Posts Tagged GABA

[Abstract] Role of Interhemispheric Cortical Interactions in Poststroke Motor Function

Background/Objective. We investigated interhemispheric interactions in stroke survivors by measuring transcranial magnetic stimulation (TMS)–evoked cortical coherence. We tested the effect of TMS on interhemispheric coherence during rest and active muscle contraction and compared coherence in stroke and older adults. We evaluated the relationships between interhemispheric coherence, paretic motor function, and the ipsilateral cortical silent period (iSP).

Methods. Participants with (n = 19) and without (n = 14) chronic stroke either rested or maintained a contraction of the ipsilateral hand muscle during simultaneous recordings of evoked responses to TMS of the ipsilesional/nondominant (i/ndM1) and contralesional/dominant (c/dM1) primary motor cortex with EEG and in the hand muscle with EMG. We calculated pre- and post-TMS interhemispheric beta coherence (15-30 Hz) between motor areas in both conditions and the iSP duration during the active condition.

Results. During active i/ndM1 TMS, interhemispheric coherence increased immediately following TMS in controls but not in stroke. Coherence during active cM1 TMS was greater than iM1 TMS in the stroke group. Coherence during active iM1 TMS was less in stroke participants and was negatively associated with measures of paretic arm motor function. Paretic iSP was longer compared with controls and negatively associated with clinical measures of manual dexterity. There was no relationship between coherence and. iSP for either group. No within- or between-group differences in coherence were observed at rest.

Conclusions. TMS-evoked cortical coherence during hand muscle activation can index interhemispheric interactions associated with poststroke motor function and potentially offer new insights into neural mechanisms influencing functional recovery.

 

via Role of Interhemispheric Cortical Interactions in Poststroke Motor Function – Jacqueline A. Palmer, Lewis A. Wheaton, Whitney A. Gray, Mary Alice Saltão da Silva, Steven L. Wolf, Michael R. Borich, 2019

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[WEB PAGE] When Will There Ever be a Cure for Epilepsy?

The three-pound organ that serves as command central for the human organism is certainly a marvel, just by virtue of the fact that the brain can appreciate its own awesomeness, even if it hasn’t quite perfected the flying car or even self-driving cars. Yet. Companies developing brain-computer interface technology are enabling humans to do things like send commands to computers by just flexing a bit of muscle. Still, there is much we don’t know about ourselves, no matter how much telepsychiatry we do. And that applies especially to medical conditions that affect the brain like epilepsy, a neurological condition for which there is no cure.

What is Epilepsy?

While most of us are probably familiar with some Hollywood-ized version of epilepsy in which someone starts flailing around after being hit by strobe lights on the disco floor, the reality is that epilepsy refers to a large group of neurological disorders that generally involve chronic, spontaneous seizures that vary greatly in how they manifest. The causes of epilepsy are also all over the place, from traumatic brain injuries and stroke to viral and bacterial infections to genetics.

A new set of classifications for epilepsy came out in 2017.

It is considered a brain disorder, according to the U.S. Centers for Disease Control (CDC), though some researchers have suggested it could be classified as a neurodegenerative disease like Parkinson’s or Alzheimer’s. In fact, there is research that suggests a genetic link between epilepsy and neurodegenerative diseases.

Not surprisingly, many of the companies developing therapies for neurodegenerative diseases are also working on treatments for epilepsy and vice versa. For example, a new, well-funded joint venture involving Pfizer (PFE) and Bain Capital called Cerevel, which we profiled in our piece on Parkinson’s disease, is also in advanced clinical trials for an epileptic drug. Its GABA A positive modulator drug candidate targets GABA (Gamma-Aminobutyric Acid) neurotransmitters that block impulses between nerve cells in the brain, helping keep the nervous system chill.

Impacts of Epilepsy

More than 50 million people worldwide have epilepsy, making it one of the most common neurological diseases globally, according to the World Health Organization (WHO). The CDC estimates about 3.4 million Americans live with the condition. Globally, an estimated 2.4 million people are diagnosed with epilepsy each year. Interestingly, the disorder seems to target those who can least afford it: WHO said nearly 80% of people with epilepsy live in low- and middle-income countries.

