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
A parade marking the US Army’s 250th anniversary – and President Trump’s 79th birthday – is under way.
You can watch the event in the livestream above.
President Trump said it was going to be a “big day” and admitted: “We want to show off a little bit.”
Today is the first time in more than 30 years that tanks have rolled through the US capital.
Officials have estimated around 200,000 people could turn out, including protesters, plus 6,600 soldiers, 150 vehicles and 50 aircraft.
However, it appears far fewer have turned out – possibly due to the poor weather – and the president has warned any protesters who interfere “will be met with very big force”.
Image: Pic: AP
Image: Pic: AP
Image: Pic: AP
Image: Pic: Reuters
Mr Trump is watching alongside the first lady and defence secretary as troops and military hardware file past – accompanied at times by up tempo rock music.
The event started half an hour early due to forecasted heavy rain, with cloud forcing the cancellation of a flypast by fighter jets.
Helicopters such as Apaches, Chinooks and Black Hawks are still taking part however.
Image: Pic: Reuters
Image: Pic: Reuters
Image: Pic: Reuters
Military parachutists from the Golden Knights began the parade by swooping in, and some of the soldiers are parading in historic uniforms, complete with horses and wagons.
Vehicles from the Second World War era are also taking part.
President Trump stood and saluted many of the passing soldiers. He is said to have got the idea for the parade after being impressed with France’s Bastille Day celebrations during a visit in 2017.
Metal plates have been put down on some of Washington’s streets to protect the tarmac against the heaviest tanks – the 60-ton M1 Abrams.
Even so, the US Army has set aside several million dollars in case of any damage.
The last time such a major display took place in the US was 1991 when tanks and troops paraded to celebrate the ousting of Saddam Hussein’s army from Kuwait.
Image: Pic: Reuters
Image: Pic: Reuters
Image: Pic: Reuters
The event has been criticised by some for being something more associated with a dictatorial regime such as Russia or North Korea.
An estimated cost as high as $45m (£33.33m) has also raised eyebrows given the administration’s efforts to slash the budget of many federal departments.
Among the critics is California governor Gavin Newsom, who has been trading barbs with Mr Trump since the outbreak of riots in LA.
“And we all know, this Saturday, he’s ordering our American heroes – the United States military – forcing them to put on a vulgar display to celebrate his birthday, just as other failed dictators have done in the past,” he said.
Image: Pic: AP
Image: Pic: Reuters
Image: Pic: Reuters
The show of military might also comes as more than 1,500 protests against the Trump administration, organised under the slogan ‘No Kings’, have been planned across the US on Saturday.
Los Angeles is the scene of one demonstration, with police firing tear gas to disperse people and US Marines stationed outside the city’s federal building.
Unless Bitcoin upgrades its core cryptography in the next five years, the trust it has built over 16 years could be wiped out by a single quantum attack. Urgent upgrades are needed to protect the world’s leading cryptocurrency.
The son of an Air India plane crash victim, who was sitting one row behind the man who survived, has told Sky News he will relive “her last moments” until the day he dies.
Manju Mahesh Patel, 79, was on the London Gatwick-bound plane when it crashed in Ahmedabad shortly after take-off on Thursday.
In an interview with Sky News, Chirag Mahesh Patel, Manju’s son, said he hopes his mother’s death was “instant” and “painless”.
“To the day I die I will think, ‘what were her last moments?’,” he said.
Pointing to a framed family photograph of Ms Patel at the family home, he added: “I want to remember mum like this.
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“I don’t want to have to go and identify a burnt corpse, your own parent. How does someone, how do you ever get over that? That will be with me, that’s with me for life.”
Ms Patel had been staying in Ahmedabad for the past few months doing charity work at a temple. She was due to be picked up by her son at Gatwick on Thursday night.
Image: A family photo of Chirag Mahesh Patel with his mother
In tears, Mr Patel described his mother as “very strong” and a woman “who really loved her family”.
“The thing about my mum,” he said, “is her bond with her faith. It’s unbreakable.
“She had ultimate faith… and in times of stress she would always say God’s name… So, I know that upon take-off, I know that she was saying his name.”
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1:57
What could have caused the India plane crash?
Mr Patel said that when he realised his mother was on the flight it was just “a normal day” and “it didn’t seem real”.
