Multifunctional TRPV1 Ion Channels in Physiology and Pathology with Focus on the Brain, Vasculature, and Some Visceral Systems.

TRPV1 has been originally cloned as the heat and capsaicin receptor implicated in acute pain signalling, while further research has shifted the focus to its importance in chronic pain caused by inflammation and associated with this TRPV1 sensitization. However, accumulating evidence suggests that, apart from pain signalling, TRPV1 subserves many other unrelated to nociception functions in the nervous system. In the brain, TRPV1 can modulate synaptic transmission via both pre- and postsynaptic mechanisms and there is a functional crosstalk between GABA receptors and TRPV1. Other fundamental processes include TRPV1 role in plasticity, microglia-to-neuron communication, and brain development. Moreover, TRPV1 is widely expressed in the peripheral tissues, including the vasculature, gastrointestinal tract, urinary bladder, epithelial cells, and the cells of the immune system. TRPV1 can be activated by a large array of physical (heat, mechanical stimuli) and chemical factors (e.g., protons, capsaicin, resiniferatoxin, and endogenous ligands, such as endovanilloids). This causes two general cell effects, membrane depolarization and calcium influx, thus triggering depending on the cell-type diverse functional responses ranging from neuronal excitation to secretion and smooth muscle contraction. Here, we review recent research on the diverse TRPV1 functions with focus on the brain, vasculature, and some visceral systems as the basis of our better understanding of TRPV1 role in different human disorders.

Curcuminoids and Novel Opportunities for the Treatment of Alzheimer's Disease: Which Molecules are Actually Effective?

BACKGROUND: Millions of people worldwide are suffering from Alzheimer's disease (AD), and there are only symptomatic treatments available for this disease. Thus, there is a great need to identify drugs capable of arresting or reversing AD. Constituents of the spice turmeric, in particular, curcuminoids, seem to be very promising, as evident from in vitro experiments and tests using animal models of AD. However, most of the clinical trials did not reveal any beneficial effects of curcuminoids in the treatment of AD. These controversies, including conflicting results of clinical trials, are thought to be related to bioavailability of curcuminoids, which is low unless it is enhanced by developing a special formulation. However, there is growing evidence suggesting that other reasons may be of even greater importance, but these avenues are less explored. OBJECTIVE: Review relevant literature, and analyze potential reasons for the controversial results. METHODOLOGY: Recent in vitro and preclinical studies; clinical trials (without a limiting period) were searched in PubMed and Google Scholar. RESULTS: While recent in vitro and preclinical studies confirm the therapeutic potential of curcuminoids in the treatment of AD and cognitive dysfunctions, results of corresponding clinical trials remain rather controversial. CONCLUSION: The controversial results obtained in the clinical trials may be in part due to particularities of the curcuminoid formulations other than bioavailability. Namely, it seems likely that the various formulations differ in terms of their minor turmeric constituent(s). We hypothesize that these distinctions may be of key importance for efficacy of the particular formulation in clinical trials. A testable approach addressing this hypothesis is suggested.

TRP Channels as Novel Targets for Endogenous Ligands: Focus on Endocannabinoids and Nociceptive Signalling.

BACKGROUND: Chronic pain is a significant clinical problem and a very complex pathophysiological phenomenon. There is growing evidence that targeting the endocannabinoid system may be a useful approach to pain alleviation. Classically, the system includes G protein-coupled receptors of the CB1 and CB2 subtypes and their endogenous ligands. More recently, several subtypes of the large superfamily of cation TRP channels have been coined as "ionotropic cannabinoid receptors", thus highlighting their role in cannabinoid signalling. Thus, the aim of this review was to explore the intimate connection between several "painful" TRP channels, endocannabinoids and nociceptive signalling. METHODS: Research literature on this topic was critically reviewed allowing us not only summarize the existing evidence in this area of research, but also propose several possible cellular mechanisms linking nociceptive and cannabinoid signaling with TRP channels. RESULTS: We begin with an overview of physiology of the endocannabinoid system and its major components, namely CB1 and CB2 G protein-coupled receptors, their two most studied endogenous ligands, anandamide and 2-AG, and several enzymes involved in endocannabinoid biosynthesis and degradation. The role of different endocannabinoids in the regulation of synaptic transmission is then discussed in detail. The connection between the endocannabinoid system and several TRP channels, especially TRPV1-4, TRPA1 and TRPM8, is then explored, while highlighting the role of these same channels in pain signalling. CONCLUSION: There is increasing evidence implicating several TRP subtypes not only as an integral part of the endocannabinoid system, but also as promising molecular targets for pain alleviation with the use of endo- and phytocannabinoids, especially when the function of these channels is upregulated under inflammatory conditions.

Possible role of mitochondria in posttetanic potentiation of GABAergic synaptic transmission in rat neocortical cell cultures.

It has been previously demonstrated that mitochondria are of crucial importance for posttetanic potentiation (PTP) at neuromuscular junction. The aim of our study was to examine whether this may also be the case at a central synapse. To address this question, we studied possible mitochondrial involvement in PTP of GABAergic synaptic transmission in rat neocortical cultures, a preparation in which PTP has not been previously documented. Synaptic responses were evoked by local extracellular stimulation. Whole-cell patch-clamp technique was employed to record inhibitory postsynaptic currents (IPSCs) from postsynaptic neurons. Tetanic stimulation (30 Hz, 4 s) of the presynaptic neuron evoked an increase of IPSC amplitude, lasting for about 1 min. PTP was accompanied by a decrease of coefficient of variation of the IPSC and a decrease of paired-pulse (IPSC(2)/IPSC(1)) ratio, indicating involvement of presynaptic mechanism(s) in PTP. Possible role of mitochondria in PTP was addressed using drugs affecting Ca(2+) uptake and subsequent Ca(2+) efflux: carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and tetraphenylphosphonium ions (TPP(+)). It was found that both CCCP (1-2 microM) and TPP(+) (10 microM) either substantially decreased or eliminated PTP. These results further confirm presynaptic origin of PTP in neocortical neurons and suggest an important role of mitochondrial Ca(2+) turnover in this form of synaptic plasticity at the central synapse.

Differential properties of GABAergic synaptic connections in rat hippocampal cell cultures.

Based on the effect of prolonged tetanic stimulation (30 Hz, 4 sec), we divided GABAergic synaptic connections in hippocampal cell cultures into two groups: connections facilitated ( approximately 45%) and connections depressed ( approximately 55%) by the tetanic stimulation. In order to reveal possible reasons for the differential effect of the tetanization, we compared several properties of the connections belonging to both groups. We found that, on average, evoked IPSCs in the connections facilitated by the tetanization have a smaller amplitude and larger coefficient of variation (CV) of IPSC amplitude compared to connections depressed by the tetanization. We also estimated quantal parameters for both groups of connections assuming that transmitter release is reasonably described by a binomial distribution. We found that a background release probability (P) is substantially lower in the connections facilitated by the tetanization (P approximately 0.5) than in the connections depressed by the tetanization (P approximately 0.9) and suggest that this difference may underlie the differential effect of the tetanization. We also found that the tetanization induces the opposite effect on connections made by distinct presynaptic neurons with the same postsynaptic cell (convergent connections) in a fraction of postsynaptic neurons studied (3 out of 9). These results support the idea that properties of the presynaptic neuron are of primary importance for the observed differential effect of the tetanization, but they do not exclude a role of the postsynaptic neuron in this effect.

Chronic treatment with ionotropic glutamate receptor antagonist kynurenate affects GABAergic synaptic transmission in rat hippocampal cell cultures.

It is well documented that prolonged treatment with antagonists of ionotropic glutamate receptors activates a number of homeostatic mechanisms including alteration of glutamatergic transmission. We studied whether this treatment can also affect GABAergic transmission. Using whole-cell voltage clamp recording and local extracellular stimulation we investigated evoked inhibitory postsynaptic currents (IPSCs) in cultured rat hippocampal neurons grown in the presence of ionotropic glutamate receptor antagonist kynurenate (1 mM) and in control conditions. Chronic kynurenate treatment did not significantly affect the amplitude of evoked IPSCs and IPSC reversal potentials. In contrast we found that the paired-pulse depression was increased by 67% in cultures treated with kynurenic acid. We conclude that additional mechanism(s), alteration of GABAergic synaptic transmission, may contribute to homeostatic plasticity induced by chronic block of ionotropic glutamate receptors.

Post-tetanic depression of GABAergic synaptic transmission in rat hippocampal cell cultures.

The effect of tetanic stimulation (30 Hz, 4 s) on evoked GABAergic inhibitory postsynaptic currents (IPSCs) was studied in cell cultures of dissociated hippocampal neurons with established synaptic connections. It was found that tetanic stimulation elicited post-tetanic depression (PTD) of the evoked IPSCs with a duration of more than 50 s in about 60% of the connections tested; post-tetanic potentiation was induced in 25% of the connections. We propose that the opposite effects of tetanization on IPSC amplitude are due to differences in the type of the interneuron that was tetanized. Since PTD in our experiments was usually accompanied by changes in the IPSC coefficient of variation and changes of a paired pulse depression, which are thought to reflect presynaptic mechanisms of modulation, we suggest that part of the PTD is due to a presynaptic mechanism(s).