PACAP38

Researchers have found set of neurons that mediate panic-like symptoms in mice, which showcase a novel brain pathway that could be a target for new panic disorder therapeutics. Overwhelming fear, sweaty palms, shortness of breath, rapid heart rate -- these are the symptoms of a panic attack, which people with panic disorder have frequently and unexpectedly. Creating a map of the regions, neurons, and connections in the brain that mediate these panic attacks can provide guidance for developing more effective panic disorder therapeutics. Now, Salk researchers have begun to construct that map by discovering a brain circuit that mediates panic disorder. This circuit consists of specialized neurons that send and receive a neuropeptide -- a small protein that sends messages throughout the brain -- called PACAP. What's more, they determined that PACAP and the neurons that produce its receptor are possible druggable targets for new panic disorder treatments. The findings were published in Nature Neuroscience on January 4, 2024. "We've been exploring different areas of the brain to understand where panic attacks start," says senior author Sung Han, associate professor at Salk. "Previously, we thought the amygdala, known as the brain's fear center, was mainly responsible -- but even people who have damage to their amygdala can still experience panic attacks, so we knew we needed to look elsewhere. Now, we've found a specific brain circuit outside of the amygdala that is linked to panic attacks and could inspire new panic disorder treatments that differ from current available panic disorder medications that typically target the brain's serotonin system." To begin sketching out a panic disorder brain map, the researchers looked at a part of the brain called the lateral parabrachial nucleus (PBL) in the pons (part of the brain stem), which is known as the brain's alarm center. Interestingly, this small brainstem area also controls breathing, heart rate, and body temperature. It became evident that the PBL was likely implicated in generating panic and bringing about emotional and physical changes. Furthermore, they found that this brain area produces a neuropeptide, PACAP (pituitary adenylate cyclase-activating polypeptide), known as the master regulator of stress responses. But the link between these elements was still unclear, so the team turned to a mouse model of panic attacks to confirm and expand their proposed map. "Emotional and stress-related behaviors have been associated with PACAP-expressing neurons in the past," says co-first author Sukjae Kang, senior research associate in Han's lab. "By mimicking panic attacks in the mice, we were able to watch those neurons' activity and discover a unique connection between the PACAP brain circuit and panic disorder." They found that during a panic attack, PACAP-expressing neurons became activated. Once activated, they release PACAP neuropeptide messenger to another part of the brain called the dorsal raphe, where neurons expressing PACAP receptors reside. The released PACAP messengers activate those receptor neurons, thereby producing panic-associated behavioral and physical symptoms in the mice. This connection between panic disorder and the PACAP brain circuit was an important step forward for mapping panic disorder in the brain, Han says. The team also found that by inhibiting PACAP signaling, they could disrupt the flow of PACAP neuropeptides and reduce panic symptoms -- a promising finding for the future development of panic disorder-specific therapeutics. According to Han, despite panic disorder's categorization as an anxiety disorder, there are many ways that anxiety and panic are different -- like how panic induces many physical symptoms, like shortness of breath, pounding heartrate, sweating, and nausea, but anxiety does not induce those symptoms. Or how panic attacks are uncontrollable and often spontaneous, while other anxiety disorders, like post-traumatic stress disorder (PTSD), are more memory-based and have predictable triggers. These differences, says Han, are why it is critical to construct this panic disorder brain map, so that researchers can create therapeutics specially tailored to panic disorder. "We found that the activity of PACAP-producing neurons in the brain's parabrachial nucleus is inhibited during anxiety conditions and traumatic memory events -- the mouse's amygdala actually directly inhibits those neurons," says Han, who is also the Pioneer Fund Developmental Chair at Salk. "Because anxiety seems to be operating conversely to the panic brain circuit, it would be interesting to look at the interaction between anxiety and panic, since we need to explain now how people with anxiety disorder have a higher tendency to experience panic attack." The team is excited to explore PACAP-expressing neurons and PACAP neuropeptides as novel druggable targets for panic disorder. Additionally, they are hoping to further build out their map of panic disorder in the brain to see where the PACAP receptor-producing neurons in the dorsal raphe send their signals, and how other anxiety-related brain areas interact with the PACAP panic system. Other authors include Jong-Hyun Kim (co-first author), Dong-Il Kim, and Benjamin Roberts of Salk. The work was supported by the National Institutes of Mental Health (BRAINS grant 1R01MH116203) and the Simons Foundation (Bridge to Independence award SFARI #388708).

