Cholecystokinin release triggered by NMDA receptors produces LTP and sound-sound associative memory.

Memory is stored in neural networks via changes in synaptic strength mediated in part by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here we show that a cholecystokinin (CCK)-B receptor (CCKBR) antagonist blocks high-frequency stimulation-induced neocortical LTP, whereas local infusion of CCK induces LTP. CCK-/- mice lacked neocortical LTP and showed deficits in a cue-cue associative learning paradigm; and administration of CCK rescued associative learning deficits. High-frequency stimulation-induced neocortical LTP was completely blocked by either the NMDAR antagonist or the CCKBR antagonist, while application of either NMDA or CCK induced LTP after low-frequency stimulation. In the presence of CCK, LTP was still induced even after blockade of NMDARs. Local application of NMDA induced the release of CCK in the neocortex. These findings suggest that NMDARs control the release of CCK, which enables neocortical LTP and the formation of cue-cue associative memory.

The neuritogenic and neuroprotective potential of senegenin against Aß-induced neurotoxicity in PC 12 cells.

BACKGROUND: Improved therapeutics aimed at ameliorating the devastating effects of neurodegenerative diseases, such as Alzheimer's disease (AD), are pertinent to help attenuate their growing prevalence worldwide. One promising avenue for such therapeutics lies in botanical medicines that have been efficaciously employed in the likes of traditional medicine doctrines for millennium. Integral to this approach is the necessity of neuritogenesis and/or neuroprotection to counterbalance the deleterious effects of amyloid-ß (Aß) proteins. Senegenin, a principle saponin of Polygala tenuifolia Willd., which has empirically shown to improve cognition and intelligence, was chosen to evaluate its cytoprotective potential and possible neuritogenic and neuroprotective effects. METHODS: The purpose of the present study was then to analyze morphological changes in neurite development and altered protein expression of two proteins requisite to neuritogenesis, growth associated protein 43 (Gap-43) and microtubule-associated protein 2 (MAP2) in PC 12 cells. Neuritogenic analysis was conducted with immunofluorescence after incubation with Aß (25-35) peptide, and to deduce information on cell viability and mitochondrial functionality MTT (3,(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide) was employed. RESULTS: This study found that cells pre-incubated with senegenin for 24 h (40 µg and 20 µg/ml) before introducing Aß attenuated Aß-cytotoxicity, and significantly increased cell viability by 23 % and 34 % (P < 0.001), respectively. In neurite outgrowth experiments, Aß was compared to NGF positive control and senegenin treated groups which showed a drastic decrease in the quantity, average length and maximum length of neurites (P < 0.001). At concentrations of 1 µg/ml (P < 0.01) and 5 µg/ml (P < 0.05) senegenin triggered neuritogenesis with significant increases in total neurite number, average length and maximum length. This was additionally shown through the augmented expression of MAP2 and Gap-43. CONCLUSIONS: These results suggest that senegenin possesses cytoprotective properties, can moderate neurite outgrowth and augment MAP2 and Gap-43, thus suggesting a potential therapeutic value for Polygala tenuifolia in neurodegenerative disorders.

Are herbal compounds the next frontier for alleviating learning and memory impairments? An integrative look at memory, dementia and the promising therapeutics of traditional chinese medicines.

Recent advances in neuroscience have revealed a greater, in-depth understanding of the complexities associated with memory. Contemporary theories hold that an integral relationship between memory formation, stabilization and consolidation revolve around plasticity of neuronal networks. The associated requisite receptors α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-d-aspartate (NMDA) and cellular mechanisms surrounding plasticity (posed to incite molecular functionality), also display strong correlations in the pathogenesis of dementias. When the brain is in a diseased state as a result of malignant neurotransmission (i.e. in Alzheimer's disease; AD), the homeostatic balance required for normal neuronal processes is disrupted, which leads to degeneration of neural circuitry. Present efforts to find new treatments aimed at reversing or halting neurodegeneration are immense, with increasing attention being placed on investigating various herbal medicines. A wide variety of herbal plants (i.e. Panax ginseng, Polygala tenuifolia, Acorus gramineus and Huperzia serrata, examined here within), extracts and compounds have, to date, already presented advantageous results when tested against known pathogenic markers related to AD-associated dementia. The efficaciousness of herbal medicines appears to be a modulatory effect on neurotrophins, kinases and their substrates that, in turn, initiate or take part in intracellular cascades related to memory processes.