Could certain antidepressants provide frontline treatment for multiple infectious diseases?

Many bacteria steal cholesterol from the cells that they infect in order to grow and cause disease. Shown is Anaplasma phagocytophilum bacteria living in vacuoles (red circles) inside a tissue culture cell, the nucleus of which is blue. Cholesterol-carrying proteins (green) are accumulated inside the bacterial vacuoles. VCU researchers and collaborators discovered that an FDA-approved class of drugs called FIASMAs inhibit bacterial cholesterol acquisition to stop the growth of or kill A. phagocytophilum and other disease-causing intracellular bacteria. FIASMAs could potentially be repurposed to treat a number of infectious diseases. (Photo courtesy of Life Science Alliance).

Some antidepressants could potentially be used to treat a wide range of diseases caused by bacteria living within cells, according to work by researchers in the Virginia Commonwealth University School of Medicine and collaborators at other institutions.

Research published in the April print edition of the journal Life Science Alliance, shows that antidepressant drugs called FIASMAs, including desipramine, amitriptyline, and nortriptyline, halt the growth or kill four different intracellular bacterial pathogens in tissue cell culture and animal models.

“Antibiotic options for diseases caused by intracellular bacteria are limited because many of these drugs cannot penetrate our cell membranes. In essence, the bacteria are protected,” said Jason Carlyon, Ph.D., leader of the study and professor in the VCU Department of Microbiology and Immunology.

Tetracycline antibiotics are most commonly prescribed to treat intracellular bacterial infections because they can cross cell membranes to reach the microbes. However, tetracyclines can cause allergic reactions in some patients and physicians advise against their use by pregnant women and children due to undesirable side effects. Additionally, antibiotic resistance in some intracellular bacteria has been reported.

“It would be highly beneficial to have a class of drugs to treat such diseases in patients for whom tetracyclines are contraindicated,” Carlyon said. “These drugs could provide an alternative to antibiotics or even be used in conjunction with them as an augmentation approach to treat infections that typically require prolonged courses of antibiotic therapy, such as those caused by Chlamydia pneumoniae and Coxiella burnetti.”

The team of researchers from VCU, Indiana University Medical Center, University of Nebraska Medical Center, University of Arkansas for Medical Sciences, and the University of South Florida, including Carlyon and lead author Chelsea Cockburn, an M.D.-Ph.D. candidate, are the first to investigate the mechanisms by which FIASMAs target multiple intracellular bacteria in detail.

The scientists tested FIASMA susceptibility for four bacterial species that cause human granulocytic anaplasmosis, a tick-borne disease that attacks white blood cells called neutrophils and can be fatal to immune compromised individuals; Q fever, a debilitating pneumonic disease; and two chlamydia infections.

FIASMAs ultimately disrupt how cholesterol, a key nutrient utilized by many intracellular pathogens, traffics inside cells to alter bacterial access to the lipid. The researchers first proved FIASMA treatment efficacy by halting anaplasmosis in both tissue culture and mice. Next, they extended their observations to demonstrate that FIASMA treatment killed the Q fever agent,Coxiella burnetii, and partially inhibited chlamydial infections in cell culture.

“Since FIASMAs influence cholesterol trafficking in the cell and cholesterol plays a role in so many facets of our biology, they have been used to treat a wide variety of conditions and diseases,” Carlyon said.

He added that the effect of FIASMAs on intracellular cholesterol ultimately bypasses the need to directly target the bacteria.

“What is so exciting about this study is that the class of drugs we evaluated targets an enzyme in our cells regulating cholesterol, not the bacteria,” Carlyon said. “I do not envision the pathogens being able to develop resistance to this treatment because it is targeting a host pathway that they very much need to grow and survive inside of the body.”

Learn more: Certain antidepressants could provide a frontline treatment for multiple infectious diseases, testing shows

 

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Cannabidiol is effective in eliminating the symptoms of depression on the same day – in rats

The results were obtained with a single dose, and the effect lasted up to one week in rats in a study by scientists from Brazil and Denmark (image: Ben Mills)

Commercial antidepressants typically take two to four weeks to have a significant effect on a depressed patient.

They are also ineffective in many cases. Finding new drugs for depression that are fast-acting and have more lasting effects is the goal of research conducted by Brazilian scientists in São Paulo State in collaboration with Danish colleagues.

Their study found that a single dose of cannabidiol in rats with symptoms of depression was highly effective, eliminating the symptoms on the same day and maintaining the beneficial effects for a week.