He said the last time he had spoken to her he had reminded her to take her diabetes medicine and had then missed a call from her at 4am to say she had arrived at the airport.
He described “the most heartbreaking thing” was how much Ms Patel was looking forward to seeing her grandchildren, saying “it was everything to her”.
She had told him she packed her suitcase with lollipops for her six-year-old grandson, and special crisps for her 15-year-old older grandchild.
Image: Ms Patel with her six-year-old grandson
“It’s unimaginable even in my worst nightmare,” he said. “And the thing that kills me… is she was so looking forward to seeing us… she kept saying I bought this for you, I bought that, I bought the things for the kids.”
Mr Patel and his wife are due to fly to India on Saturday night to provide a DNA sample to help identify his mother’s remains.
He expressed his anger at what he called a “disgusting” and “appalling” lack of communication from Air India – which he said passed his details to a hospital but never contacted him personally.
He described feeling “neglected” by the airline, which he said would only offer him an Air India flight – and no help organising accommodation.
Mr Patel said he refused to get on the Gatwick flight back to Ahmedabad and has booked with another provider to travel to India instead.
Image: Ms Patel with her elder grandchild
“I said [to the airline] all of this happened on Thursday, you’re telling me on Friday afternoon, do you want that flight this evening? That one crashed? The one coming back where 172 goes out? They asked do you want Air India 172? I said how can you ask me that. My mum just died on Air India.”
Mr Patel said he wanted “answers” and transparency in any air accident investigation.
Air India said in a statement: “Air India stands in solidarity with the families of the passengers who tragically lost their lives in the recent accident. Our teams on the ground are doing everything possible to extend care and support during this incredibly difficult time.
“As part of our continued efforts, Air India will be providing an interim payment of ₹25 lakh or approximately £21,000 each to the families of the deceased and to the survivor, to help address immediate financial needs. This is in addition to the ₹1 crore or approximately £85,000 support already announced by Tata Sons.
“All of us at Air India are deeply saddened by this loss. We mourn with the families, loved ones, and everyone affected.”
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3:24
Families in India wait for bodies of relatives
The company’s chief executive and managing director Campbell Wilson said in a video message posted on social media that over 200 “trained caregivers” were now in place to offer dedicated assistance to families, along with counselling and other services.
He said Air India was in the process of completing precautionary safety checks on Boeing 787 aircraft as directed by regulator the Directorate General of Civil Aviation (DGCA), which would “be completed within the timelines prescribed by the regulator”.
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Mr Wilson said he had also visited the crash site and said other members of the management team would remain present “for as long as it takes”.
The aircraft’s data recorder, often referred to as a black box, has been recovered and will form part of the investigation into the worst aviation crash in a decade.
‘He was too young’: Families grieve those lost in Air India crash
It was an emotional service at Derby’s Geeta Bhawan Hindu temple, as dozens of friends, colleagues and neighbours gathered to remember Dr Prateek Joshi, his wife Komi, their daughter Miraya, and twin sons Nakul and Pradyut.
Some wiped tears from their eyes, as a colleague was asked spontaneously to pay tribute to Dr Joshi, who had been bringing his family to live in the city, when the Air India flight they were on crashed seconds after take-off.
“He was too young, too much still to give, too much still to be done, too much to offer,” his friend told worshippers.
“He was taken from us in a very cruel and abrupt way, and his family as well, and we all think about his family back in India who is missing a son, missing a daughter-in-law and missing all their grandchildren who they’ll never see growing up.”
Derby South MP Catherine Atkinson said Dr Joshi, who was a radiologist at the Royal Derby hospital, had been “contributing to our NHS and the health of so many in our city and beyond”.
She said his wife was a pathologist who had resigned from her job in India.
“I won’t forget the photograph of them on the plane, full of optimism about their new adventure,” she said, as her voice broke.
“The losses make us all hug our families and loved ones a little closer and remind us how precious our time together is.”
Dr Joshi was described as a “warm, smiling man, full of joy” who enjoyed walking in the Peak District and who had discovered “a love of fish and chips”.
His neighbour and colleague Manoj Ramtohal told Sky News Dr Joshi always had time for people.
“He was very caring and very polite, very friendly, you couldn’t meet a better man than Prateek,” he said.