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By Dr. Priyom Bose, Ph.D. Mar 8 2024 Reviewed by Danielle Ellis, B.Sc.

A recent Brain and Behavior study investigated the antidepressant effect of dulaglutide and the mechanism that underlies this effect. Study: Dulaglutide treatment reverses depression-like behavior and hippocampal metabolomic homeostasis in mice exposed to chronic mild stress. Image Credit: luchschenF/Shutterstock.com Background

Depression is a chronic mood disorder that is associated with low mood, insomnia, weight loss, a state of unhappiness, aversion to activity, fatigue, and low self-esteem. According to the World Health Organization, depression has become one of the major health burdens across the world.

This mental health condition is commonly treated with an antidepressant that takes around a month to alleviate the symptoms. However, several side effects are associated with the use of antidepressant drugs and could be toxic at high doses.

A combination of psychological, genetic, and neurological factors contributes to the manifestations of depression. Even though the exact etiology of this mental health issue is not fully understood, research has shown chronic stress to be an inducer of depression. 

The hippocampus is a region of the brain that is associated with depression and modifies functionally and morphologically in response to stress. Animal model studies have shown that a decrease in neuronal and glial size, reduction in synaptic markers, loss of dendrites, and increase in apoptosis in the hippocampus leads to depression.

Many studies have uncovered the metabolic aspects of depression. For instance, diabetes and obesity are two common metabolic disorders that increase the risk of depression. Considering its high prevalence, novel therapies with high efficacy and fewer side effects are required to combat depression. The chronic mild stress (CMS) model has been recognized as a reliable rodent model to study depression. 

Glucagon-like peptide-1 (GLP-1) and its receptor agonists are involved with anti-inflammatory effects and neuroprotective activities and can improve mental disorders, particularly depression and cognition. GLP-1 is a peptide hormone that stimulates the secretion of insulin and restricts the synthesis of glucagon in the pancreas in a glucose-dependent manner. Liraglutide is a GLP-1 analog that exhibited a positive effect in reducing anxiety and depression symptoms.

Dulaglutide is a novel long-acting GLP-1 receptor agonist that improves cognitive dysfunction and neuronal damage in rats with vascular dementia. Although many studies highlighted the efficacy of dulaglutide in preventing depression-like behavior triggered by chronic social defeat stress (CSDS), the underlying mechanism of this effect is not clearly understood. About the study

The current study used a metabolomics strategy to evaluate the effect of dulaglutide in a CMS model. Furthermore, the underlying mechanism of this effect was also assessed. Adult male ICR mice, which is a strain of albino mice, were selected for this study. All test mice were around seven weeks old.

After one week of acclimatization, 60 mice were randomly assigned in four groups, namely, control (CON), the CMS and Vehicle group (CMS+Veh), the CMS and 0.3 mg/kg dulaglutide group (Low Dula), and the CMS and 0.6 mg/kg dulaglutide group (High Dula). Except for the CON group, all other groups were exposed to stressors. Related StoriesSugar tax shows sweet results in cutting obesity and diabetes ratesAI-based model enhances efficiency of Type II diabetes prevention effortsStudy reveals mechanisms behind antidepressant effects of diabetes drug

To establish the CMS model of depression, selected mice were exposed to two or three different stressors for 28 days continuously. For stress induction, mice were deprived of water and food for 12 hours, kept in wet bedding for 24 hours, kept in a tilted cage for 24 hours, pintail for 1 minute, and cold water treatment for five minutes. The body weight of each test mouse was measured weekly, and behavioral tests, such as the tail suspension test (TST), open field test (OFT), and forced swimming test (FST), were performed. Study findings

The mice subjected to CMS for four weeks exhibited depressive- and anxiety-like symptoms. An LC-MS/MS metabolomics study was performed to understand the potential pathophysiological mechanisms and investigate the efficacy of drugs to alleviate depression-like symptoms.

A distinct difference between the CON group, CMS+Veh group, and High Dula group was observed in accordance with the metabolic disorders induced by chronic stress, which was altered through dulaglutide treatment. Many potential biomarkers were identified that are associated with purine metabolism, arginine and proline metabolism, glycerophospholipid metabolism, glutamate metabolism, sphingolipid metabolism, and bile secretion.