The findings reinforce those of prior research showing that cannabidiol, a component of Cannabis sativa, the plant most commonly used to make marijuana, has promising therapeutic potential in the treatment of broad-spectrum depression in preclinical and human models.

The results have been published in an article in the journal Molecular Neurobiology by researchers of the group led by Sâmia Regiane Lourenço Joca, a professor in the University of São Paulo’s Ribeirão Preto School of Pharmaceutical Sciences (FCFRP-USP) in Brazil.

The first author is Amanda Juliana Sales, who has a PhD scholarship from FAPESP. The research itself was supported by FAPESP via a Thematic Project, by Brazil’s National Council for Scientific and Technological Development (CNPq), and by Denmark’s Aarhus University Research Foundation.

The research on cannabidiol is being performed in collaboration with a group led by Francisco Silveira Guimarães, a professor at the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP). Gregers Wegener, a professor in Aarhus University’s Department of Clinical Medicine, is also collaborating.

“Brazil has pioneered the study of cannabidiol. Today is very different from 30 years ago, when we began studying the substance and faced prejudice because of the association with marijuana,” Guimarães told Agência FAPESP.

Although cannabidiol is extracted from the marijuana plant, Guimarães stressed that it produces neither dependence nor psychotropic effects. “The main psychoactive component of marijuana is tetrahydrocannabinol, known as THC. Cannabidiol, on the contrary, blocks some of the effects of THC,” he said.

Scientists are investigating the effects of cannabidiol in search of drugs with shorter latency and hence the capacity to be faster-acting than conventional antidepressants.

According to Guimarães, the available antidepressants obtain results in approximately 60% of patients. The rest receive inadequate treatment even after trying various different options for several months. “This evidences the need to find new drugs with better therapeutic potential,” she said.

The researchers used rat and mouse lines selected by cross-breeding to develop symptoms of depression. The tests and behavioral analysis involved a total of 367 animals.

Five tests were performed altogether. “We submitted the animals to situations of stress such as the forced swimming test,” said Joca, who is also a visiting professor at Aarhus University.

Before the test, some of the animals were given an injection of cannabidiol with doses of 7, 10 and 30 mg/kg in saline solution, and the rest, which were the control group, received only saline.

After 30 minutes, the animals were placed for five minutes in cylinders with a height of 25 cm and a diameter of 17 cm, containing 10 cm of water for mice and 30 cm of water for rats.

“The water depth is calculated to force them to swim by preventing them from touching the bottom with their feet or tails. They learn to float after swimming for a short time. They remain practically immobile while floating, merely keeping their heads above water to avoid drowning. This floating behavior, when they stop swimming, is classified as immobility,” Joca said.

“The forced swim test is used to measure the effect of antidepressant drugs because all known antidepressants shorten the duration of immobility and hence lengthen swim time. A reduction in immobility time in this test is interpreted as ‘antidepressant-like’ behavior.”

The researchers found that cannabidiol induced acute and sustained antidepressant-like effects in mice submitted to the forced swim test.

“However, to make sure this result isn’t due to the increase in movement caused by a psychostimulant effect leading the animals to swim more vigorously, for example, we performed a separate test to control for locomotor activity,” Joca explained.

“To do this we used the open-field test, which consists of putting the animal in a novel arena and letting it explore the new environment freely while its locomotor and exploratory activity is recorded. A drug is said to have potential antidepressant effects if it reduces immobility time and increases swim time in the forced swim test without increasing locomotor activity in the open-field test, showing that the effects observed in the forced swim test aren’t secondary to nonspecific alterations in locomotor activity.”

Restoration of neuronal circuitry 

The conclusion was that the effects of treatment with cannabidiol were fast-acting and sustained, persisting for up to seven days after a single dose was administered to animals belonging to different models of depression (including a stress model and a genetic susceptibility model).

The findings were reproduced in three different sets of animals at the laboratories of FCFRP-USP, FMRP-USP and Aarhus University.

“When we studied the mechanisms involved in these effects, we found that treatment with cannabidiol induces a rapid rise in levels of brain-derived neurotrophic factor, or BDNF, a neurotrophin that plays a key role in neuronal survival and neurogenesis, the formation of new neurons in the brain,” Joca said. “We also observed an increase in synaptogenesis in the prefrontal cortex of these animals.” Synaptogenesis is the formation of synapses between neurons in the central nervous system.

Seven days after treatment, the researchers observed a rise in the number of synaptic proteins in the prefrontal cortex, which is closely linked to depression in humans. “In light of this finding, we believe cannabidiol rapidly triggers neuroplastic mechanisms that help repair the neuronal circuitry that gets damaged in depression,” Joca said.

