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New research addresses a gap in understanding how ketamine's impact on individual neurons leads to pervasive and profound changes in brain network function. A World Health Organization Essential Medicine, ketamine is widely used at varying doses for sedation, pain control, general anesthesia and as a therapy for treatment-resistant depression. While scientists know its target in brain cells and have observed how it affects brain-wide activity, they haven't known entirely how the two are connected. A new study by a research team spanning four Boston-area institutions uses computational modeling of previously unappreciated physiological details to fill that gap and offer new insights into how ketamine works. "This modeling work has helped decipher likely mechanisms through which ketamine produces altered arousal states as well as its therapeutic benefits for treating depression," co-senior author Emery N. Brown, Edward Hood Taplin Professor of Computational Neuroscience and Medical Engineering at The Picower Institute for Learning and Memory at MIT, as well as an anesthesiologist at MGH and a Professor at Harvard Medical School. The researchers from MIT, Boston University, Massachusetts General Hospital and Harvard University said the predictions of their model, published May 20 in Proceedings of the National Academy of Sciences, could help physicians make better use of the drug. "When physicians understand what's mechanistically happening when they administer a drug, they can possibly leverage that mechanism and manipulate it," said study lead author Elie Adam, a Research Scientist at MIT who will soon join the Harvard Medical School faculty and launch a lab at MGH. "They gain a sense of how to enhance the good effects of the drug and how to mitigate the bad ones." Blocking the door The core advance of the study involved biophysically modeling what happens when ketamine blocks the "NMDA" receptors in the brain's cortex -- the outer layer where key functions such as sensory processing and cognition take place. Blocking the NMDA receptors modulates the release of excitatory neurotransmitter glutamate. When the neuronal channels (or doorways) regulated by the NMDA receptors open, they typically close slowly (like a doorway with a hydraulic closer that keeps it from slamming), allowing ions to go in and out of neurons, thereby regulating their electrical properties, Adam said. But, the channels of the receptor can be blocked by a molecule. Blocking by magnesium helps to naturally regulate ion flow. Ketamine, however, is an especially effective blocker. Blocking slows the voltage build-up across the neuron's membrane that eventually leads a neuron to "spike," or send an electrochemical message to other neurons. The NMDA doorway becomes unblocked when the voltage gets high. This interdependence between voltage, spiking and blocking can equip NMDA receptors with faster activity than its slow closing speed might suggest. The team's model goes further than ones before by representing how ketamine's blocking and unblocking affect neural activity. "Physiological details that are usually ignored can sometimes be central to understanding cognitive phenomena," said co-corresponding author Nancy Kopell, a professor of math at BU. "The dynamics of NMDA receptors have more impact on network dynamics than has previously been appreciated." With their model, the scientists simulated how different doses of ketamine affecting NMDA receptors would alter the activity of a model brain network. The simulated network included key neuron types found in the cortex: one excitatory type and two inhibitory types. It distinguishes between "tonic" interneurons that tamp down network activity and "phasic" interneurons that react more to excitatory neurons. The team's simulations successfully recapitulated the real brain waves that have been measured via EEG electrodes on the scalp of a human volunteer who received various ketamine doses and the neural spiking that has been measured in similarly treated animals that had implanted electrode arrays. At low doses, ketamine increased brain wave power in the fast gamma frequency range (30-40 Hz). At the higher doses that cause unconsciousness, those gamma waves became periodically interrupted by "down" states where only very slow frequency delta waves occur. This repeated disruption of the higher frequency waves is what can disrupt communication across the cortex enough to disrupt consciousness. But how? Key findings Importantly, through simulations, they explained several key mechanisms in the network that would produce exactly these dynamics. The first prediction is that ketamine can disinhibit network activity by shutting down certain inhibitory interneurons. The modeling shows that natural blocking and unblocking kinetics of NMDA-receptors can let in a small current when neurons are not spiking. Many neurons in the network