Impacts of epilepsy graphic

A 2015 study of a bunch of other studies that estimated the cost of epilepsy in the United States found that epilepsy-specific costs probably average out to about $10,000 based on the variety of ranges, which means epilepsy costs the United States healthcare system about $34 billion, though the numbers are widely debated. Conversely, WHO says low-cost treatments are available, with daily medication coming as cheaply as $5 per year, so another win for the U.S. healthcare system.

Treatments for Epilepsy

There are more than 20 antiepileptic drugs used to treat epilepsy, usually to help prevent or slow the occurrence of seizures. Other therapies include surgery and electroceutical treatment in which electrical stimulation is applied, usually to the vagus nerve, the longest cranial nerve in the body. While many find relief from one or more of these options, a third of those who suffer from epilepsy are not able to manage their seizures, according to the U.S. National Institutes of Health (NIH). Below we take a look at a range of innovative therapies designed to detect, stop, or find a cure for epilepsy.

Brain Stimulation Therapies

In our article on electroceutical treatments, we highlighted a London company called LivaNova (LIVN) that offers an implantable Vagus Nerve Stimulation (VNS) therapy that has been approved by the U.S. Food and Drug Administration (FDA) to help treat those with partial seizures who do not respond to seizure medications. A medical device company with a lengthy track record of returning value to investors, Medtronic (MDT) got FDA pre-market approval last year for its Deep Brain Stimulation (DBS) therapy for use in reducing partial-onset seizure for those who have proven to not respond to three or more antiepileptic medications. DBS therapy delivers controlled electrical pulses to an area in the brain called the anterior nucleus of the thalamus, which is part of a network involved in seizures. Yet another company offering a variation of brain stimulation therapy is NeuroPace, which markets its responsive neurostimulation device, or RNS system, as “the first and only brain-responsive neurostimulation system designed to prevent epileptic seizures at their source.”

Artificial Intelligence to Detect, Predict, and Control Epilepsy

The NIH is funding further research into implantable devices that can detect, predict, and stop a seizure before it happens, “working closely with industry partners to develop pattern-recognition algorithms,” which sounds an awful lot like artificial intelligence and machine learning will be at the forefront of some future diagnostics and treatment. AI in healthcare has been an ongoing theme around here, with a recent dive into AI and mental health. Back to AI and epilepsy: A group of neurologists at the Medical University of South Carolina developed a new method based on artificial intelligence to predict which patients will see success with surgical procedures designed to stop seizures. Sounds like a great idea to learn beforehand if it’s necessary to crack open your skull.

Click for company websiteA Boston area startup called Empatica, spun out from MIT in 2011, has raised $7.8 million for a smartwatch that detects possible seizures by monitoring subtle electrical changes across the surface of the skin. Other methods normally rely on electrical activity in the brain that tracks and records brain wave patterns called an electroencephalogram. Empatica’s seizure detection algorithm, on the other hand, can detect complex physiological patterns from electrodermal activity that is most likely to accompany a convulsive seizure. Psychology Today reportedthat the device, Embrace Watch, received FDA approval earlier this year for seizure control in children after getting the green light for the technology for adults in 2018.

The Empatica smartwatch can detect electrical currents in the skin to predict the onset of an epileptic seizure.

Click for company websiteAI and drug discovery for better epileptic drug candidates is yet another application that we would expect to see grow in the coming years. Silicon Valley-based startup System1 Biosciences raised $25 million last year, which included Pfizer among its dozen investors. System1 builds a sort of brain model for testing drug candidates using stem cell lines derived from patients with brain disease. The company uses robotic automation to develop these three-dimensional cerebral organoids, allowing it to generate huge datasets in a relatively short amount of time, then applying “advanced data analysis” (also AI?) to detect patterns that might match the characteristics of a neurological disease (what it refers to as deep phenotypes) such as epilepsy with novel treatments.

Cannabis for Controlling Seizures

We’ve written extensively about the suddenly booming hemp CBD market, noting that the FDA approved a CBD-based drug for epilepsy last year in our recent article on the best certified CBD oils on the market. However, we’ve only briefly profiled the company behind Epidiolex for treating rare forms of epilepsy, GW Pharmaceuticals (GWPH). Sporting a market cap just south of $5 billion, GW Pharmaceuticals has taken in about $300 million in post-IPO equity since our article, bringing total post-IPO equity funding to about $568 million. Aside from its successful epileptic drug, GW also developed the world’s first cannabis-based prescription medicine for the treatment of spasticity due to multiple sclerosis that is available in 25 countries outside the United States.