The beneficial action of cannabidiol is not limited to the prefrontal cortex, however. “In a separate study, we showed that the effects of cannabidiol also involve neuroplastic mechanisms in the hippocampus, another structure involved in the neurobiology of depression,” she noted.

According to Joca, if studies in humans also find cannabidiol to be beneficial in treating depression, given that cannabidiol is already used in humans to treat other diseases or disorders, “they could result in an important advance in the treatment of depression, potentially helping patients who suffer for weeks, often with a risk of suicide, until the treatment starts working.”

Studies in humans

The researchers are currently investigating other mechanisms involved in the effects of cannabidiol, as well as its efficacy in animal models of resistance to conventional treatment.

“For example, we’re studying whether cannabidiol would also be effective in patients who don’t respond to conventional therapy and whether combining it with antidepressants would improve their symptoms. Indeed, we’ve just published another paper in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry, showing that treatment with cannabidiol facilitates serotonergic neurotransmission in the central nervous system and that combining it with low doses of selective serotonin reuptake inhibitor antidepressant drugs, or SSRIs, such as fluoxetine induces a significant antidepressant effect,” Joca said.

“So there’s a possibility that combining cannabidiol with SSRIs might allow the latter to be used in lower doses, perhaps reducing their adverse side-effects while maintaining the therapeutic effect of higher doses.”

According to the authors, therefore, cannabidiol may not only be a faster-acting antidepressant than conventional drugs but also improve the response to such drugs when taken in combination with them.

“Our evidence suggests these effects occur by inducing neuroplastic alterations in the prefrontal cortex and hippocampus, which are brain structures involved in the development of depression. Because cannabidiol is used in humans to treat other conditions, we believe it can also be studied in humans for the treatment of depression in the near future,” Joca said.

Learn more: Research suggests cannabidiol can reduce symptoms of depression

 

 

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A potential new antidepressant and antianxiety treatment with a unique mechanism of action

Laboratory tests in mice have shown promise

A potential new antidepressant and antianxiety treatment with a unique mechanism of action has been developed by scientists at the University of Bath.

The compound has shown significant potential after studies in mice. The research is published in the British Journal of Pharmacology.

Dr Sarah Bailey and Professor Steve Husbands with their research team

Around one in six adults will experience depression in their lifetimes. New drugs to treat depression in particular are needed because many existing antidepressants don’t work in up to 50% of patients. This new University of Bath compound, known as BU10119, works in a different way to the most common antidepressant drugs; selective serotonin reuptake inhibitors (SSRIs), and may therefore offer a new potential treatment for those in whom SSRIs don’t work.

Unlike SSRIs which target the serotonin system in the brain, BU10119 works by blocking receptors called kappa opioid receptors.  Blocking these receptors has been shown to have anti-depressant like effects in mice.

In a series of laboratory trials, mice given BU10119 demonstrated behaviours consistent with providing antidepressant–like effects.

Dr Sarah Bailey, Senior Lecturer in the Department of Pharmacy & Pharmacology at the University of Bath, said: “I’m really quite excited by the potential of this compound. Developing new medicines is why I got into pharmacology and, in 20 years of research, this is the closest I have come to a new compound that might translate towards the clinic. It’s promising, but that said, we are still at an early stage, these experiments are in mice and further research is still required for example to establish safety.

“SSRIs can work very well for some patients, but we know they don’t work for everyone which is one reason why developing new antidepressant and antianxiety drugs could be really beneficial.”

The researchers were inspired to develop the compound after previous University of Bath research showed that a combination of two existing drugs, buprenorphine and naltrexone, had potential as an antidepressant. BU10119 combines the effects of this combination in one drug.

Professor Stephen Husbands, Head of Medicinal Chemistry at the University of Bath added: “This research builds on our previous work which showed that combining buprenorphine and naltrexone can give antidepressant effects in mice. By combining the effects of both drugs in one molecule we hope that a safe and effective drug will eventually be the outcome. BU10119 is part of a series of compounds now licensed to, and under development with, Orexigen Therapeutics.”

The study was funded a by a National Institute on Drug Abuse grant and a PhD scholarship from the Government of Saudi Arabia.