that are at the right level of excitation would rely on this current to spontaneously spike. But when ketamine impairs the kinetics of the NMDA receptors, it quenches that current, leaving these neurons suppressed. In the model, while ketamine equally impairs all neurons, it is the tonic inhibitory neurons that get shut down because they happen to be at that level of excitation. This releases other neurons, excitatory or inhibitory from their inhibition allowing them to spike vigorously and leading to ketamine's excited brain state. The network's increased excitation can then enable quick unblocking (and reblocking) of the neurons' NMDA receptors, causing bursts of spiking. Another prediction is that these bursts become synchronized into the gamma frequency waves seen with ketamine. How? The team found that the phasic inhibitory interneurons become stimulated by lots of input of the neurotransmitter glutamate from the excitatory neurons and vigorously spike, or fire. When they do, they send an inhibitory signal of the neurotransmitter GABA to the excitatory neurons that squelches the excitatory firing, almost like a kindergarten teacher calming down a whole classroom of excited children. That stop signal, which reaches all the excitatory neurons simultaneously, only lasts so long, ends up synchronizing their activity, producing a coordinated gamma brain wave. "The finding that an individual synaptic receptor (NMDA) can produce gamma oscillations and that these gamma oscillations can influence network-level gamma was unexpected," said co-corresponding author Michelle McCarthy, a research assistant professor of math at BU. "This was found only by using a detailed physiological model of the NMDA receptor. This level of physiological detail revealed a gamma time scale not usually associated with an NMDA receptor." So what about the periodic down states that emerge at higher, unconsciousness-inducing ketamine doses? In the simulation, the gamma-frequency activity of the excitatory neurons can't be sustained for too long by the impaired NMDA-receptor kinetics. The excitatory neurons essentially become exhausted under GABA inhibition from the phasic interneurons. That produces the down state. But then, after they have stopped sending glutamate to the phasic interneurons, those cells stop producing their inhibitory GABA signals. That enables the excitatory neurons to recover, starting a cycle anew. Antidepressant connection? The model makes another prediction that might help explain how ketamine exerts its antidepressant effects. It suggests that the increased gamma activity of ketamine could entrain gamma activity among neurons expressing a peptide called VIP. This peptide has been found to have health promoting effects, such as reducing inflammation, that last much longer than ketamine's effects on NMDA receptors. The research team proposes that the entrainment of these neurons under ketamine could increase the release of the beneficial peptide, as observed when these cells are stimulated in experiments. This also hints at therapeutic features of ketamine that may go beyond anti-depressant effects. The research team acknowledges, however, that this connection is speculative and awaits specific experimental validation. "The understanding that the sub cellular details of the NMDA receptor can lead to increased gamma oscillations was the basis for a new theory about how ketamine may work for treating depression," Kopell said. Additional co-authors of the study are Marek Kowalski, Oluwaseun Akeju, and Earl K. Miller. The JPB Foundation, The Picower Institute for Learning and Memory, The Simons Center for The Social Brain, the National Institutes of Health, George J. Elbaum (MIT '59, SM '63, PhD '67), Mimi Jensen, Diane B. Greene (MIT, SM '78), Mendel Rosenblum, Bill Swanson, and annual donors to the Anesthesia Initiative Fund supported the research.

This new formulation may have important clinical uses for a variety of rare lung diseases GENEVA, SWITZERLAND / ACCESSWIRE / August 3, 2022 / RELIEF THERAPEUTICS Holding SA (SIX:RLF)(OTCQB:RLFTF)(OTCQB:RLFTY) ("Relief"), a biopharmaceutical company seeking to provide patients therapeutic benefit from serious diseases with high unmet need, announced today promising three-month stability data on a new formulation of RLF-100® (aviptadil). Based on the results thus far, Relief is evaluating the opportunity to additional patent protection. "Aviptadil, when dissolved in saline, is known to have uncertain stability properties, resulting in significant challenges for pharmaceutical supply and use. The development of this novel RLF-100® formulation, therefore, has significant clinical and commercial value. In particular, Relief's new formulation appears to be shelf-stable at temperatures suitable for shipping and long-term storage" stated Raghuram (Ram) Selvaraju, Ph.D., Chairman of the Board of Directors of Relief. "This new, stable formulation potentially allows