The forms of epilepsy that GW Pharmaceuticals can treat or can potentially treat.

Back on the epilepsy side, Epidiolex has been approved for two rare forms of epilepsy, with clinical trials underway for two more rare neurological disorders associated with seizures – tuberous sclerosis complex and Rett syndrome. Also in the pipeline is a drug dubbed CBDV (GWP42006) that’s also for treating epileptic seizures, though the results of a trial last year were not encouraging. The same compound is also being investigated for autism. Be sure to check out our article on Charlotte’s Web, a CBD company that came about because of epilepsy.

Helping Cells Get Their Vitamin K

Click for company websiteNeuroene Therapeutics is a small startup spun out of the Medical University of South Carolina that recently picked up $1.5 million in funding to tests its lead drug compounds, which are analogous to the naturally occurring form of vitamin K that is essential for brain health. In particular, the lab-developed vitamin K protects the integrity of the cell’s mitochondria, which serves as a sort of power plant for brain cells, helping the neural circuit fire better. Unfortunately, you can’t get the effect from simply eating a bowl of Special K each morning covered in an organic sugar substitute, so the company is developing a method to deliver the effects directly to the brain.

A Nasal Spray to Stop Seizures

Click for company websiteFounded in 2007 near San Diego, Neurelis licenses, develops, and commercializes treatments for epilepsy and other neurological diseases. It has raised $44.8 million in disclosed funding, most coming in a $40.5 million venture round last November. The company’s flagship product is called Valtoco, a formulation that incorporates diazepam, an existing drug used to control seizures and alcohol withdrawal, with a vitamin E-based solution that is delivered using a nasal spray when a sudden seizure episode occurs. The product uses an absorption enhancement technology called Intravail developed by another San Diego area company called Aegis Therapeutics that Neurelis acquired in December last year. Neurelis submitted Valtoco to the FDA for approval in September.

Conclusions

While many people with epileptic conditions can control their seizures with many of the current medications or other therapies available now, there’s a big chunk of the population that is living with uncertainty. Considering the strong link between neurological disorders like epilepsy and certain neurodegenerative disorders, expect to see some good synergies in the next five to 10 years, especially as automation and advanced analytics using AI start connecting the dots between genetics, biochemistry, and brain disorders.

via When Will There Ever be a Cure for Epilepsy? – Nanalyze

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[WEB SITE] A New Research for a better epilepsy treatment

A New Research for a better epilepsy treatment

About 1.2 percent of the population have active epilepsy. Although the majority of the people respond to anti-seizure medications, these medications may not work for every person. They may come with a risk of side effects. About 20 to 40 percent of patients with epilepsy continue to have seizures even after various anti-seizure medications.

Even when the drugs work, individuals may develop memory difficulties and depression. It may be due to the combination of the underlying seizure disorder and the drugs used to treat it.

A research team was led by Ashok K. Shetty. He is a Ph.D. professor at the Texas A&M College of Medicine. He is working on a permanent and better treatment for epilepsy. Their findings were published in the Proceedings of the National Academy of Sciences (PNAS).

“This publication by Dr. Shetty and his team is a step forward in treating incurable diseases of the brain,” said Darwin J. Prockop. He is an MD, Ph.D., the Stearman Chair in Genomic Medicine, director of the Texas A&M Institute for Regenerative Medicine and professor at the Texas A&M College of Medicine.

Working of excitatory and inhibitory neurons

Seizures are caused by the over-excitation of the excitatory neurons in the brain. Due to this overexcitation, they fire too much. And inhibitory neurons aren’t as abundant or aren’t effective at their optimum level.

Inhibitory neurons are required to stop the firing of excitatory neurons. Thus, the chief inhibitory neurotransmitter present in the brain is GABA, short for gamma-Aminobutyric acid.

Over the last decade, researchers have learned to generate induced pluripotent stem cells from normal adult cells, like a skin cell. Therefore, these stem cells can develop into nearly any type of cells in the body, including neurons which use GABA, called GABAergic interneurons.

“For this, transplant human induced pluripotent stem cell-derived GABAergic progenitor cells into the hippocampus in an animal model of early temporal lobe epilepsy,” Shetty said.

The hippocampus is an area in the brain where seizures originate in temporal lobe epilepsy. It is also important for learning, mood, and memory. “Also, this region of brain functioned very well to overwhelm seizures. It even improves mental as well as mood functioning in the chronic epilepsy phase.”

Outcomes of the research

Additional testing exposed that the transplanted human neurons formed synapses with the excitatory neurons of the host. “They were also helpful for GABA and other markers of specific subclasses of inhibitory interneurons,” Shetty said.

“Another captivating aspect of this research is that transplanted human GABAergic neurons were found to be involved directly in controlling seizures. As silencing the transplanted GABAergic neurons caused an increased number of seizures.”

“One central aspect of the effort is that the similar cells can be attained from a patient.” This process, called autologous transplant, is patient specific. It means that there would be no rejection risk of the new neurons. And the person would not need anti-rejection drugs.

“However, we should make sure that we’re doing more good than harm,” Shetty said. “Going onward, we need to be certain that all the transplanted cells have turned into neurons. Because putting undifferentiated pluripotent stem cells could lead to tumors and other problems in the body.”

The epilepsy development often occurs after a head injury. That is why the Department of Defense is involved in funding the development of improved treatment and prevention options.

Treatment of other disorders

“Therefore, good research is essential before patients can be treated safely,” Prockop said. “But this study shows a technique through which patients can someday be treated with their own cells for the shocking epilepsy effects but possibly also other disorders like Parkinsonism and Alzheimer’s disease.”

Hence, Shetty advised that these tests were early interferences after the initial brain injury caused by status epilepticus. This is a state of continuous seizures in humans lasting more than five minutes.

The next phase is to understand if similar transplants would work for chronic epilepsy cases, mainly drug-resistant epilepsy. “Presently, there is no effective treatment for drug-resistant epilepsy. It is associated with memory problems, depression, and a death rate 5 to 10 times that of the general population,” he said.

“Hence, our findings propose that induced pluripotent stem cell-derived GABAergic cell therapy has the potential for providing a lifelong seizure control and releasing co-morbidities associated with epilepsy.”

 

via A New Research for a better epilepsy treatment

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[WEB SITE] Stem cell-derived neurons stop seizures and improve cognitive function

People with untreatable epilepsy may one day have a treatment: ‘Convincing’ their own cells to become the neurons they need

IMAGE

IMAGE: THIS IS ASHOK K. SHETTY. 
CREDIT: TEXAS A&M UNIVERSITY HEALTH SCIENCE CENTER.

About 3.4 million Americans, or 1.2 percent of the population, have active epilepsy. Although the majority respond to medication, between 20 and 40 percent of patients with epilepsy continue to have seizures even after trying multiple anti-seizure drugs. Even when the drugs do work, people may develop cognitive and memory problems and depression, likely from the combination of the underlying seizure disorder and the drugs to treat it.

A team led by Ashok K. Shetty, PhD, a professor in the Department of Molecular and Cellular Medicine at the Texas A&M College of Medicine, associate director of the Institute for Regenerative Medicine and a research career scientist at the Olin E. Teague Veterans’ Medical Center, part of the Central Texas Veterans Health Care System, is working on a better and permanent treatment for epilepsy. Their results published this week in the Proceedings of the National Academy of Sciences (PNAS).

Seizures are caused when the excitatory neurons in the brain fire too much and inhibitory neurons–the ones that tell the excitatory neurons to stop firing–aren’t as abundant or aren’t operating at their optimal level. The main inhibitory neurotransmitter in the brain is called GABA, short for gamma-Aminobutyric acid.

Over the last decade, scientists have learned how to create induced pluripotent stem cells from ordinary adult cells, like a skin cell. These stem cells can then be coaxed to become virtually any type of cells in the body, including neurons that use GABA, called GABAergic interneurons.

“What we did is transplant human induced pluripotent stem cell-derived GABAergic progenitor cells into the hippocampus in an animal model of early temporal lobe epilepsy,” Shetty said. The hippocampus is a region in the brain where seizures originate in temporal lobe epilepsy, which is also important for learning, memory and mood. “It worked very well to suppress seizures and even to improve cognitive and mood function in the chronic phase of epilepsy.”