The University of Bath has signed the Concordat on Openness on Animal Research. The University is committed to enhancing our communications with the media and public about our research using animals. Find out more: http://www.bath.ac.uk/collections/animal-research/

Learn more: New drug shows potential as a different kind of antidepressant in mouse trials

 

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Taking antidepressants during pregnancy increases risk of autism by 87%

via Universite de Montreal

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Using antidepressants during pregnancy greatly increases the risk of autism, Professor Anick Bérard of the University of Montreal and its affiliated CHU Sainte-Justine children’s hospital revealed today.

Prof. Bérard, an internationally renowned expert in the fields of pharmaceutical safety during pregnancy, came to her conclusions after reviewing data covering 145,456 pregnancies. “The variety of causes of autism remain unclear, but studies have shown that both genetics and environment can play a role,” she explained. “Our study has established that taking antidepressants during the second or third trimester of pregnancy almost doubles the risk that the child will be diagnosed with autism by age 7, especially if the mother takes selective serotonin reuptake inhibitors, often known by its acronym SSRIs.” Her findings were published today in JAMA Pediatrics.

Bérard and her colleagues worked with data from the Quebec Pregnancy Cohort and studied 145,456 children between the time of their conception up to age ten. In addition to information about the mother’s use of antidepressants and the child’s eventual diagnosis of autism, the data included a wealth of details that enabled the team to tease out the specific impact of the antidepressant drugs. For example, some people are genetically predisposed to autism (i.e., a family history of it.) Maternal age, and depression are known to be associated with the development of autism, as are certain socio-economic factors such as being exposed to poverty, and the team was able to take all of these into consideration. “We defined exposure to antidepressants as the mother having had one or more prescription for antidepressants filled during the second or third trimester of the pregnancy. This period was chosen as the infant’s critical brain development occurs during this time,” Prof. Bérard said. “Amongst all the children in the study, we then identified which children had been diagnosed with a form of autism by looking at hospital records indicating diagnosed childhood autism, atypical autism, Asperger’s syndrome, or a pervasive developmental disorder. Finally, we looked for a statistical association between the two groups, and found a very significant one: an 87% increased risk.” The results remained unchanged when only considering children who had been diagnosed by specialists such as psychiatrists and neurologists.

The findings are hugely important as six to ten percent of pregnant women are currently being treated for depression with antidepressants.

In the current study, 1,054 children were diagnosed with autism (0.72% of the children in the study), on average at 4.5 years of age. Moreover, the prevalence of autism amongst children has increased from 4 in 10,000 children in 1966 to 100 in 10,000 today. While that increase can be attributed to both better detection and widening criteria for diagnosis, researchers believe that environmental factors are also playing a part. “It is biologically plausible that anti-depressants are causing autism if used at the time of brain development in the womb, as serotonin is involved in numerous pre- and postnatal developmental processes, including cell division, the migration of neuros, cell differentiation and synaptogenesis – the creation of links between brain cells,” Prof. Bérard explained. “Some classes of anti-depressants work by inhibiting serotonin (SSRIs and some other antidepressant classes), which will have a negative impact on the ability of the brain to fully develop and adapt in-utero”

The World Health Organization indicates that depression will be the second leading cause of death by 2020, which leads the researchers to believe that antidepressants will likely to remain widely prescribed, including during pregnancy.

“Our work contributes to a better understanding of the long-term neurodevelopmental effects of anti-depressants on children when they are used during gestation. Uncovering the outcomes of these drugs is a public health priority, given their widespread use,” Prof. Bérard said.

Read more: Taking antidepressants during pregnancy increases risk of autism by 87%

 

 

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Burning Incense Is Psychoactive: New Class Of Antidepressants Might Be Right Under Our Noses

frankincense tree (Photo credit: Alexbip)

Burning frankincense (resin from the Boswellia plant) activates poorly understood ion channels in the brain to alleviate anxiety or depression.

Religious leaders have contended for millennia that burning incense is good for the soul. Now, biologists have learned that it is good for our brains too.

An international team of scientists, including researchers from Johns Hopkins University and the Hebrew University in Jerusalem, describe how burning frankincense (resin from the Boswellia plant) activates poorly understood ion channels in the brain to alleviate anxiety or depression. This suggests that an entirely new class of depression and anxiety drugs might be right under our noses.

“In spite of information stemming from ancient texts, constituents of Bosweilla had not been investigated for psychoactivity,” said Raphael Mechoulam, one of the research study’s co-authors. “We found that incensole acetate, a Boswellia resin constituent, when tested in mice lowers anxiety and causes antidepressive-like behavior. Apparently, most present day worshipers assume that incense burning has only a symbolic meaning.”

Read more . . .

 

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