Curcumin and major depression: A randomised, double-blind, placebo-controlled trial investigating the potential of peripheral biomarkers to predict treatment response and antidepressant mechanisms of change

A recent randomised, double-blind, placebo controlled study conducted by our research group, provided partial support for the efficacy of supplementation with a patented curcumin extract (500 mg, twice daily) for 8 weeks in reducing depressive symptoms in people with major depressive disorder. In the present paper, a secondary, exploratory analysis of salivary, urinary and blood biomarkers collected during this study was conducted to identify potential antidepressant mechanisms of action of curcumin. Pre and post-intervention samples were provided by 50 participants diagnosed with major depressive disorder, and the Inventory of Depressive Symptomatology self-rated version (IDS-SR30) was used as the primary depression outcome measure. Compared to placebo, 8 weeks of curcumin supplementation was associated with elevations in urinary thromboxane B2 (p<0.05), and substance P (p<0.001); while placebo supplementation was associated with reductions in aldosterone (p<0.05) and cortisol (p<0.05). Higher baseline plasma endothelin-1 (rs=−0.587; p<0.01) and leptin (rs=−0.470; p<0.05) in curcumin-treated individuals was associated with greater reductions in IDS-SR30 score after 8 weeks of treatment. Our findings demonstrate that curcumin supplementation influences several biomarkers that may be associated with its antidepressant mechanisms of action. Plasma concentrations of leptin and endothelin-1 seem to have particular relevance to treatment outcome. Further investigations using larger samples sizes are required to elucidate these findings, as the multiple statistical comparisons completed in this study increased the risk of type I errors

Counter-propagating entangled photons from a waveguide with periodic nonlinearity

The conditions required for spontaneous parametric down-conversion in a waveguide with periodic nonlinearity in the presence of an unguided pump field are established. Control of the periodic nonlinearity and the physical properties of the waveguide permits the quasi-phase matching equations that describe counter-propagating guided signal and idler beams to be satisfied. We compare the tuning curves and spectral properties of such counter-propagating beams to those for co-propagating beams under typical experimental conditions. We find that the counter-propagating beams exhibit narrow bandwidth permitting the generation of quantum states that possess discrete-frequency entanglement. Such states may be useful for experiments in quantum optics and technologies that benefit from frequency entanglement.Comment: submitted to Phys. Rev.

Topical prazosin attenuates sensitivity to tactile stimuli in patients with complex regional pain syndrome

Background The sympathetic nervous system may play an important role in certain forms of chronic pain. The main aim of this study was to determine whether functional blockade of α1-adrenoceptors would alter sensitivity to cutaneous stimulation in patients with complex regional pain syndrome (CRPS). Methods and Results In an initial study, high-performance liquid chromatography-mass spectrometry of intradermal interstitial fluid collected from the forearms of three healthy individuals established that the α1-adrenoceptor antagonist prazosin penetrated the skin barrier when mixed in Lipoderm® cream base. Next, we found that application of this cream to the forearm of 10 healthy participants attenuated axon reflex vasodilatation to the iontophoresis of phenylephrine, demonstrating functional blockade of α1-adrenoceptors. Subsequently, effects of the cream on sensitivity to mechanical and thermal stimulation were investigated in 14 healthy participants and 19 patients with CRPS (eight with an apparent adrenergic component of pain). Both in patients and controls, topical application of the prazosin cream increased sensitivity to skin cooling but reduced sensations evoked by gentle brushing. In addition, hyperalgesia to sharp stimulation was lower at the prazosin- than vehicle-treated site in the CRPS-affected limb, and allodynia to brushing was lower at the prazosin-treated than vehicle-treated site in patients with an adrenergic component of pain. Conclusions Prazosin cream inhibited adrenergic axon reflex vasodilatation in healthy volunteers, and also inhibited dynamic allodynia and punctate hyperalgesia in the CRPS-affected limb of some patients. Further studies are required to assess the potential benefits of topically applied prazosin for CRPS

A review of peripheral biomarkers in major depression: The potential of inflammatory and oxidative stress biomarkers