Further testing showed that these transplanted human neurons formed synapses, or connections, with the host excitatory neurons. “They were also positive for GABA and other markers of specialized subclasses of inhibitory interneurons, which was the goal,” Shetty said. “Another fascinating aspect of this study is that transplanted human GABAergic neurons were found to be directly involved in controlling seizures, as silencing the transplanted GABAergic neurons resulted in an increased number of seizures.”

“This publication by Dr. Shetty and his colleagues is a major step forward in treating otherwise incurable diseases of the brain,” said Darwin J. Prockop, MD, PhD, the Stearman Chair in Genomic Medicine, director of the Texas A&M Institute for Regenerative Medicine and professor at the Texas A&M College of Medicine. “One important aspect of the work is that the same cells can be obtained from a patient.” This type of process, called autologous transplant, is patient specific, meaning that there would be no risk of rejection of the new neurons, and the person wouldn’t need anti-rejection medication.

“We will need to make sure that we’re doing more good than harm,” Shetty said. “Going forward, we need to make sure that all of the cells transplanted have turned into neurons, because putting undifferentiated pluripotent stem cells into the body could lead to tumors and other problems.”

The development of epilepsy often happens after a head injury, which is why the Department of Defense is interested in funding the development of better treatment and prevention options.

“A great deal of research is required before patients can be safely treated,” Prockop said. “But this publication shows a way in which patients can someday be treated with their own cells for the devastating effects of epilepsy but perhaps also other diseases such as Parkinsonism and Alzheimer’s disease.”

Shetty cautioned that these tests were early interventions after the initial brain injury induced by status epilepticus, which is a state of continuous seizures lasting more than five minutes in humans. The next step is to see if similar transplants would work for cases of chronic epilepsy, particularly drug-resistant epilepsy. “Currently, there is no effective treatment for drug-resistant epilepsy accompanying with depression, memory problems, and a death rate five to 10 times that of the general population,” he said. “Our results suggest that induced pluripotent stem cell-derived GABAergic cell therapy has the promise for providing a long-lasting seizure control and relieving co-morbidities associated with epilepsy.”

 

via Stem cell-derived neurons stop seizures and improve cognitive function | EurekAlert! Science News

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[WEB SITE] Antiepileptic Drugs – Medscape

Overview

Modern treatment of seizures started in 1850 with the introduction of bromides, which was based on the theory that epilepsy was caused by an excessive sex drive. In 1910, phenobarbital (PHB), which then was used to induce sleep, was found to have antiseizure activity and became the drug of choice for many years. A number of medications similar to PHB were developed, including primidone.

In 1938, Houston Merrit and Tracy Putnam described animal models for screening multiple compounds for antiepileptic activity in the Journal of the American Medical Association. In 1940, phenytoin (PHT) was found to be an effective drug for the treatment of epilepsy, and since then it has become a major first-line antiepileptic drug (AED) in the treatment of partial and secondarily generalized seizures.

In 1968, carbamazepine (CBZ) was approved, initially for the treatment of trigeminal neuralgia; later, in 1974, it was approved for partial seizures. Ethosuximide has been used since 1958 as a first-choice drug for the treatment of absence seizures without generalized tonic-clonic seizures. Valproate (VPA) was licensed in Europe in 1960 and in the United States in 1978, and now is widely available throughout the world. It became the drug of choice in primary generalized epilepsies and in the mid 1990s was approved for treatment of partial seizures.

These anticonvulsants were the mainstays of seizure treatment until the 1990s, when newer AEDs with good efficacy, fewer toxic effects, better tolerability, and no need for blood level monitoring were developed. A study of live-born infants in Denmark found that exposure to the newer-generation AEDs lamotrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam in the first trimester was not associated with an increased risk in major birth defects. [1]

The new AEDs have been approved in the United States as add-on therapy only, with the exception of topiramate and oxcarbazepine (OXC); lamotrigine (LTG) is approved for conversion to monotherapy. A meta-analysis of 70 randomized clinical trials confirms the clinical impression that efficacy does not significantly differ among AEDs used for refractory partial epilepsy. [2]

Antiepileptic drugs should be used carefully, with consideration of medication interactions and potential side effects. This is particularly important for special populations, such as patients with HIV/AIDS. [3]

For more information, see Epilepsy and Seizures.

Mechanism of Action

It is important to understand the mechanisms of action and the pharmacokinetics of antiepileptic drugs (AEDs) so that these agents can be used effectively in clinical practice, especially in multidrug regimens (see the image below).

Pearls of antiepileptic drug use and management.
Pearls of antiepileptic drug use and management.

Many structures and processes are involved in the development of a seizure, including neurons, ion channels, receptors, glia, and inhibitory and excitatory synapses. The AEDs are designed to modify these processes so as to favor inhibition over excitation and thereby stop or prevent seizure activity (see the image below).

Dynamic target of seizure control in management of epilepsy is achieving balance between factors that influence excitatory postsynaptic potential (EPSP) and those that influence inhibitory postsynaptic potential (IPSP).

The AEDs can be grouped according to their main mechanism of action, although many of them have several actions and others have unknown mechanisms of action. The main groups include sodium channel blockers, calcium current inhibitors, gamma-aminobutyric acid (GABA) enhancers, glutamate blockers, carbonic anhydrase inhibitors, hormones, and drugs with unknown mechanisms of action (see the image below).

Antiepileptic drugs can be grouped according to th
Antiepileptic drugs can be grouped according to their major mechanism of action. Some antiepileptic drugs work by acting on combination of channels or through some unknown mechanism of action.

[…]

For more Visit site —>  Antiepileptic Drugs: Overview, Mechanism of Action, Sodium Channel Blockers

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[WEB SITE] Small device detects initial signal of epileptic attack and provides effective relief.

Published on August 23, 2016 

The results, from the Laboratory for Organic Electronics at LiU’s Campus Norrköping, have been published in the prestigious journal Proceedings of the National Academy of Sciences (PNAS), with Asst. Prof. Daniel Simon as main author.

According to a recently produced estimate, no less than six percent of the Earth’s population suffers from some type of neurological illness such as epilepsy or Parkinson’s. Some medicines are available, but when these are taken orally or injected into the bloodstream, they also end up where they aren’t needed and may cause serious problems. All medicines have more or less severe side effects, and no fully satisfactory treatment for neurological illnesses is available.

Neurons, or nerve cells, are the cells in the body that both transmit and receive nerve impulses. The small 20×20 µm device developed by the scientists can both capture signals and stop them in the exact area of nerve cells where they arise. No other part of the body needs to be involved.

“Our technology makes it possible to interact with both healthy and sick neurons. We can now start investigating opportunities for finding therapies for neurological illnesses that arise so rapidly and so locally that the patient doesn’t notice them,” says Daniel Simon.

The experiments were conducted in the laboratory on slices of brains from mice. The device consists of a sensor that detects nerve signals, and a small ion pump that doses an exact amount of the neurotransmitter GABA, a substance the body itself uses to inhibit stimuli in the central nervous system.

“The same electrode that registers the activity in the cell can also deliver the transmitter. We call it a bioelectronic ‘neural pixel’, since it imitates the functions of biological neurons,” says Daniel Simon.

“Signalling in biological systems is based on chemical signals in the form of cations, which are passed between transmitters and receptors, which consist of proteins. When a signal is transferred to another cell, the identification of the signal and the triggering of a new one occur within a very small distance – only a few nanometers. In certain cases, it happens at the same point. That’s why being able to combine electronic detection and release in the same electrode is a major advance,” says Professor Magnus Berggren.

The small ion pump, which was developed at the Laboratory for Organic Electronics, attracted a great deal of attention when it´s first application as a therapeutic device was published a year ago. The sensor that captures the nerve signal has subsequently been developed by the LiU researchers’ collaborators at the école Nationale Supérieure des Mines in Gardanne, France. The mouse experiments were performed at Aix-Marseille University. The entire device is manufactured from conductive, biocompatible plastic.

Source: Small device detects initial signal of epileptic attack and provides effective relief

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[WEB SITE] Ketamine – More Than a Recreational Drug.

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Ketamine was first introduced in 1962. It was initially presented as a fast acting general anesthetic, being widely used as a battlefield anesthetic in the 1970s. Ketamine is considered a dissociative anesthetic – it creates an altered state of consciousness, distorting the perception of sound and vision, and producing a feeling of detachment from oneself and from the environment which provides pain relief, sedation, and amnesia.