Researchers have identified that a peptide called pituitary adenylate cyclase activating polypeptide (PACAP), is involved in heavy alcohol drinking. In addition, they have discovered that this peptide acts in the BNST area. Alcohol is the most common addictive substance in the world. Every year in the U.S. excessive alcohol use costs $249 billion and causes approximately 88,000 deaths, as well as various chronic diseases and social issues. Alcohol use disorder, a highly prevalent, chronic, relapsing disorder, affects more than 14 million people in the U.S. alone, in addition to being severely under-treated, with only three modestly effective pharmacological therapies available. Chronic exposure to alcohol has been shown to produce profound neuroadaptations in specific brain regions, including the recruitment of key stress neurotransmitters, ultimately causing changes in the body that sustain excessive drinking. The area of the brain known as the "bed nucleus of the stria terminalis" (BNST) is critically involved in the behavioral response to stress as well as in chronic, pathological alcohol use. Researchers from Boston University Chobanian & Avedisian School of Medicine have identified that a peptide called pituitary adenylate cyclase activating polypeptide (PACAP), is involved in heavy alcohol drinking. In addition, they have discovered that this peptide acts in the BNST area. Using an established experimental model for heavy, intermittent alcohol drinking, the researchers observed that during withdrawal this model showed increased levels of the stress neuropeptide PACAP selectively in the BNST, compared to the control model. Interestingly, a similar increase was also observed in the levels of another stress neuropeptide closely related to PACAP, the calcitonin gene-related peptide, or CGRP. Both peptides have been implicated in stress as well as pain sensitivity, but their role in alcohol addiction is less established. The researchers then used a virus in a transgenic model to block the neural pathways containing PACAP that specifically arrive to the BNST. "We found that inhibiting PACAP to the BNST dramatically reduced heavy ethanol drinking," explained co-corresponding author Valentina Sabino, PhD, co-director of the School's Laboratory of Addictive Disorders as well as professor of pharmacology, physiology & biophysics. According to the researchers, these results provide evidence that this protein mediates the addictive properties of alcohol. "We found a key player, PACAP, driving heavy alcohol drinking, which can be targeted for the development of novel pharmacological therapies," added co-corresponding author Pietro Cottone, PhD, associate professor of pharmacology, physiology & biophysics and co-director of the Laboratory of Addictive Disorders. These findings appear online in the journal eNeuro. Funding for this study was to grants number AA026051 (PC), AA025038 (VS), and AA024439 (VS) from the National Institute on Alcohol and Alcoholism (NIAAA), the Boston University Undergraduate Research Opportunities Program (UROP), the Boston University Micro and Nano Imaging Facility and the Office of the Director of the National Institutes of Health (S10OD024993).

The further advanced of Eli Lilly’s two scrapped assets is LY3451838, which was undergoing a phase 2 trial for treatment-resistant migraine. While Eli Lilly celebrated a “solid quarter” of earnings this morning, a look over the Big Pharma’s third-quarter presentation reveals that the company has quietly dumped two clinical-stage assets. One of these is LOXO-338, which was undergoing a phase 1 trial in patients with advanced hematologic malignancies. Lilly licensed the ex-China rights to the drug—a selective small-molecule inhibitor of a protein called B-cell lymphoma-2—from Shanghai Fosun Pharmaceutical two years ago. At the time of the deal, Fosun hyped up BCL-2 as an “increasingly important therapeutic target in cancer biology.” Lilly presumably agreed, handing over $40 million and pledging up to $400 million to follow in potential biobucks. AbbVie and Roche have previously scored success by bringing the first BCL-2 inhibitor to market in the form of leukemia drug Venclexta. Fosun has its own phase 1 trial of LOXO-338, which it calls FCN-338, underway in China for chronic lymphocytic leukemia and small lymphocytic lymphoma. The further advanced of Lilly’s two scrapped assets is LY3451838, which was undergoing a phase 2 trial for treatment-resistant migraine. The monoclonal antibody, which is administered intravenously, is designed to target the pituitary adenylate cyclase activating polypeptide-38 receptor. The midstage study kicked off in November 2020 and was due to complete at the end of September 2022, according to ClinicalTrials.gov. It’s not clear whether a peek at the data spooked Lilly into dropping the drug. Lilly had not responded to Fierce Biotech’s request for more information on the discontinuations at time of publication.