Biomarkers are regularly used in medicine to provide objective indicators of normal biological processes, pathogenic processes or pharmacological responses to therapeutic interventions, and have proved invaluable in expanding our understanding and treatment of medical diseases. In the field of psychiatry, assessment and treatment has, however, primarily relied on patient interviews and questionnaires for diagnostic and treatment purposes. Biomarkers in psychiatry present a promising addition to advance the diagnosis, treatment and prevention of psychiatric diseases. This review provides a summary on the potential of peripheral biomarkers in major depression with a specific emphasis on those related to inflammatory/immune and oxidative stress/antioxidant defences. The complexities associated with biomarker assessment are reviewed specifically around their collection, analysis and interpretation. Focus is placed on the potential of peripheral biomarkers to aid diagnosis, predict treatment response, enhance treatment-matching, and prevent the onset or relapse of major depression

Metabolomics as a tool to investigate α-adrenergic recept-mediated signaling in cortical neurons

Purpose: Complex regional pain syndrome (CRPS) is a neuropathic pain condition that can be acquired after minor trauma or surgery to soft tissues and nerves. Biopsies from affected tissue show an increased density of α1-adrenergic receptors (AR1) compared to controls. In order to further study the role of AR1 in CRPS, we wish to use an immortalized cortical neuron cell line, NIE115. The present study aimed to (i) characterise the expression of AR1 on NIE115 cells and (ii) document how the metabolic profile of NIE115 cells is affected by adrenergic pharmacological intervention. Methods: NIE115 cultures (n = 15) were dual-or triple-labelled with antibodies directed against AR1 as well as specific neuronal markers (neurofilament, TRPV1, TUJ1, CGRP). Cells were then exposed to an AR1 agonist (phenylephrine, n = 18), an antagonist (prazosin, n = 12) or a combination of both (n = 12) and the biochemical effects studied using gas chromatography-mass spectrometry-based metabolomics. Results: Immunohistochemistry confirmed the presence of AR1 on the NIE115 cells. Treatment of the cells with phenylephrine led to changes in both carbon and nitrogen metabolism consistent with stimulation of AR1. It was expected that prazosin would block the metabolic effects of phenylephrine, but a different set of changes to carbon and nitrogen metabolism were observed. This provides further evidence to the observations that prazosin may in fact be acting as an inverse agonist. Conclusion: These data indicate that metabolomics is a powerful technology in the study of receptor signaling, and have provided us with a new tool to investigate CRPS

The potential of metabolomic analysis techniques for the characterisation of α1-adrenergic receptors in cultured N1E-115 mouse neuroblastoma cells

Several studies of neuropathic pain have linked abnormal adrenergic signalling to the development and maintenance of pain, although the mechanisms underlying this are not yet fully understood. Metabolomic analysis is a technique that can be used to give a snapshot of biochemical status, and can aid in the identification of the mechanisms behind pathological changes identified in cells, tissues and biological fluids. This study aimed to use gas chromatography-mass spectrometry-based metabolomic profiling in combination with reverse transcriptase-polymerase chain reaction and immunocytochemistry to identify functional α1-adrenergic receptors on cultured N1E-115 mouse neuroblastoma cells. The study was able to confirm the presence of mRNA for the α1D subtype, as well as protein expression of the α1-adrenergic receptor. Furthermore, metabolomic data revealed changes to the metabolite profile of cells when exposed to adrenergic pharmacological intervention. Agonist treatment with phenylephrine hydrochloride (10 µM) resulted in altered levels of several metabolites including myo-inositol, glucose, fructose, alanine, leucine, phenylalanine, valine, and n-acetylglutamic acid. Many of the changes observed in N1E-115 cells by agonist treatment were modulated by additional antagonist treatment (prazosin hydrochloride, 100 µM). A number of these changes reflected what is known about the biochemistry of α1-adrenergic receptor activation. This preliminary study therefore demonstrates the potential of metabolomic profiling to confirm the presence of functional receptors on cultured cells