Lipid metabolism pathways could be potential targets through which dulaglutide alleviates depression. Lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE), lysophosphatidylethanolamine (LPE), phosphatidylinositol (PI), sphingolipids, and phosphatidylcholine (PC), are involved with the therapeutic effect of dulaglutide in alleviating depression. Consistent with previous studies findings, this study highlighted the association between lipid metabolism and the antidepressant effect of dulaglutide.

The current study indicated the downregulation of N-acetyl-L-aspartic acid (NAA) in the CMS model group. NAA, which is one of the most important metabolites of the vertebrate nervous system, was found in decreased levels in rats with chronic, unpredictable, mild stress. However, the current study indicated that dulaglutide therapy increased the levels of NAA through its upregulation in the hippocampus.

In the CMS model group, an upregulation in L-glutamic acid and L-arginine was observed. Dulaglutide treatment caused a decrease in arginine and proline, thereby indirectly exhibiting a neuroprotective effect. Conclusions

The current study highlighted the antidepressant effects of dulaglutide using the CMS depression model. Notably, the potential metabolisms that underlie the antidepressant effect of dulaglutide have been elucidated in this study.  Journal reference: Jin, M., Zhang, S., Huang, B., Li, L., Liang, H., Ni, A., Han, L., Liang, P., Liu, J., Shi, H. and Lv, P. (2024) Brain and Behavior, 14(3). doi: 10.1002/brb3.3448. https://onlinelibrary.wiley.com/doi/10.1002/brb3.3448?utm_medium=email

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UK

How e-bike riders are doing double the speed limit – and many of them work for fast food delivery firms

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How e-bike riders are doing double the speed limit - and many of them work for fast food delivery firms

It’s lunchtime on Birmingham’s New Street. 

Close to its many restaurants, food delivery riders are congregating on their bikes.

The area is packed with shoppers and workers.

PC Paige Gartlan is approaching with other officers. She’s on the lookout for illegally modified e-bikes – and she knows she’ll find them here.

“You can physically tell by looking at the bike that it’s generally going to be illegal – the battery pack is taped on to the sides and generally the size of the motor that’s on the back wheel,” she explains.

Sky News has been invited on an operation by West Midlands Police to find these bikes and get them off the streets.

PC Gartlan has been hit by one before. She’s had to tackle a rider to the floor after he drove into her.

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Within minutes, she’s spotted a suspicious-looking bike. The rider makes a run for it – followed by plain-clothed officers.

PC Gartlan tests the bike – it’s showing a top speed of 52km/hr on the speedometer – just over 30mph.

PC Paige Gartlan with a seized e-bike
Image:
PC Paige Gartlan with a seized e-bike

The speed limit for e-bikes in the UK is 15.5mph when using electric power for assistance.

I look up the street and another two riders have been detained. In less than an hour, officers have confiscated four bikes – all were being ridden by fast food delivery drivers.

The commotion is attracting a lot of attention.

“They are dangerous,” Sandra, who has just finished work, tells me.

Demoz had his bike taken by police
Image:
Demoz had his bike taken by police

She’s stood watching the riders being questioned. She says she’s had near-misses herself and is worried for the safety of the elderly and children.

It’s not just West Midlands police officers here – immigration officials are carrying out checks too. They’re involved in a nationwide operation, which has seen more than 7,000 arrests in the last year – a 50% increase on last year.

Matthew Foster, the immigration enforcement lead officer for the West Midlands, tells me they’ve already found one individual who has entered the UK unlawfully.

“He’s been detained,” he says, “to affect his removal from the UK.”

Further down the street, police are loading illegally modified bikes on to a van – they’re destined to be crushed. One of them had belonged to Demoz.

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A e-bike that was seized by police in West Midlands
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An e-bike seized by West Midlands Police

He’s on his way home, carrying a big box with the logo of one of the main fast food delivery firms on it.

He tells me he used to have an illegal bike, but he thought his new one was legal.

“I make a mistake, I have to say sorry, I will do better for the future,” he says.

I get in touch with the big delivery firms; Deliveroo, Uber Eats, and Just Eat.

Their representatives say they constantly remind workers of their safety obligations, and that they’re all working closely with the government to increase security checks on riders.

As he leaves, Demoz, now bike-free, tells me he’s thinking of changing his job.

