As part of Microdose’s continuing series of guest contributors, today we have experts in the scientific field giving us an exclusive look at potential new methods to aid and accelerate psychedelic drug approval with regulatory agencies.
Can we better understand the unique genetic language underlying the development of chronic diseases?
Introduction
Diverse emotional states, behaviors, and thoughts that affect the quality of life are an everyday part of chronic neuroinflammatory conditions such as Alzheimer’s disease, Parkinson’s disease, depression, addiction, autism spectrum disorder, and even obesity.
What cellular communication in the brain underlies such disruption in daily activities? Does the gut play a role? What is the cellular language of orchestrated biological activity? What happens when things go wrong?
The Language/Communication Playing Field
Nerve cells communicate through their own language which involves sending and receiving signals – much like an electrical current that must be transmitted and elicit a response. Signals may be electrical or chemical and may originate within the cells or in their surrounding environment.
Signal transduction refers to the transmission of a molecular signal, in the form of a chemical modification. Protein complexes move along a signaling pathway that ultimately triggers a biochemical event. Activation of a specific receptor, either on the cell surface or inside of the cell triggers a signaling cascade that eventually elicits a response. Depending upon the cell involved, this response may alter the cells metabolism, shape, gene expression, or ability to divide.
At any step, the signal can be amplified – a single molecule can generate a response involving hundreds to millions of molecules. These molecules are often secreted by the cell and released into the extracellular space where other cells respond and react. To trigger a response, the signal must be transmitted across the cellular membrane. Other times the signal works by interacting with receptor proteins that contact both the outside and inside of the cell. In this case, only cells that have the correct receptors on their surfaces will respond to the signal.
Cellular communication is a dynamic system that adjusts itself in response to the local and systemic cellular environment. For example, the immune system uses local and systemic signal transduction mechanisms to defend the body from disease or invading pathogens. Normally, the immune response is activated and then promptly terminated to avoid excessive tissue damage. In a neuroinflammatory state, the immune response is sustained and becomes disrupted, as cells dynamically adjust their activation threshold.
A good example of a pathogen-activated immune response and the subsequent production of signals is shown by the brain’s response to endotoxemia, the presence of bacteria in the bloodstream (Srinivasan, K. et al. 2016).
This scattergram picture shows the inflammatory genetic response within the brain of a mouse to a bacterial blood infection. The various signals show different gene expression profiles for the immune cells in the central nervous system (CNS): microglia and astrocytes, which mediate much of the neuroinflammatory response. The peripheral endotoxemia had a profound effect on gene expression in both microglia and astrocytes, as samples within these cell types clustered naturally into treatment and control groups (Srinivasan, 2016).
Nutritional science and probiotics have gained notoriety in preventive and holistic medicine, shedding light on the so-called ‘brain-gut axis,’ which mediates communication between the CNS and the gastrointestinal system (GI). The vagus nerve is a major component of this bidirectional cellular communication highway, overseeing a vast array of important bodily functions including but not limited to immune response, heart rate, mood control, digestion, etc. The most important function of the vagus nerve is afferent, bringing information of the inner organs, such as gut, liver, heart, and lungs to the brain. This suggests that the inner organs are major sources of sensory information to the brain and connect emotional and cognitive areas of the brain with gut functions (Breit, 2018). Thus, when the neuroinflammatory state affects the vagus nerve, symptoms appear along the entire brain-gut axis, affecting cognition, mood, and flexibility in the social environment.
The gastrointestinal nervous system/enteric nervous system (ENS) controls GI behavior independently of the central nervous system (CNS). Many neurotransmitters, signaling pathways, and anatomical properties are common to the ENS and CNS, and therefore, many CNS and metabolic diseases have GI symptoms. Chronic disorders with both GI and CNS consequences include Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), and obesity to name a few. Most interesting is that proteins and hormones released by the ENS into the bloodstream can cross the blood-brain barrier (BBB) as well as interact with the vagus nerve and regulate food intake and appetite (Hagemann, 2003).
Key players in the GI tract are the gut microbiota and are involved in the bidirectional communication between the gut and the brain. “Based on the evidence, the gut microbiota is associated with metabolic disorders such as obesity, diabetes mellitus, and neuropsychiatric disorders such as schizophrenia, autistic disorders, anxiety disorders, and major depressive disorders. In the past few years, neuroscientific research has shown the importance of the microbiota in the development of brain systems” (Evrensel, 2015).
(Breit, S. et al. 2018)
Hard biomarkers: An emerging role for mRNA protein-coding genes
A prime example is the chemokine Eotaxin-1 (CCL11) which was originally implicated in the recruitment of eosinophiles into inflammatory sites during allergic reactions. In addition to its previously accepted role in immune response, studies have now revealed that eotaxin-1/CCL11 is associated with aging, neurogenesis, and neurodegeneration, being able to influence neural progenitor cells and microglia. Increased circulating levels of eotaxin-1/CCL11 have been described in major psychiatric disorders (schizophrenia, bipolar disorder, major depression), sometimes correlating with the severity of psychopathological and cognitive parameters (Teixera, 2018). Another cytokine IL10 has potent anti-inflammatory properties and plays a role in limiting host response to pathogens thereby preventing damage to the host while maintaining normal tissue function. IL-10 also limits inflammation in the brain; it does so by three major pathways: (1) reducing the synthesis of proinflammatory cytokines, (2) suppressing cytokine receptor expression, and (3) inhibiting receptor activation (Strle, 2001).
