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Forty-seven million people are living with memory-related disorders worldwide. Phytomedicines are gaining extensive interest in the treatment of these ailments. Memory-enhancing (acute and chronic) potentials of commercial grade extracts of Bacopa monnieri (200 mg/kg, po), Ginkgo biloba (150 mg/kg, po), and Lavandula angustifolia (200 mg/kg, po) and their mixture (B. monnieri 100 mg/kg, G. biloba 75 mg/kg, and L. angustifolia 100 mg/kg, po) were compared for their synergistic/additive effects on the Morris water maze (MWM) test and elevated plus maze (EPM) test in scopolamine-induced amnesia in mice. Escape latency and accumulative path length were significantly reduced both in acute (up to day 6) and chronic trials (days 8-14) in B. monnieri-, G. biloba-, and L. angustifolia-treated animals and their mixtures (n = 8, p < .05) in MWM. Furthermore, in probe trials (acute on day 7 and chronic on day 15), the number of crossing-overs at platform position and time spent in platform quadrant were significantly increased, while transfer latency in EPM was decreased in treated animals as compared to the saline group (n = 8, p < .05). The mixture showed synergistic effects on memory enhancement as compared to each extract individually in mice. Further studies may be carried out on the active compounds of B. monnieri at the cellular and molecular levels.

Herein, we report the green synthesis of silver nanoparticles using the aqueous extract of root of Angilica glauca Edgew. UV-vis and FT-IR spectroscopies, X-ray diffraction analysis and scanning el...

Norepinephrine, is involved in the enhancement of learning and memory formation by regulating synaptic mechanisms through its ability to activate pre- and post-synaptic adrenergic receptors. Here we show that β-agonists of norepinephrine facilitate the induction of both associational LTP and sharp wave ripples (SPW-Rs) in acute slices of rat hippocampus in area CA3. Surprisingly, this facilitating effect persists when slices are only pretreated with β-receptor agonists followed by wash out and application of the unspecific β-adrenoreceptor (βAR) antagonist propranolol. During application of βAR agonists repeated stimulation resulted in facilitated induction of SPW-Rs. Since SPW-Rs are thought to be involved in memory replay we studied the effects of βAR-agonists on spontaneous SPW-Rs in murine hippocampus and found that amplitude and incidence of SPW-Rs increased. These effects involve cyclic-AMP and the activation of protein kinase A and suggest a supportive role in memory consolidation. © 2016 Wiley Periodicals, Inc.

Parasitic Cuscuta reflexa Roxb. possesses many medicinal properties and is a rich source of a variety of biologically relevant natural products. Natural products are the prime source of leads, drugs, and drug templates, and many of the anticancer and antiviral drugs are either based on natural product or derived from them. Cancer is a devastating disease and one of the leading causes of death worldwide despite improvements in patient survival during the past 50 years; new and improved treatments for cancer are therefore actively sought. Colorectal cancer is the fourth most prevalent cancer worldwide and is responsible for nearly 9% of all cancer deaths. Our search for anticancer natural products from C. reflexa has yielded four natural products: Scoparone (1), p-coumaric acid (2), stigmasta-3,5-diene (3) and 1-O-p-hydroxycinnamoylglucose (4) and among them 1-O-p-hydroxycinnamoyldlucose (4) showed promising antiproliferative activities in HCT116 colorectal cell lines, whereas compounds 1–3 showed moderate activities.

Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated.

Nicotine sensory perception is generally thought to be mediated by nicotinic acetylcholine (nACh) receptors. However, recent data strongly support the idea that other receptors (e.g., transient receptor potential A1 channel, TRPA1) and other pathways contribute to the detection mechanisms underlying the olfactory and trigeminal cell response to nicotine flavor. This is in accordance with the reported ability of humans to discriminate between (+)- and (-)- nicotine enantiomers. To get a more detailed understanding of the molecular and cellular basis underlying the sensory perception of nicotine, we studied the activity of (+)- and (-)-nicotine on cultured murine trigeminal sensory neurons and on a range of heterologously expressed receptors. The human TRPA1 channel is activated by (-)-nicotine. In this work, we show that (+)-nicotine is also an activator of this channel. Pharmacological experiments using nicotinic acetylcholine receptors and transient receptor potential blockers revealed that trigeminal neurons express one or more unidentified receptors that are sensitive to (+)- and/or (-)-nicotine. Results also indicate that the presence of extracellular calcium ions is required to elicit trigeminal neuron responses to (+)- and (-)-nicotine. Results also show that both (+)-nicotine and (-)-nicotine can block 5-hydroxytryptamine type 3 (5-HT3) receptor-mediated responses in recombinant expression systems and in cultured trigeminal neurons expressing 5-HT3 receptors. Our investigations broaden the spectra of receptors that are targets for nicotine enantiomers and give new insights into the physiological role of nicotine.