RLF-100® to be delivered via multiple routes of administration for treatment of multiple lung disease indications including pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), berylliosis and checkpoint inhibitor-induced pneumonitis (CIP), all of which Relief seeks to pursue. As previously reported, we intend to initiate a phase 2b dose ranging study in 72 patients with pulmonary sarcoidosis using inhaled RLF-100® administered over a 12-week period, following which patients will have the option to participate in the extension phase. A pre-IND meeting with the U.S. Food and Drug Administration (FDA) is planned to confirm the efficacy and safety endpoints as well as the proposed dosing regimen and, based on a positive outcome, the trial is expected to begin during 2023." ABOUT RLF-100® RLF-100® (aviptadil) is a synthetic form of Vasoactive Intestinal Peptide ("VIP") consisting of 28 amino acids, which was first discovered in 1970. Although initially identified in the intestinal tract, human VIP is known to be produced throughout the body and to be primarily concentrated in the lungs where it has shown a multimodal mechanism of action: specifically, a decrease of inflammatory cytokines release leading to prevention of cytokine storm syndrome and viral replication, an immunomodulating effect, vasodilating and broncho-dilating effects, and prevention of surfactant depletion. Seventy percent of VIP in the body is bound to a less common type of cell in the lung, the alveolar type 2 cell, which is critical to the transmission of oxygen to the body. RLF-100 has a 20-year history of safe use in humans in multiple human trials for sarcoidosis, idiopathic pulmonary fibrosis, asthma, pulmonary arterial hypertension, and sepsis-induced acute respiratory distress syndrome. A combination of aviptadil with phentolamine is approved for the treatment of erectile dysfunction by intra-cavernous injections in countries outside the U.S. RLF-100® is under development for certain acute and chronic lung diseases, including pulmonary sarcoidosis, for which it was granted an Orphan Drug Designation ("ODD") by the FDA. RLF-100® is also being explored for treatment of checkpoint inhibitor-induced pneumonitis ("CIP"), an indication in which Relief's wholly-owned subsidiary, AdVita LifeScience GmbH, received Swiss method-of-use patent protection related to the inhaled formulation of RLF-100® into at least 2039. RLF-100® will also be evaluated in treating non-COVID-19-related ARDS with a particular focus on infectious ARDS. There are also plans to conduct European proof-of-concept clinical development of RLF-100® in the treatment of chronic berylliosis, an orphan lung disease for which there are no treatments approved and which is characterized by severe inflammation of the lungs, coughing and increasing breathlessness (dyspnea). ABOUT RELIEF Relief focuses primarily on clinical-stage programs based on molecules with a history of clinical testing and use in human patients or a strong scientific rationale. Relief has a Collaboration and License Agreement with Acer Therapeutics for the worldwide development and commercialization of ACER-001 (sodium phenylbutyrate) for the treatment of various inborn errors of metabolism, including UCDs and Maple Syrup Urine Disease (MSUD). Relief also continues to study aviptadil for several possible lung related conditions. Finally, Relief's 2021 acquisitions of APR Applied Pharma Research SA and AdVita Lifescience GmbH brought to Relief a diverse pipeline of marketed and development-stage programs. RELIEF THERAPEUTICS Holding SA is listed on the SIX Swiss Exchange under the symbol RLF and quoted in the U.S. on OTCQB under the symbols RLFTF and RLFTY. For more information, visit . Follow Relief on LinkedIn. CONTACT: RELIEF THERAPEUTICS Holding SA Jack Weinstein Chief Financial Officer and Treasurer contact@relieftherapeutics.com FOR MEDIA/INVESTOR INQUIRIES: Rx Communications Group Michael Miller +1-917-633-6086 mmiller@rxir.com Disclaimer: This communication expressly or implicitly contains certain forward-looking statements concerning RELIEF THERAPEUTICS Holding SA. Such statements involve certain known and unknown risks, uncertainties and other factors, including (i) whether aviptadil will ever be approved in the U.S., the U.K., or the E.U. for any disease, and (ii) those risks discussed in RELIEF THERAPEUTICS Holding SA's press releases and filings with the SIX and with the U.S. Securities and Exchange Commission, which could cause the actual results, financial condition, performance or achievements of RELIEF THERAPEUTICS Holding SA to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. RELIEF THERAPEUTICS Holding SA is providing this communication as of this date and does not undertake to update any forward-looking statements contained herein as a result of new information, future events or otherwise. SOURCE: Relief Therapeutics Holdings AG View source version on accesswire.com: