This paper reviews the body of evidence that not only tryptophan and consequent 5-HT depletion, but also induction of indoleamine 2,3-dioxygenase (IDO) and the detrimental effects of tryptophan catabolites (TRYCATs) play a role in the pathophysiology of depression. IDO is induced by interferon (IFN)γ, interleukin-6 and tumor necrosis factor-α, lipopolysaccharides and oxidative stress, factors that play a role in the pathophysiology of depression. TRYCATs, like kynurenine and quinolinic acid, are depressogenic and anxiogenic; activate oxidative pathways; cause mitochondrial dysfunctions; and have neuroexcitatory and neurotoxic effects that may lead to neurodegeneration. The TRYCAT pathway is also activated following induction of tryptophan 2,3-dioxygenase (TDO) by glucocorticoids, which are elevated in depression. There is evidence that activation of IDO reduces plasma tryptophan and increases TRYCAT synthesis in depressive states and that TDO activation may play a role as well. The development of depressive symptoms during IFNα-based immunotherapy is strongly associated with IDO activation, increased production of detrimental TRYCATs and lowered levels of tryptophan. Women show greater IDO activation and TRYCAT production following immune challenge than men. In the early puerperium, IDO activation and TRYCAT production are associated with the development of affective symptoms. Clinical depression is accompanied by lowered levels of neuroprotective TRYCATs or increased levels or neurotoxic TRYCATs, and lowered plasma tryptophan, which is associated with indices of immune activation and glucocorticoid hypersecretion. Lowered tryptophan and increased TRYCATs induce T cell unresponsiveness and therefore may exert a negative feedback on the primary inflammatory response in depression. It is concluded that activation of the TRYCAT pathway by IDO and TDO may be associated with the development of depressive symptoms through tryptophan depletion and the detrimental effects of TRYCATs. Therefore, the TRYCAT pathway should be a new drug target in depression. Direct inhibitors of IDO are less likely to be useful drugs than agents, such as kynurenine hydroxylase inhibitors; drugs which block the primary immune response; compounds that increase the protective effects of kynurenic acid; and specific antioxidants that target IDO activation, the immune and oxidative pathways, and 5-HT as well.

The new '5-HT' hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression.

Adenosine is a ubiquitous endogenous autacoid whose effects are triggered through the enrollment of four G protein-coupled receptors: A1, A2A, A2B, and A3. Due to the rapid generation of adenosine ...

Pharmacology of Adenosine Receptors: The State of the Art

This review addresses the oncopharmacological properties of curcumin at the molecular level. First, the interactions between curcumin and its molecular targets are addressed on the basis of curcumin's distinct chemical properties, which include H-bond donating and accepting capacity of the β-dicarbonyl moiety and the phenylic hydroxyl groups, H-bond accepting capacity of the methoxy ethers, multivalent metal and nonmetal cation binding properties, high partition coefficient, rotamerization around multiple C-C bonds, and the ability to act as a Michael acceptor. Next, the in vitro chemical stability of curcumin is elaborated in the context of its susceptibility to photochemical and chemical modification and degradation (e.g., alkaline hydrolysis). Specific modification and degradatory pathways are provided, which mainly entail radical-based intermediates, and the in vitro catabolites are identified. The implications of curcumin's (photo)chemical instability are addressed in light of pharmaceutical curcumin preparations, the use of curcumin analogues, and implementation of nanoparticulate drug delivery systems. Furthermore, the pharmacokinetics of curcumin and its most important degradation products are detailed in light of curcumin's poor bioavailability. Particular emphasis is placed on xenobiotic phase I and II metabolism as well as excretion of curcumin in the intestines (first pass), the liver (second pass), and other organs in addition to the pharmacokinetics of curcumin metabolites and their systemic clearance. Lastly, a summary is provided of the clinical pharmacodynamics of curcumin followed by a detailed account of curcumin's direct molecular targets, whereby the phenotypical/biological changes induced in cancer cells upon completion of the curcumin-triggered signaling cascade(s) are addressed in the framework of the hallmarks of cancer. The direct molecular targets include the ErbB family of receptors, protein kinase C, enzymes involved in prostaglandin synthesis, vitamin D receptor, and DNA.

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy.