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UK

I can’t help feel Harry’s team are trying to push the reset button – here’s why

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I can't help feel Harry's team are trying to push the reset button - here's why

Watching pictures of Prince Harry in Angola this week took me back to 2019, when we were there for his first visit following in Princess Diana’s footsteps.

The pictures on Wednesday looked so similar; his effortless interactions with people who face the daily dangers of landmines, and his obvious passion to help a charity that he cares deeply about.

Of course so much has happened in the six years since then, but with other headlines this week, I couldn’t help but feel like we could be looking at the beginning of a reset for Harry.

It started last Saturday night, as the story emerged of a meeting between the King’s communications secretary, Harry’s new London-based head of PR, and Harry’s most senior aide in America.

Three people you may not have heard of, but a meeting that was quickly described as “peace talks”.

File photo dated 12/12/18 of King Charles III, then Prince of Wales, and the Duke of Sussex during a discussion about violent youth crime at a forum held at Clarence House in London. The Duke of Sussex's relationship with the King remains "distant", with Harry's letters and calls to his father going unanswered, sources have said. Issue date: Tuesday April 15, 2025.
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The King and Prince Harry in 2018. Pic: PA

The pictures of the get-together were being sold for thousands of pounds by the paper that ran them, just one indication of the global fascination about whether father and son may be on the road to reconciliation.

Neither side are willing to go there when you ask what exactly they talked about, although I suspect some of it was much more practical than about trying to mend this fractured relationship.

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Things like trying to avoid unnecessary negative stories, for example, the kind where Harry is accused of snubbing his father because they just happen to be doing jobs on the same day.

Prince Harry meets landmine victim Sandra Tigica in Angola in 2019, who Princess Diana met on her visit to Angola in 1997.
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Prince Harry meets landmine victim Sandra Tigica in Angola in 2019, who Princess Diana met on her visit to Angola in 1997

It’s tricky for Harry’s camp to avoid such a situation when they don’t have sight of the King’s diary.

There’s also been the chatter about who may, or may not, have leaked the meeting.

There has been speculation around why they were out on a balcony, and who spotted the photographer in the park.

But whether it was a leak, or just a really good spot from a journalist or photographer, it’s not a bad thing for either side that we’re now all talking about whether father and son may be close to patching things up.

It did however raise other questions, about what it means for Prince William and his relationship with his brother.

So far there have been no indications of any meeting between William’s team and that of his brother.

The feelings of William also, you may think, a consideration for the King.

File photo dated 12/12/18 of King Charles III, then Prince of Wales, and the Duke of Sussex during a discussion about violent youth crime at a forum held at Clarence House in London. The Duke of Sussex's relationship with the King remains "distant", with Harry's letters and calls to his father going unanswered, sources have said. Issue date: Tuesday April 15, 2025.
Image:
The King and Prince Harry in 2018. Pic: PA

The unexpected headlines around Harry just kept coming, as on Tuesday he popped up in Angola.

His second visit there, this time with no press pack in tow.

So why the surprise visit?

Harry has worked with the Halo Trust for some time, and it’s clearly still a priority for them to highlight the dangers faced by those living with the potential dangers of landmines in Angola.

But it also feels like part of a push to get Harry out on more public engagements.

I’ve been told that since moving away from the UK he has continued to have regular contact with those charities with which he’s maintained ties, but being on the phone or a video call, isn’t the same as physically being there in person.

We saw something similar with his trip to China with Travalyst earlier this year, some may argue not the best choice of destination, but another example of wanting to get him physically out on visits to reinforce publicly those connections with causes that matter so much to him.

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Prince Harry follows in Diana’s footsteps

For some months now it’s felt like Meghan has regained an element of control over how she wants to be seen.

Just look at her social media accounts and the success of her “As Ever” brand.

Whether Harry for the first time would step on to the social media scene with his own public account we wait to see, although the idea of his own commercial project is more likely, with suggestions something may be in the pipeline, we wait and see what.

After a constant flow of stories in recent months relating to court cases or his ongoing row with his family, this week has felt different.

A lot has been made about Harry and Meghan establishing a new “court” and what lies behind their decision to hire new people, five years after they stepped away from royal life.

There are of course elements of the recent past that it is impossible to erase, even Harry, in his recent interview talked of how he would “love reconciliation with my family” but added, “Of course, some members of my family will never forgive me for writing a book. Of course, they will never forgive me for… lots of things.”

But it does feel like their new team are tentatively attempting to push the reset button; getting Harry out on more engagements just one way they hope to focus our minds back on to what he has always done best.

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World

Migrants locked up in notorious El Salvador jail released in Venezuela-US prisoner swap

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Migrants locked up in notorious El Salvador jail released in Venezuela-US prisoner swap

On Friday, Paola Paiva waited in a hotel near Caracas airport, nervous but giddy with excitement to be reunited with her brother, finally.

For five months, Arturo Suarez has been detained in a notorious prison in El Salvador.

“I am going to wait for my brother to call me,” she told Sky News, “and after giving him a hug, I want to just listen to him, listen to his voice. Let him talk and tell us his story.”

Suarez was one of the more than 250 Venezuelan migrants who had been living in America but were arrested in immigration raids by the Trump administration and sent to El Salvador, a showpiece act in the president’s promise to deport millions of migrants.

Paola Paiva holds a vigil for brother Arturo Suarez. Pic: Reuters
Image:
Paola Paiva holds a vigil for brother Arturo Suarez. Pic: Reuters

Most of the men had never even been to El Salvador before. Their detention has been controversial because the White House claims the men are all part of the dangerous Tren de Aragua gang but has provided little evidence to support this assertion.

The only evidence Paola had that Suarez was still alive was a picture of him published on a news website showing the inside of the maximum security CECOT jail.

He is one of dozens of men with their hands and feet cuffed, heads shaved and bodies shackled together.

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Now he is returning to his home country, one of the bargaining chips in a deal that saw the release of ten Americans and US permanent residents who had been seized by the Venezuelan authorities.

Venezuelans arrive back in home country after being detained in El Salvador
Image:
Venezuelans arrive back in home country after being detained in El Salvador

Paola had tried to go to the airport to greet her brother as he disembarked a charter plane bringing the men back from El Salvador but authorities told her to wait at a nearby hotel.

“They told us they are taking them all to a hotel to rest,” she said.

“But I managed to get someone to give my phone number on a piece of paper to my brother, so I am expecting his call tomorrow, as soon as he can access a phone.

“We heard they are going to perform some medical exams on them and check their criminal records,” she added. “I’m not afraid; I’m not worried since my brother has a clean record.

“I am so happy. I knew this day would happen, and that it would be unexpected, that no one was going to notify us. I knew it was going to be a total surprise.”

US citizens released from Venezuela. Pic: Reuters
Image:
US citizens released from Venezuela. Pic: Reuters

The Trump administration had paid the El Salvador government, led by President Nayib Bukele, millions of dollars to imprison the men.

Homeland security secretary Kristi Noem visited CECOT last month, posing in front of prisoners for a photo opportunity.

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But Cristosal, an international human rights group based in El Salvador, says it has “documented systematic physical beatings, torture, intentional denial of access to food, water, clothing, health care,” inside the prison.

A video which was seemingly filmed aboard the charter flight bringing the Venezuelan migrants back to Caracas shows Arturo briefly talking about his experience inside.

He looks physically well but speaks into the camera and says: “We were four months with no communication, no phone calls, kidnapped, we didn’t know what (the) day was, not even the time.

“We were beat up at breakfast, lunch and dinner,” he continues.

Sky News interviewed Arturo Suarez‘s brother Nelson near his home in the US in April, weeks after Arturo – an aspiring singer – had been arrested by immigration and customs enforcement (ICE) agents while filming a music video inside a house.

Nelson said he believed Arturo’s only crime was “being Venezuelan and having tattoos.” He showed me documents that indicate Arturo has no criminal record in Venezuela, Chile, Colombia or the United States, the four countries he has lived in.

Now Nelson is delighted Arturo is being released – but worries for his future.

“The only thing that casts a shadow in such a moment of joy is that bit of anger when I think that all the governments involved are going to use my brother’s story, and the others on that flight, as political gain,” he said.

“Each of them will tell a different story, making themselves the heroes, when the reality is that many innocent people suffered unfairly and unnecessarily, and many families will remain separated after this incident due to politics, immigration and fear.”

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