The next questions are whether eotaxin-1/CCL11 and IL10 can be regarded as prognostic biomarkers of disease and/or as therapeutic targets for resistant/progressive cases. “The regulation of IL-10 production by central nervous cells remains a challenging field. Answering the many remaining outstanding questions will contribute to the design of targeted approaches aiming at controlling deleterious inflammation in the brain” (Lobo-Silva, 2016).
Nova Mentis Life Science Corp sought to answer these questions in a recent fragile X syndrome preclinical study using the KO knockout rat and wild type (WT) controls. We found differences in neuroinflammatory biomarkers between KO and WT animals. Moreover, we uncovered significant changes in serum cytokine levels pre and post-treatment with psilocybin. Analytic cytokine flow cytometry studies were performed by Thermo Fisher Scientific, Vienna BioCenter, Austria (Perederiy and Hausman et al., manuscript in preparation).
The FDA Psychedelic Drug Chess Game
- Manufacture synthetic c-GMP psilocybin, greater than 98% purity.
- Show proof of efficacy for the desired therapeutic claim; Positive behavioral changes without associated cognition loss side effects.
- Prepare Drug Master File (DMF) to be submitted to the regulatory agency for a specific phase of human IND study.
- Establish a data bank with hard biomarkers to confirm therapeutic behavioral changes with drug treatment. Avoid basing results solely on biased behavioral testing.
- In the case of autism spectrum disorder (ASD), for example, confirm behavior changes with positive pre and post-treatment mRNA neuroinflammatory biomarker data.
Conclusion
Neuroinflammatory conditions – especially those that have the added complexity of disrupted emotional states and behaviors – are still difficult to diagnose accurately and treat effectively. We need new biomarkers that characterize aberrant gene expression and cellular communication in neurological disease or injury and provide insights into possible interventions and disease monitoring.
The multiple functions of mRNA inflammatory genes in the brain, as well as in peripheral organs, will create new and intriguing vistas that will promote a better understanding of neurodegenerative diseases. These discoveries could lead to the development of innovative approaches for the use of anti-inflammatory cytokines in major debilitating diseases of the CNS.
Psychedelic medicine is offering much promise as a new therapeutic paradigm with the potential to provide much-needed treatment options, especially in areas with unmet medical needs. The ability to penetrate the unique genetic language underlying the development of chronic diseases and assess therapeutic responses will assist in obtaining psychedelic drug approval with the regulatory agencies.
References
Breit, S. et al. 2018. Vagus nerve as a modulator of the brain-gut axis in psychiatric and inflammatory disorders. Fron. in Psych. Review. 13 March 2018.
Evrensel A, Ceylan ME. The gut-brain axis: the missing link in depression. Clin Psychopharmacol Neurosci(2015) 13:239–44.
Hagemann, D. et al. 2003. Appetite regulation by ghrelin – a novel neuro-endocrine gastric peptide hormone in the gut-brain- axis. Z Gastroenterol.41:929–36.
Huber, KH. et al. 2016. An emerging role for eotaxins in neurodegenerative disease. Clin. Immun. 189: 29-33.
Lobos-Silva, D. et al. 2016. Balancing the immune response in the brain: IL-10 and its regulation. J Neuroinflammation. 13(1):297
Srinivasan, K. et al. 2016. Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses. Nature Communications. DOI: 10.1038.
Strle, K. et al. 2001. Interleukin-10 in the brain. Crit Rev Immunol. 21(5):427-49.
Teixera, AL. et al. 2018. Revisiting the Role of Eotaxin-1/CCL11 in Psychiatric Disorders. Fron. in Psych. Review. 14 June 2018. 10.1038/ncomms11295 DOI: 10.1038/ncomms11295
About the Author
Dr. Marvin S. Hausman, MD
Chairman of Nova Mentis’ Scientific Advisory Board; Board Chairman & Chief Scientific Officer for Pilz Bioscience
Dr. Marvin S. Hausman is the Chief Medical Officer of Pilz Bioscience Corp., a wholly-owned subsidiary of Nova Mentis, and is leading their research and development efforts in medicinal psychedelics. Dr. Hausman is also Chairman of Nova Mentis’ Scientific Advisory Board. Dr. Hausman is an immunologist and board-certified urological surgeon with more than 30 years of drug research and development experience with various pharmaceutical companies, including Bristol-Myers International, Mead-Johnson Pharmaceutical Co., E.R. Squibb, Medco Research, and Axonyx.
Julia Perederiy, PhD
Specializing in early-stage technologies and data-driven corporate strategy, Dr. Julia Perederiy holds scientific and commercialization expertise along the full spectrum of biological innovation, from single-cell analytics to systems-level therapeutics. An established academic scientist, Dr. Perederiy is an author of multiple peer-reviewed publications, including highly regarded research on the neurogenetics of autism. In the private sector, Julia is an experienced entrepreneur and management consultant, helping biotechnology companies with business planning, market entry strategy, and fundraising. Dr. Perederiy holds Bachelor’s degrees in Neurobiology and Psychology from the University of California, Berkeley, a Master’s in Technology Entrepreneurship from the University of Portland, and a Ph.D. in Neuroscience from Oregon Health & Science University.
Editor’s Note
This piece is part of a series produced by guest contributors to expand the voices on our site and in the greater conversation. While Microdose supports the education and exploration of these topics, the facts and opinions presented in this work are the author’s alone.
