Acetylcholine Chloride

A team of researchers has uncovered new clues about how chemicals released by brain cells regulate our attention span. A team of researchers from Nanyang Technological University, Singapore (NTU Singapore) has uncovered new clues about how chemicals released by brain cells regulate our attention span. Findings from the study could pave the way for new therapies to treat neurological conditions associated with concentration difficulties, such as depression and attention-deficit hyperactivity disorder (ADHD). To communicate with one another, neurons in the brain and nervous system release chemicals called neurotransmitters that relay messages from one cell to another. Neurotransmitters are crucial for brain function and regulating all bodily functions, ranging from breathing and heart rate to reproduction. These chemicals also coordinate cognitive processes that enable us to focus on important information within the constant barrage of stimuli the brain receives from the external environment, otherwise known as our attention span. Researchers have long thought that our attention span was directed by only one neurotransmitter, acetylcholine, which excites neurons and causes them to fire electrical signals. However, recent work suggests that attention could require another neurotransmitter, gamma-aminobutyric acid (GABA), which inhibits neurons from receiving and sending messages. In their study published in the Proceedings of the National Academy of Sciences (PNAS), the team demonstrated for the first time that GABA works together with acetylcholine in a precise sequence to regulate the transmission of signals from a part of the brain's information processing network, called the claustrum. Hidden deep in the brain, the claustrum is a thin sheet-like structure that receives and processes information from different parts of it. The claustrum helps to regulate concentration, but its exact role remains unknown. Neurotransmitters toggle 'like a switch' to relay information In lab experiments, the NTU scientists investigated how neurons in the claustrum in mice respond to acetylcholine and GABA produced by a part of the brain called the forebrain, that plays a central role in several brain functions. The key technological advance that allowed the researchers to make this discovery is called optogenetics. Optogenetics uses light-sensitive proteins to selectively control the activity of specific types of neurons within the brain. In this case, the neurons within the forebrain that release acetylcholine and GABA were activated by light, allowing the team to measure the response of the claustrum to such a stimulus. They discovered that two types of neurons in the claustrum, which send output signals to different parts of the brain, respond in opposing ways to acetylcholine and GABA. Neurons that extend to structures deep in the brain were excited by acetylcholine while neurons that extend to structures on the surface of the brain were inhibited by GABA. Through this coordinated sequence of opposing actions, the two neurotransmitters toggle the transfer of information between the claustrum and the rest of the brain, like a switch. The study provides evidence that the neurotransmitters regulate a "microcircuit" in the brain, that allows the organ to differentiate important information from noise, helping a person pay attention. The opposing actions of the neurotransmitters (acetylcholine and GABA) on neurons in the claustrum enable brain signals to be encoded efficiently, allowing the brain to pay attention and ignore noise. First author Mr Aditya Nair, former researcher at LKCMedicine and a current Ph.D. student at Caltech, said, "Our study advances our understanding of the claustrum's role in directing attention span. Understanding how the claustrum regulates attention span at the cellular level also provides a window into other areas regulated by similar signalling pathways, such as arousal and learning." Lead investigator and neuroscientist Professor George Augustine from NTU's Lee Kong Chian School of Medicine (LKCMedicine) said, "By understanding how acetylcholine and GABA work together to direct our attention, new and more effective therapies may be developed in the future to improve the attention span of patients with conditions such as ADHD and depression." Commenting as an independent expert, Dr Geoffrey Tan, Consultant (Psychiatry) Clinician-Scientist at the Institute of Mental Health Singapore, said, "Directing attention and multi-tasking are crucial cognitive processes for everyday functioning that require toggling between networks or circuits in the brain. This study identifies a 'switch' in the claustrum that provides a mechanism by which acetylcholine may drive computations such as these. It is timely as we increasingly incorporate brain networks into how we think about cognition, psychiatric conditions and even interventions like mindfulness." The next steps for this project will be to determine how altering the dual-transmitter switch alters attention and brain disorders that affect attention, such as ADHD. It will also be important to determine whether the switch mechanism applies to other brain processes, such as arousal and learning.