In the clinic, ketamine is mainly used for starting and maintaining anesthesia. Given its fast sedative action, it is frequently used in emergency situations. Its main effects usually begin within five minutes of injection and last up to 25 minutes.

But ketamine can have some impactful psychological side-effects as the medication wears off, such as agitation, confusion, or hallucinations. The latter is the main reason for its use as a drug of abuse or recreational drug. Ketamine began to be illicitly consumed in the 1970s and, nowadays, it is equally known for its medical and recreational use. Ketamine can produce illusions or hallucinations that are enhanced by environmental stimuli, which explains its popularity as a club drug.

Ketamine is still used in medical contexts as an anesthetic, although its use has become less common and more restricted. However, in recent years, a new use for ketamine has been emerging.

Ketamine as an antidepressant drug

Recent studies have shown that ketamine has fast antidepressant actions in patients with major depressive disorder, even in those with the most treatment-resistant forms of depression. Major depressive disorder is a highly disabling condition with limited treatment options that are often ineffective. The onset of depression is poorly understood but it is thought to derive from a combination of neurochemical factors and triggering life events, such as overwhelming stress. Potential neurochemical factors include defects in the major neurotransmitters of the central nervous system, glutamate and GABA.

Glutamate is the major excitatory neurotransmitter in the central nervous system. Experimental studies in animal models of depression have associated glutamate with depression, showing that there may be altered levels of glutamate receptors; increased glutamate concentrations have also been found in the brains of patients with major depressive disorder. Since ketamine acts by blocking the action of the NMDA glutamate receptors, this is a likely mechanism for its fast action in depression.

Indeed, a single dose of ketamine has been shown to be able to normalize the activity of glutamate receptors. Importantly, the effects of ketamine occurred only at low doses, indicating that these antidepressant effects can occur without the psychological side effects associated with high doses of ketamine.

GABA, on the other hand, is the major inhibitory neurotransmitter in the central nervous system. It has also been associated with depression – mice with an impairment of GABAergic transmission exhibit behavioral signs that mimic the emotional patterns of depression, which supports the view of a causal link between GABAergic neurotransmission and depression. Major depressive disorder has been linked to reduced levels of GABA and GABA receptors, and to reduced expression of glutamic acid decarboxylase, an enzyme that converts glutamate to GABA.

These two effects may seem contradictory, but these deficits in the GABAergic system may actually lead to increased glutamate concentrations. However, some studies have also reported reduced rather than increased brain levels of glutamate. This has led to the hypothesis that depression may actually be associated with a dynamic balance between changes in GABAergic and glutamatergic transmission. The mechanisms underlying this possible relationship were mostly unknown, but a new study published on the journalBiological Psychiatry sheds light on this subject.

A matter of balance

A stable and regular functioning of neural networks relies on an ability to maintain a balance between inhibitory and excitatory neurotransmission. In the mentioned study, and with the goal of understanding how the balance between GABA and glutamate levels may be linked to depression, the consequences of GABAergic deficits on glutamatergic synapses were investigated. It was found that mice with depression associated with GABAergic deficits also showed reduced expression and function of glutamate receptors.

A decrease in the number and activity of glutamatergic synapses was also found. Treatment with a sub-anesthetic dose of ketamine led to a lasting normalization of glutamate receptor levels and glutamatergic synapse function. These results indicate that depression in mice with impaired GABAergic neurotransmission involves a balancing reduction of glutamatergic transmission that can be normalized for a prolonged period of time by the rapidly acting antidepressant ketamine.

This study thereby establishes the link between the GABAergic and glutamatergic deficits described for depression, and suggests that it may be caused by a dysregulation of the equilibrium mechanisms that act to restore the balance of excitation and inhibition. It is possible that conditions of chronic or repeated stress, which may trigger the development of depression, may do so by affecting the balance between GABA and glutamate levels, or by impairing the mechanisms that could restore that balance. Indeed, chronic stress has been shown to decrease the production of glutamate receptors and to render GABAergic inhibition ineffective.

This work also reinforced the antidepressant efficacy of ketamine. However, ketamine will always have a huge drawback due to its drug-of-abuse properties. The use of other NMDA glutamate receptor antagonists without the side-effects of ketamine has been tested with promising results, leading to similar effects as those obtained with ketamine. Here may lay the answer.

