Day: May 29, 2025

Categories : NeurologyTags :

How Molecules can ‘Remember’ and Contribute to Memory and Learning

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Researchers have discovered how an ion channel in the brain’s neurons has a kind of ‘molecular memory’, which contributes to the formation and preservation of lifelong memories. The researchers have identified a specific part of the ion channel at which new drugs for certain genetic diseases could be targeted.

Learning from past experiences and forming memories depend on the reshaping of connections between neurons in the brain. Synapses are strengthened or weakened throughout life in such a way that the brain is, in a certain sense, constantly being reshaped at the cellular level. This phenomenon is called synaptic plasticity.

There are several processes contributing to synaptic plasticity in the nervous system. One of these processes has to do with a type of molecules called calcium ion channels, which have long been of interest to researchers at Linköping University, LiU.

“I want to uncover the secret lives of these ion channel molecules. Calcium ion channels have very important functions in the body – by opening and closing, they regulate, among other things, nerve-to-nerve signalling. But beyond that, these molecules also have a kind of memory of their own, and can remember previous nerve signals,” says Antonios Pantazis, associate professor at the Department of Biomedical and Clinical Sciences at LiU, who led the study published in Nature Communications.

How can a molecule remember?

The focus of this study was on a specific type of ion channel, the CaV2.1 channel, which is the most common calcium ion channel in the brain. The ion channel is located at the synapse, at the very end of the neuron. When an electrical signal passes through the neuron, the ion channel open, setting in motion a process leading to neurotransmitter being released towards the receiving neuron in the synapse. In this way, CaV2.1 channels are the gatekeepers of synaptic, neuron-to-neuron communication.

Prolonged electrical activity reduces the number of CaV2.1 channels that can open, resulting in less transmitter release, so the receiving neuron receives a weaker message. It is as if the channels can ‘remember’ previous signalling, and in doing so, make themselves unavailable to open by subsequent signals. How this works at the molecular level has been unknown to scientists until now.

The Linköping researchers have now discovered a mechanism for how the ion channel can ‘remember’. The channel is a large molecule made up of several interconnected parts, which can move relative to each other in response to electrical signals. They discovered that the ion channel can take almost 200 different shapes depending on the strength and duration of an electrical signal; it is a very complex molecular machine.

“We believe that during sustained electrical nerve signalling, an important part of the molecule disconnects from the channel gate, similar to the way the clutch in a car breaks the connection between the engine and the wheels. The ion channel can then no longer be opened. When hundreds of signals occur over long enough time, they can convert most channels into this ‘declutched memory state’ for several seconds,” says Antonios Pantazis.

Target for future drugs

If the ion channel can ‘remember’ for just a few seconds, how does it contribute to lifelong learning? This type of collective memory in the ion channels can accumulate over time and reduce the communication between two neurons. This then leads to changes in the receiving neuron, lasting for hours or days. Eventually, it results in much longer-lived changes in the brain, such as the elimination of weakened synapses.

“In this way, a ‘memory’ that lasts for a few seconds in a single molecule can make a small contribution to a person’s memory that lasts for a lifetime,” says Antonios Pantazis.

Increased knowledge of how these calcium ion channels work can in the long term contribute to the treatment of certain diseases. There are many variants of the gene that produces the CaV2.1 channel, CACNA1A, that are linked to rare but serious neurological diseases, that often run in families. To develop drugs against these, it helps to know which part of the large ion channel you want to affect and in what way its activity should be changed.

“Our work pinpoints which part of the protein should be targeted when developing new drugs,” says Antonios Pantazis.

Source: Linköping University

Categories : Cancer Obstetrics & GynaecologyTags :

Do Bevacizumab’s Ovarian Cancer Clinical Trial Results Hold up in the Real World?

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Photo by Tima Miroshnichenko on Pexels

A real-world study based on information from an electronic health records–derived database reveals limited benefits of adding bevacizumab to first-line chemotherapy for patients with ovarian cancer, consistent with previous clinical trials. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

Bevacizumab is a monoclonal antibody against vascular endothelial growth factor A that acts to inhibit malignant cell growth and blood vessel formation. It’s approved as a treatment for various types of cancer. In clinical trials of patients with ovarian cancer, adding bevacizumab to first-line chemotherapy did not prolong overall survival compared with chemotherapy alone, but this treatment strategy did improve overall survival in analyses limited to patients with high-risk prognostic factors—such as those with advanced disease and those who had residual cancer present after surgery. A final long-term analysis did not find an overall survival benefit associated with bevacizumab in the full patient cohort.

To investigate whether these findings also hold true in real-world clinical practice, researchers examined the electronic health records of 1,752 patients with stage III or IV ovarian cancer who initiated chemotherapy with or without bevacizumab in 2017–2023 and were followed for a median time of 1.5 years.

Among patients with high-risk prognostic factors, the median time to next treatment was significantly longer for those receiving chemotherapy plus bevacizumab compared with those receiving chemotherapy alone: 13.6 versus 11.7 months. (Time to next treatment is used to assess the duration of clinical benefit by measuring the time between initiating a treatment and starting the next line of therapy). In these patients, there was also a trend towards longer median overall survival for the combination therapy: 31.1 versus 27.4 months. Among patients without high-risk prognostic factors, outcomes did not differ with the addition of bevacizumab. Benefits therefore seemed limited to special subpopulations, mirroring the findings from clinical trials.

“Our results were similar to results from clinical trials,” said lead author Linda R. Duska, MD, MPH, of the University of Virginia School of Medicine. “Our findings suggest that clinicians should consider a patient’s risk factors before using bevacizumab with first-line chemotherapy in the treatment of advanced ovarian cancer.”  

Source: Wiley

Categories : Cardiovascular Disease Metabolic DisordersTags :

Timely Initiation of Statins in Diabetes Shown to Dramatically Reduce Cardiovascular Risk

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Photo by Towfiqu Barbhuiya on Unsplash

Despite clinicians recommending that many patients with diabetes take statins, nearly one in five opt to delay treatment. In a new study, researchers from Mass General Brigham found that patients who started statin therapy right away reduced the rate of heart attack and stroke by one third compared to those who chose to delay taking the medication. The results, which can help guide decision-making conversations between clinicians and their patients, are published in the Journal of the American Heart Association.

“I see patients with diabetes on a regular basis, and I recommend statin therapy to everyone who is eligible,” said senior author Alexander Turchin, MD, MS, of the Division of Endocrinology at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system. “Some people refuse because they want to first try lifestyle interventions or other drugs. But other interventions are not as effective at lowering cholesterol as starting statin therapy as soon as possible. Time is of the essence for your heart and brain health.”

Heart attacks and strokes remain the leading cause of complications and mortality for patients with diabetes. Statin therapy reduces risk of these cardiovascular events by preventing plaque buildup in the blood vessels.

The researchers used an artificial intelligence method called Natural Language Processing to gather data from the electronic health records of 7239 patients at Mass General Brigham who ultimately started statin therapy during the nearly 20-year study period. The median patient age was 55, with 51% being women, 57% white, and a median HbA1c of 6.9.

Nearly one-fifth (17.7%) of the patients in the study declined statin therapy when it was first recommended by their clinicians, then later accepted the therapy (after a median of 1.5 years) upon repeated recommendation by their clinician. Of those who delayed, 8.5% had a heart attack or stroke. But for patients who started statins immediately, the rate of those cardiovascular events was just 6.4%.

“Clinicians should recognize the increased cardiovascular risk associated with delaying statin therapy for patients with diabetes and use this information to guide shared decision-making conversations with their patients,” said Turchin.

Source: Mass General Brigham

Categories : Cardiovascular DiseaseTags :

Heart Valve Abnormality is Associated with Malignant Arrhythmias

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People with a certain heart valve abnormality, mitral annular disjunction, are at increased risk of severe heart rhythm disorders, even after successful valve surgery. This is according to a new study from Karolinska Institutet and Karolinska University Hospital in Sweden published in the European Heart Journal. The condition is more common in women and younger patients with valve disorder and can, in the worst case, lead to sudden cardiac arrest.

Mitral annular disjunction, MAD, is a heart abnormality in which the mitral valve attachment ‘slides’. In recent years, the condition has been linked to an increased risk of severe cardiac arrhythmias. Until now, it has not been known whether the risk of arrhythmias disappears if MAD is surgically corrected.

MAD is often associated with a heart disease called mitral valve prolapse, which affects 2.5% of the population and causes one of the heart’s valves to leak. This can lead to blood being pumped backwards in the heart, causing heart failure and arrhythmias. The disease can cause symptoms such as shortness of breath and palpitations.

Followed patients after surgery

In the current study, researchers at Karolinska Institutet investigated the risk of cardiac arrhythmias in 599 patients with mitral valve prolapse who underwent heart surgery at Karolinska University Hospital between 2010 and 2022. Sixteen percent of the patients also had the cardiac abnormality MAD.

“We have been able to show that people with MAD have a significantly higher risk of suffering from ventricular arrhythmias, a dangerous type of heart rhythm disorder that in the worst case can lead to cardiac arrest in a subset of patients,” says Bahira Shahim, associate professor at the Department of Medicine, Solna, Karolinska Institutet and cardiologist at Karolinska University Hospital

People with MAD were more likely to be female and were on average eight years younger than those without MAD. They also had more extensive mitral valve disease. Although the surgery was successful in correcting MAD, these patients had more than three times the risk of ventricular arrhythmias during five years of follow-up compared to patients without preoperative MAD.

“Our results show that it is important to closely monitor patients with this condition, even after a successful operation,” says Bahira Shahim.

Investigating new hypotheses

The study has led to new hypotheses that the researchers are now investigating further. One hypothesis is that MAD causes permanent changes in the heart muscle over time. Another is that MAD is a sign of an underlying heart muscle disease. The researchers are now continuing to study scarring in the heart using MRI (magnetic resonance imaging) and analyse tissue samples from the heart muscle.

Source: Karolinska Institutet

Categories : Mental Health NeurologyTags :

Extending Ketamine’s Relieving Effect on Depression

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Photo by Sydney Sims on Unsplash

For 30% of people with major depressive disorder (MDD), antidepressants don’t work. When infused at a low dose, ketamine shows remarkable efficacy as a rapidly acting antidepressant, with effects observed within hours even in patients who have been resistant to other antidepressant treatments. One drawback is that consistent infusions of ketamine are needed to maintain symptoms at bay, which could result in side effects, such as dissociative behaviours and the possibility of addiction, and stopping treatment can result in relapse.

In a new study published in Science, Lisa Monteggia’s and Ege Kavalali’s labs show that it is feasible to substantially extend the efficacy of a single dose of ketamine from its current duration of up to a week to a longer period of up to two months.

“The premise of this study, which was led by Zhenzhong Ma, a fantastic research assistant professor, was based on a testable mechanistic model that we developed that accounts for ketamine’s rapid antidepressant action,” Monteggia said.

Previously, researchers in the field had determined that ketamine’s antidepressant effect requires the activation of a key signalling pathway called ERK, but only ketamine’s long-term effects – not its rapid effects – are abolished when ERK is inhibited. As a fast-acting antidepressant, ketamine relies on ERK-dependent synaptic plasticity to produce its rapid behavioural effects. Ma and colleagues hypothesised that they could maintain ketamine’s effects for longer periods by enhancing ERK activity. 

In the recent paper, Ma discovered that ketamine’s antidepressant effects could be sustained for up to two months by using a drug called BCI, which inhibits a protein phosphatase and results in increased ERK activity. By inhibiting the phosphatase, the authors retained ERK’s activity and augmented the synaptic plasticity that drives ketamine’s prolonged antidepressant effects. 

lthough the use of BCI makes the application of these results to the clinic difficult, Monteggia said that the results provide a proof of principle that ketamine’s antidepressant action can be sustained by targeting intracellular signaling. She and Kavalali, the William Stokes Professor of Experimental Therapeutics and the chair of the Department of Pharmacology, have worked on the project since its inception and hope that it will foster other studies looking to identify specific molecules to enhance and sustain the action of a single dose of ketamine.

Ultimately, this work will be a stepping stone toward improving MDD patients’ lives by reducing the burden of treatment.

Source: Vanderbilt University