New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors

Dry eye can be caused by a variety of iatrogenic interventions. The increasing number of patients looking for eye care or cosmetic procedures involving the eyes, together with a better understanding of the pathophysiological mechanisms of dry eye disease (DED), have led to the need for a specific report about iatrogenic dry eye within the TFOS DEWS II. Topical medications can cause DED due to their allergic, toxic and immuno-inflammatory effects on the ocular surface. Preservatives, such as benzalkonium chloride, may further aggravate DED. A variety of systemic drugs can also induce DED secondary to multiple mechanisms. Moreover, the use of contact lens induces or is associated with DED. However, one of the most emblematic situations is DED caused by surgical procedures such as corneal refractive surgery as in laser-assisted in situ keratomileusis (LASIK) and keratoplasty due to mechanisms intrinsic to the procedure (i.e. corneal nerve cutting) or even by the use of postoperative topical drugs. Cataract surgery, lid surgeries, botulinum toxin application and cosmetic procedures are also considered risk factors to iatrogenic DED, which can cause patient dissatisfaction, visual disturbance and poor surgical outcomes. This report also presents future directions to address iatrogenic DED, including the need for more in-depth epidemiological studies about the risk factors, development of less toxic medications and preservatives, as well as new techniques for less invasive eye surgeries. Novel research into detection of early dry eye prior to surgeries, efforts to establish appropriate therapeutics and a greater attempt to regulate and oversee medications, preservatives and procedures should be considered.

TFOS DEWS II iatrogenic report.

Major depression, a debilitating psychiatric disorder, is predicted to be the second most prevalent human illness by the year 2020. Various antidepressants, ranging from monoamine oxidase inhibitors to recently developed dual reuptake inhibitors, are prescribed for alleviating the symptoms of depression. Despite the availability of these blockbuster molecules, approximately 30% of depressed patients do not respond to the existing drug therapies and the remaining 70% fails to achieve complete remission. Moreover, antidepressants are associated with a plethora of side effects and drug-drug/drug-food interactions. In this context, novel approaches are being tried to find more efficacious and safer drugs for the treatment of major depression. Curcumin is one such molecule that has shown promising efficacy in various animal models of major depression. Although the mechanism of the antidepressant effect of curcumin is not fully understood, it is hypothesized to act through inhibiting the monoamine oxidase enzyme and modulating the release of serotonin and dopamine. Moreover, evidences have shown that curcumin enhances neurogenesis, notably in the frontal cortex and hippocampal regions of the brain. The use of curcumin in clinics for the treatment of major depression is limited due to its poor gastrointestinal absorption. The present review attempts to discuss the pharmacological profile along with molecular mechanisms of the antidepressant effect of curcumin in animal models of depression. A need for clinical trials in order to explore the antidepressant efficacy and safety profile of curcumin is emphasized.

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Potentials of curcumin as an antidepressant.

Ketogenic diet prevents epileptogenesis and disease progression in adult mice and rats.

Rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor increases pentylenetetrazol seizure threshold in mice: possible involvement of adenosinergic mechanism.

Withania somnifera (ashwagandha) is a widely used herb in the Ayurvedic system of medicine. The objective of the present study was to elucidate the effect of W. somnifera root extract (Ws) alone or in combination with exogenous gamma-amino butyric acid (GABA), a GABA receptor agonist or with diazepam, a GABA receptor modulator against pentylenetetrazol (PTZ, iv) seizure threshold in mice. Minimal dose of PTZ (iv, mg/kg) needed to induce different phases (myoclonic jerks, generalized clonus and tonic extension) of convulsions were recorded as an index of seizure threshold. Ws (100 or 200 mg/kg, po) increased the PTZ seizure threshold for the onset of tonic extension phase whereas a lower dose (50 mg/kg, po) did not show any effect on the seizure threshold. Co-administration of a sub-effective dose of Ws (50 mg/kg, po) with a sub-protective dose of either GABA (25 mg/kg, ip) or diazepam (0.5 mg/kg, ip) increased the seizure threshold. The results suggested that the anticonvulsant effect of W. somnifera against PTZ seizure threshold paradigm involved the GABAAergic modulation.

/pdf/effect-of-withania-somnifera-dunal-root-extract-against-3pzt7yquks.pdf

Kiran Kumar Akula

Papers

Potentials of curcumin as an antidepressant.

Ketogenic diet prevents epileptogenesis and disease progression in adult mice and rats.

Rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor increases pentylenetetrazol seizure threshold in mice: possible involvement of adenosinergic mechanism.

Effect of Withania somnifera Dunal root extract against pentylenetetrazol seizure threshold in mice: possible involvement of GABAergic system.

Nitric oxide signaling pathway in the anti-convulsant effect of adenosine against pentylenetetrazol-induced seizure threshold in mice