References

Garcia, L., Comim, C., Valvassori, S., Réus, G., Stertz, L., Kapczinski, F., Gavioli, E., & Quevedo, J. (2009). Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33 (3), 450-455 DOI:10.1016/j.pnpbp.2009.01.004

Hashimoto, K., Sawa, A., & Iyo, M. (2007). Increased Levels of Glutamate in Brains from Patients with Mood Disorders Biological Psychiatry, 62 (11), 1310-1316 DOI: 10.1016/j.biopsych.2007.03.017

Ionescu, D., Luckenbaugh, D., Niciu, M., Richards, E., Slonena, E., Vande Voort, J., Brutsche, N., & Zarate, C. (2014). Effect of Baseline Anxious Depression on Initial and Sustained Antidepressant Response to Ketamine The Journal of Clinical Psychiatry, 75 (09) DOI: 10.4088/JCP.14m09049

Jansen, K. (2011). A Review of the Nonmedical Use of Ketamine: Use, Users and Consequences Journal of Psychoactive Drugs, 32 (4), 419-433 DOI:10.1080/02791072.2000.10400244

Li, N., Lee, B., Liu, R., Banasr, M., Dwyer, J., Iwata, M., Li, X., Aghajanian, G., & Duman, R. (2010). mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science, 329 (5994), 959-964 DOI:10.1126/science.1190287

Luscher, B., Shen, Q., & Sahir, N. (2010). The GABAergic deficit hypothesis of major depressive disorder Molecular Psychiatry, 16 (4), 383-406 DOI:10.1038/mp.2010.120

Morgan, C., Curran, H., & , . (2012). Ketamine use: a review Addiction, 107 (1), 27-38 DOI: 10.1111/j.1360-0443.2011.03576.x

Niciu, M., Ionescu, D., Richards, E., & Zarate, C. (2013). Glutamate and its receptors in the pathophysiology and treatment of major depressive disorderJournal of Neural Transmission, 121 (8), 907-924 DOI: 10.1007/s00702-013-1130-x

Ren, Z., Pribiag, H., Jefferson, S., Shorey, M., Fuchs, T., Stellwagen, D., & Luscher, B. (2016). Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine TreatmentBiological Psychiatry DOI: 10.1016/j.biopsych.2016.02.009

Image via Unsplash / Pixabay.

Source: Ketamine – More Than a Recreational Drug | Brain Blogger

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[WEB SITE] The New Compounds That Could Treat Depression in 24-Hours

Post image for The New Compounds That Could Treat Depression in 24-HoursCurrent antidepressants take around 3 to 8 weeks to kick in and only help around 50% of people who are depressed.

A new type of antidepressant holds the promise of treating depression quickly, without too many side-effects. Professor Scott Thompson, of the University of Maryland School of Medicine who led the research, said:

“Our results open up a whole new class of potential antidepressant medications.

We have evidence that these compounds can relieve the devastating symptoms of depression in less than one day, and can do so in a way that limits some of the key disadvantages of current approaches.”

Currently used antidepressants, such as Prozac and Lexapro, target levels of the neurotransmitter serotonin.

Unfortunately they are only effective in around half of people with depression. Even amongst people they do help, it can take three to eight weeks for the effects can be felt. For patients who are suicidal, this period can be excruciating.

Also, many now believe that targeting serotonin is not effective (see: Long-Held Belief About Depression Challenged by New Study).

The new compounds focus on another neurotransmitter with the acronym GABA (gamma-aminobutyric acid), instead of serotonin. GABA mainly reduces brain activity in certain key areas related to mood.

The new class of compounds dampen down these inhibitory signals. Theoretically, the result should be to lift mood.

Professor Thompson explained that preliminary tests on animals have been encouraging:

“These compounds produced the most dramatic effects in animal studies that we could have hoped for.

It will now be tremendously exciting to find out whether they produce similar effects in depressed patients.

If these compounds can quickly provide relief of the symptoms of human depression, such as suicidal thinking, it could revolutionize the way patients are treated.”

The study found that the compounds only affected the brains of stressed rats and left unstressed rats unchanged. This may mean that the side-effects of the treatment will be less severe than those seen for current antidepressants.

The study was published in the journal Neuropsychopharmacology (Fischell et al., 2015).

via The New Compounds That Could Treat Depression in 24-Hours.

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