the mice after behavior. At hippocampal CA1 synapses, the basic synaptic transmission was abnormally elevated and long-term potentiation (LTP) was partially suppressed in 3xTg mice. These were both recovered by ISO treatment. We then confirmed suppressed BK channel activity in 3xTg mice by measuring the half-width of evoked action potentials. This was also recovered by ISO treatment. We previously showed that the recovery of BK channel activity accompanies reduction of neuronal excitability in pyramidal cells. Here again, pyramidal cell excitability, as assessed by calculating the frequency of evoked spikes, was elevated in the 3xTg mouse and was normalized by ISO. ELISA experiments demonstrated an ISO-induced reduction of Aβ1-42 content in hippocampal tissue in 3xTg mice. The present study thus suggests a potential therapeutic utility of BK channel activators for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; CA1 Region, Hippocampal; Carboxylic Acids; Charybdotoxin; Cognition Disorders; Disease Models, Animal; Drug Delivery Systems; Gene Expression Regulation; Humans; In Vitro Techniques; Large-Conductance Calcium-Activated Potassium Channels; Long-Term Potentiation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurotoxins; Patch-Clamp Techniques; Peptide Fragments; Phenanthrenes; Recognition, Psychology

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.

Topics: Aging; Animals; Cognition; Cognition Disorders; Diterpenes; Hippocampus; Male; Maze Learning; Mice; Neuronal Plasticity; Phenanthrenes; Receptors, N-Methyl-D-Aspartate; Synapses