Pictured: FDA Headquarters, iStock, Grandbrothers iStock, Grandbrothers The FDA has four decisions on deck this week, including ones for two rare disease treatments from Ipsen and Regeneron. Pictured: FDA Headquarters/iStock, Grandbrothers This week, the FDA is due to decide on four therapeutic applications, including one for Huntington’s disease and two for ultra-rare diseases. Is the Third Time the Charm for Ipsen’s Palovarotene? After stumbling in the past, Ipsen Biopharmaceuticals is once again awaiting an FDA verdict for palovarotene, which it is proposing for the treatment of the ultra-rare disease fibrodysplasia ossificans progressiva (FOP). The regulator’s deadline is Aug. 16 . FOP is a genetic disorder that arises when muscle and connective tissues are gradually replaced by bone. This extra-skeletal formation of bone hinders patients’ movements and, when the joints become afflicted, may ultimately lead to the loss of mobility. FOP patients also suffer from difficulties in speaking and eating, along with breathing problems. Palovarotene is an oral agonist of the retinoic acid receptor gamma, which plays a crucial role in the regulation of skeletal development. By mediating the interactions between the receptor and its ligands, as well as other growth factors and proteins involved in the retinoid signaling pathway, palovarotene can decrease the formation of abnormal bone. Ipsen has put its candidate in front of the FDA twice before. The first time was in 2021, but the company voluntarily withdrew its application in August of the same year after the regulator indicated the need for more data during a meeting. Ipsen filed a resubmission in 2022, which the FDA rejected in December. In its third filing, Ipsen provided data from a Phase II study with several open-label extension phases and a single-arm, open-label Phase III trial. Palovarotene failed this late-stage study, though the company maintains this was due to statistical discrepancies, as well as the biases that come with using historical controls. An advisory committee in June 2023 took Ipsen’s side and voted 11–3 that palovarotene’s benefits outweighed its risks. Revance Seeks Label Expansion for Daxxify in Cervical Dystonia On Aug. 19 , the FDA is set to decide on Revance Therapeutics ’ supplemental BLA proposing Daxxify (daxibotulinumtoxinA-lanm) for the treatment of cervical dystonia in adults. Daxxify , a neuromuscular blocking agent and acetylcholine release inhibitor, was approved in September 2022 for the temporary improvement of moderate to severe frown lines in adults. Commonly positioned as an alternative to Allergan’s (AbbVie) Botox, Daxxify is a peptide-formulated injection that has durable treatment effects. In its sBLA, which the FDA accepted in January , Revance included data from the Phase III ASPEN clinical development program, which includes the ASPEN-1 and ASPEN-OLS trials. In ASPEN-1, a pivotal late-stage study, both 125U and 250U doses of Daxxify were effective and generally well-tolerated in cervical dystonia patients and even reduced the frequency of treatments by up to 50% annually. Meanwhile, ASPEN-OLS validated the long-term safety and efficacy of Daxxify in this indication for up to four consecutive treatments. In February, Revance presented new data for Daxxify at the 2023 Association of Academic Physiatrists annual meeting, further supporting the therapeutic value of the injection. Across 88 weeks of follow-up, corresponding to up to five injection cycles and a total of 1,240 treatments, Daxxify remained safe and effective in cervical dystonia patients. Neurocrine Proposes Ingrezza for Chorea in Huntington’s Neurocrine Biosciences is proposing to expand Ingrezza’s (valbenazine) label to include chorea in Huntington’s disease. The FDA accepted the company’s supplemental NDA in December 2022 and set a target action date of August 20. Approved in 2017 to treat tardive dyskinesia, Ingrezza is a selective vesicular monoamine transporter 2 inhibitor. In its sNDA, Neurocrine included data from the Phase III KINECT-HD trial and the ongoing KINECT-HD2 open-label study to establish the safety and efficacy of Ingrezza in this proposed indication. In April 2022, the company presented results from KINECT-HD at the American Academy of Neurology 2022 annual meeting and followed this up with a Lancet Neurology publication in May. Data from the late-stage trial showed that Ingrezza treatment significantly reduced scores in the Unified Huntington’s Disease Rating Scale Total Maximal Chorea score by 3.2 units versus placebo, an effect that was statistically significant. Ingrezza likewise outperformed placebo on secondary endpoints, including the Clinical Global Impression of Change and Patient Global Impression of Change response status. Huntington’s disease is a hereditary, progressive neurodegenerative disease characterized by the gradual destruction of neurons, leading to motor and cognitive problems, as well as psychiatric symptoms. A common symptom of the condition is chorea, which refers to abnormal, unpredictable and involuntary movements affecting various parts of the body. Chorea can interfere with movement and posture, as speech and swallowing. Regeneron Awaits Verdict for Pozelimab in CHAPLE Disease The FDA’s last scheduled decision date this week is for Regeneron ’s investigational antibody pozelimab, which the company is developing to treat the ultra-rare CHAPLE disease. The regulator is scheduled to release its verdict by Aug. 20 . CHAPLE disease, also known as CD55 deficiency with hyperactivation of complement, angiopathic thrombosis and protein losing enteropathy, is a life-threatening immune system disorder characterized by the over-activation of the complement system. In turn, the hyperactive immune system also targets healthy cells, ultimately damaging blood and lymph vessels, as well as the digestive tract. Most patients with CHAPLE disease suffer from a wide variety of life-threatening symptoms, such as bloody diarrhea, malnutrition and recurrent infections. There are no known cures for CHAPLE. Pozelimab, a fully human monoclonal antibody, works by binding to the C5 complement factor, thereby disrupting the complement cascade and preventing associated diseases. Regeneron backed pozelimab’s regulatory bid with data from a Phase II/III open-label study, which showed that at 24 weeks, all 10 treated patients achieved “rapid and sustained normalization” of albumin, a key marker of CHAPLE disease activity. Pozelimab treatment also eased clinical manifestations, including abdominal pain and number of daily bowel movements. The FDA accepted pozelimab’s application in February and granted it Priority Review. If approved, Regeneron’s antibody would become the first treatment authorized for use in CHAPLE disease. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com . hbspt.forms.create({ region: "na1", portalId: "4413123", formId: "a126e976-bca0-4c13-aa9b-02e8feb92096" });