Tag: propofol

Categories : NeurologyTags :

Could a New Role for Propofol be Treating Epilepsy?

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The general anaesthetic propofol may hold the keys to developing new treatment strategies for epilepsy and other neurological disorders, according to a study led by researchers at Weill Cornell Medicine and Linköping University in Sweden.

In their study, published in Nature, the researchers determined the high-resolution structural details of how propofol inhibits the activity of HCN1, an ion channel protein found on many types of neurons. Drug developers consider inhibiting HCN1 a promising strategy for treating neurologic disorders including epilepsy and chronic pain. The researchers also found, to their surprise, that when HCN1 contains either of two epilepsy-associated mutations, propofol binds to it in a way that restores its functionality.

“We might be able to exploit propofol’s unique way of binding to HCN1 for the treatment of these drug-resistant epilepsies and other HCN1-linked disorders, either by directly repurposing propofol or by designing new, more selective drugs that have the same mechanism of action,” said study co-senior author Dr Crina Nimigean, professor of physiology and biophysics in anaesthesiology at Weill Cornell Medicine.

The study’s first author was Dr Elizabeth Kim, a postdoctoral research associate in the Nimigean laboratory.  

HCN ion channels in humans come in four basic forms, HCN1 to HCN4, and are found especially on cells in the heart and nervous system. They work as switches to control the electrical voltage across the cell membrane, opening to admit an inward flow of positively charged potassium and sodium ions – thus “depolarising” the cell – when the voltage reaches a certain threshold. This function underpins much of the rhythmic activity of brain and heart muscle cells, which is why HCN channels are also called pacemaker channels.

In the study, the researchers used cryo-electron microscopy and other methods to determine, at near-atomic scale, how propofol reduces HCN1 activity – which it does with selectivity for HCN1 over other HCNs. They found that the drug inhibits HCN1 by binding within a groove between two elements of the channel protein’s central pore structure, making it harder for the pore to open.

As they investigated propofol’s action on HCN1, the researchers examined how the drug affects different known mutants of the channel, including mutants that leave it excessively open and are associated with hard-to-treat epilepsy syndromes such as early infantile epileptic encephalopathy (EIEE). The researchers were surprised to find that for two different HCN1 mutations that cause EIEE, propofol restores the mutant channels to normal or near-normal function.

From their experiments, the researchers derived a model in which the mutations decouple HCN1’s voltage-sensing and pore mechanisms, while propofol effectively recouples them, allowing membrane voltage to control ion flow again.

The results suggest at least two possibilities for translation to therapies. One is simply to use propofol, an existing, approved drug, to treat these HCN1-mutation epilepsies and potentially other HCN1-linked disorders. Propofol is a potent anesthetic that requires careful monitoring by anaesthesiologists, but it might be able to restore HCN1 function at doses below those used for general anaesthesia.

The other possibility, the researchers said, is to use the new structural data on propofol’s binding to design modified, non-anesthetic versions of propofol, or even completely different compounds, that bind to HCN1 with a similar effect but much more selectively—in other words, without binding to other channels, including other HCNs, in the body and thereby potentially causing unwanted side effects.

“For that we will need a better understanding of how propofol inhibits HCN1 better than other HCN channels,” Dr Kim said.

Source: Weill Cornell Medicine

Categories : Neurology Pain ManagementTags :

Researchers Figure out How Propofol Makes Patients Lose Consciousness

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There are many drugs that anaesthesiologists can use to induce unconsciousness in patients. Exactly how these drugs cause the brain to lose consciousness has been a longstanding question, but MIT neuroscientists have now answered that question for the commonly used drug propofol.

Using a novel technique for analysing neuron activity, the researchers discovered that the drug propofol induces unconsciousness by disrupting the brain’s normal balance between stability and excitability. The drug causes brain activity to become increasingly unstable, until the brain loses consciousness.

“The brain has to operate on this knife’s edge between excitability and chaos. It’s got to be excitable enough for its neurons to influence one another, but if it gets too excitable, it spins off into chaos. Propofol seems to disrupt the mechanisms that keep the brain in that narrow operating range,” says Earl K. Miller, the Picower Professor of Neuroscience and a member of MIT’s Picower Institute for Learning and Memory.

The new findings, published in Neuron, could help researchers develop better tools for monitoring patients as they undergo general anaesthesia.

Miller and Ila Fiete, a professor of brain and cognitive sciences, the director of the K. Lisa Yang Integrative Computational Neuroscience Center (ICoN), and a member of MIT’s McGovern Institute for Brain Research, are the senior authors of the new study. MIT graduate student Adam Eisen and MIT postdoc Leo Kozachkov are the lead authors of the paper.

Losing consciousness

Propofol is a drug that binds to GABA receptors in the brain, inhibiting neurons that have those receptors. Other anaesthesia drugs act on different types of receptors, and the mechanism for how all of these drugs produce unconsciousness is not fully understood.

Miller, Fiete, and their students hypothesised that propofol, and possibly other anaesthesia drugs, interfere with a brain state known as “dynamic stability.” In this state, neurons have enough excitability to respond to new input, but the brain is able to quickly regain control and prevent them from becoming overly excited.

Previous studies of how anaesthesia drugs affect this balance have found conflicting results: Some suggested that during anaesthesia, the brain shifts toward becoming too stable and unresponsive, which leads to loss of consciousness. Others found that the brain becomes too excitable, leading to a chaotic state that results in unconsciousness.

Part of the reason for these conflicting results is that it has been difficult to accurately measure dynamic stability in the brain. Measuring dynamic stability as consciousness is lost would help researchers determine if unconsciousness results from too much stability or too little stability.

In this study, the researchers analysed electrical recordings made in the brains of animals that received propofol over an hour-long period, during which they gradually lost consciousness. The recordings were made in four areas of the brain that are involved in vision, sound processing, spatial awareness, and executive function.

These recordings covered only a tiny fraction of the brain’s overall activity, so to overcome that, the researchers used a technique called delay embedding. This technique allows researchers to characterize dynamical systems from limited measurements by augmenting each measurement with measurements that were recorded previously.

Using this method, the researchers were able to quantify how the brain responds to sensory inputs, such as sounds, or to spontaneous perturbations of neural activity.

In the normal, awake state, neural activity spikes after any input, then returns to its baseline activity level. However, once propofol dosing began, the brain started taking longer to return to its baseline after these inputs, remaining in an overly excited state. This effect became more and more pronounced until the animals lost consciousness.

This suggests that propofol’s inhibition of neuron activity leads to escalating instability, which causes the brain to lose consciousness, the researchers say.

Better anesthesia control

To see if they could replicate this effect in a computational model, the researchers created a simple neural network. When they increased the inhibition of certain nodes in the network, as propofol does in the brain, network activity became destabilized, similar to the unstable activity the researchers saw in the brains of animals that received propofol.

“We looked at a simple circuit model of interconnected neurons, and when we turned up inhibition in that, we saw a destabilization. So, one of the things we’re suggesting is that an increase in inhibition can generate instability, and that is subsequently tied to loss of consciousness,” Eisen says.

As Fiete explains, “This paradoxical effect, in which boosting inhibition destabilises the network rather than silencing or stabilising it, occurs because of disinhibition. When propofol boosts the inhibitory drive, this drive inhibits other inhibitory neurons, and the result is an overall increase in brain activity.”

The researchers suspect that other anesthetic drugs, which act on different types of neurons and receptors, may converge on the same effect through different mechanisms – a possibility that they are now exploring.

If this turns out to be true, it could be helpful to the researchers’ ongoing efforts to develop ways to more precisely control the level of anaesthesia that a patient is experiencing. These systems, which Miller is working on with Emery Brown, the Edward Hood Taplin Professor of Medical Engineering at MIT, work by measuring the brain’s dynamics and then adjusting drug dosages accordingly, in real-time.

“If you find common mechanisms at work across different anaesthetics, you can make them all safer by tweaking a few knobs, instead of having to develop safety protocols for all the different anaesthetics one at a time,” Miller says. “You don’t want a different system for every anesthetic they’re going to use in the operating room. You want one that’ll do it all.”

The researchers also plan to apply their technique for measuring dynamic stability to other brain states, including neuropsychiatric disorders.

“This method is pretty powerful, and I think it’s going to be very exciting to apply it to different brain states, different types of anaesthetics, and also other neuropsychiatric conditions like depression and schizophrenia,” Fiete says.

Source: MIT

Categories : Pain ManagementTags :

Shedding Light on Propofol’s Poorly Understood Anaesthetic Mechanism

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In a new study published in Molecular Biology of the Cell, a team of Rensselaer Polytechnic Institute researchers identified a previously unknown propofol anaesthetic mechanism, which, despite its frequent clinical application, is poorly understood. The study found that propofol exposure impacted the transportation of proteins to the surface of neurons, interrupting their function.

Almost all animal cells, including human cells, are highly compartmentalised and rely on efficient movement of protein material between compartments in vesicles. This transport must be efficient and highly specific to maintain cellular organisation and function.

The research team was led by Dr Marvin Bentley, associate professor at Rensselaer Polytechnic Institute, whose laboratory studies vesicle transport in neurons. Neurons are particularly reliant on vesicle transport because axons, often organised in nerve bundles. can span distances of up to 100cm in humans. Errors in vesicle transport have been linked to neurodevelopmental and neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

This new study found that propofol affects a family of proteins called kinesins – small ‘motor proteins’ that move vesicles on tiny filaments called microtubules.

Dr Bentley’s team observed that vesicle movement of two prominent kinesins, Kinesin-1 and Kinesin-3, was substantially reduced in cells exposed to propofol. The team then showed that propofol-induced transport delays led to a significant drop in protein delivery to axons.

“The mechanism by which propofol works is not fully understood,” Bentley said. “What we discovered was unexpected: propofol altered the trafficking of vesicles in live neurons.”

Overall, the research contributes significantly to our understanding of how propofol works. Most studies on propofol’s anaesthetic mechanism have instead focused on its interaction with an ion channel called the GABAA receptor, which inhibits neurotransmission when activated.

This new study demonstrates that vesicle transport is an additional mechanism that may be important for propofol’s anaesthetic effect. Discovery of this new propofol effect has important applications for human health and may lead to the development of better anaesthetic drugs.

Source: Rensselaer Polytechnic Institute

Categories : GastrointestinalTags :

Propofol and Physician Anaesthesiologists Speed Up Endoscopy

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Using a physician anaesthesiologist-led model administering fast-acting propofol increases patient access to care, compared to previous models which used nurse-administered sedation for gastrointestinal (GI) endoscopy procedures, according to work done by the University of Colorado Hospital.

“The Anaesthesia Care Team model allows us to optimise patient flow and utilise faster-acting medications, resulting in shorter total case lengths and reduced post-anaesthesia care unit (PACU) length of stay for upper and lower GI endoscopic procedures, compared to a model where nurses provided sedation,” said Dr Adeel A. Faruki, senior author of the study. “This allows for scheduling more patients in fewer rooms in the GI suite per day and increases patient access to care.”

Most anaesthesia care in the US is delivered either by a physician anaesthesiologist or a non-physician anaesthesia practitioner supervised by a physician anaesthesiologist within the Anaesthesia Care Team model. This model and physician-led anaesthesia care is seen as the gold standard for ensuring patient safety and the best outcomes.

The University of Colorado Hospital previously used a model where GI procedural nurses provided sedation under supervision from gastroenterologists for cases that did not require general anesthesia (called the GI luminal unit). The hospital transitioned to the Anaesthesia Care Team model for all GI cases July 1, 2021.

In the study, researchers compared GI cases performed under the previous nurse-provided sedation model to those performed under the Anaesthesia Care Team model. They found it took less time to start the procedure (sedation start to scope-in time) when deep sedation with propofol (MAC) was provided by the Anaesthesia Care Team than when nurses administered sedation with fentanyl, midazolam and diphenhydramine. That change, along with a redesigned patient flow, provided the opportunity to increase daily GI procedural volume by 25%, while using the same number of procedural suites, Dr Faruki said.

Propofol is a fast-acting and effective medication with a higher-risk-profile, which physician anesthesiologists have the skills and training to deliver and monitor. “Propofol can result in very deep levels of sedation in a short period of time and, therefore, at most institutions, is restricted for use by anesthesia providers,” said Andrew Mariotti, lead author of the study and M.D. candidate at the University of Colorado. “Unlike GI procedural nurses, the Anesthesia Care Team has the training and expertise to perform advanced airway and cardiovascular interventions if an emergency arises.”

The researchers analysed the sedation-to-scope-in time of 5640 endoscopy patients, comparing 4,606 who received nurse-administered sedation for GI procedures, to 1034 who had MAC. The time was reduced by 2 to 2-1/2 minutes per case with MAC. Extrapolating to the typical cases performed at their hospital over a year (more than 2600 cases), the authors said the time savings equates to more than 5300 minutes, or 90 hours.

Sincerecovery also is faster with propofol, there were time savings in the PACU of 7 minutes for upper GI endoscopies and 2 minutes in lower-GI cases. The researchers also found patients reported being less groggy.

GI endoscopies account for about two-thirds of all endoscopies in the US. The time savings for Anesthesia Care Team-administered MAC sedation likely would apply to non-GI procedures as well, the authors noted.

This research is presented at the American Society of Anesthesiologists’ ADVANCE 2022, the Anesthesiology Business Event.

Source: EurekAlert!