Transient receptor potential vanilloid subtype 3 (TRPV3) is a thermosensitive ion channel expressed in a variety of neural cells and in keratinocytes. It is activated by warmth (33–39°C), and its responsiveness is dramatically increased at nociceptive temperatures greater than 40°C. Monoterpenoids and 2-APB are chemical activators of TRPV3 channels. We found that Icilin, a known cooling substance and putative ligand of TRPM8, reversibly inhibits TRPV3 activity at nanomolar concentrations in expression systems likeXenopus laevesoocytes, HEK-293 cells, and in cultured human keratinocytes. Our data show that icilin's antagonistic effects for the warm-sensitive TRPV3 ion channel occurs at very low concentrations. Therefore, the cooling effect evoked by icilin may at least in part be due to TRPV3 inhibition in addition to TRPM8 potentiation. Blockade of TRPV3 activity by icilin at such low concentrations might have important implications for overall cooling sensations detected by keratinocytes and free nerve endings in skin. We hypothesize that blockage of TRPV3 might be a signal for cool-sensing systems (like TRPM8) to beat up the basal activity resulting in increased cold perception when warmth sensors (like TRPV3) are shut off.

PURPOSE: Transient receptor potential melastatin-8 (TRPM8) is an ion channel expressed extensively in sensory nerves, human prostate and overexpressed in a variety of cancers including prostate, breast, lung, colon and skin melanomas. It is activated by innoxious cooling and chemical stimuli. TRPM8 activation by cooling or chemical agonists is reported to induce profound analgesia in neuropathic pain conditions. Known TRPM8 agonists like menthol and icilin cross-activate other thermo-TRP channels like TRPV3 and TRPA1 and mutually inhibit TRPM8. This limits the usefulness of menthol and icilin as TRPM8 ligands. Consequently, the identification of selective and potent ligands for TRPM8 is of high relevance both in basic research and for therapeutic applications. In the present investigation, a group of menthol derivates was characterized. These ligands are selective and potent agonists of TRPM8. Interestingly they do not activate other thermo-TRPs like TRPA1, TRPV1, TRPV2, TRPV3 and TRPV4. These ion channels are also nociceptors and target of many inflammatory mediators. METHODS: Investigations were performed in a recombinant system: Xenopus oocytes microinjected with cRNA of gene of interest were superfused with the test substances after initial responses of known standard agonists. Evoked currents were measured by two-electrode voltage clamp technique. RESULTS: The newly characterized ligands possess an up to six-fold higher potency (EC50 in low µM) and an up to two-fold increase in efficacy compared to the parent compound menthol. In addition, it is found that chemical derivatives of menthol like CPS-368, CPS-369, CPS-125, WS-5 and WS-12 are the most selective ligands for TRPM8. The enhanced activity and selectivity seems to be conferred by hexacyclic ring structure present in all ligands as substances like WS-23 which lack this functional group activate TRPM8 with much lower potency (EC50 in mM) and those with pentacyclcic ring structure (furanone compounds) are totally inactive. CONCLUSION: The new substances activate TRPM8 with a higher potency, efficacy and specificity than menthol and will thus be of importance for the development of pharmacological agents suitable for treatment and diagnosis of certain cancers and as analgesics. STATEMENT OF NOVELTY: The new compounds have an unmatched specificity for TRPM8 ion channels with additional display of high potency and efficacy. Thus these substances are better pharmacological tools for TRPM8 characterization then known compounds and it is suggested that these menthol-derivates may serve as model substances for the development of TRPM8 ligands.

Transient receptor potential vanilloid-3 (TRPV3) is a thermo-sensitive ion channel expressed in skin keratinocytes and in a variety of neural cells. It is activated by warmth as well as monoterpenoids including camphor, menthol, dihydrocarveol and 1,8-cineol. TRPV3 is described as a putative nociceptor and previous studies revealed sensitization of the channel during repeated short-term stimulation with different agonists. In the present investigation TRPV3 was transiently expressed in either Xenopus oocytes or HEK293 cells. Whole-cell voltage-clamp techniques were used to characterize the behavior of TRPV3 when challenged with different agonists. Similarly, a human keratinocyte-derived cell line (HaCaT cells) was used to monitor the behavior of native TRPV3 when challenged with different agonists. We report here that prolonged exposure (5-15 minutes) of monoterpenoids results in agonist-specific desensitization of TRPV3. Long-term exposure to camphor and 1,8-cineol elicits desensitizing currents in TRPV3 expressing oocytes, whereas the non-terpenoid agonist 2-APB induces sustained currents. Agonist-specific desensitization of endogenous TRPV3 was also found in HaCaT cells, which may be taken as a representative for the native system. Terpenoids have a long history of use in therapeutics, pharmaceuticals and cosmetics but knowledge about underpinning molecular mechanisms is incomplete. Our finding on agonist-induced desensitization of TRPV3 by some monoterpenoids displays a novel mechanism through which TRP channels could be functionally modulated. Therefore, we conclude that desensitization of TRPV3 channels might be the molecular basis of action for some of the medicinal properties of camphor and 1,8-cineol.