https://link.springer.com/content/pdf/10.1007%2Fs13311-017-0585-0.pdf

Anxiety, Depression, and the Microbiome: A Role for Gut Peptides.

The physiological stress response is responsible for the maintenance of homeostasis in the presence of real or perceived challenges. In this function, the brain activates adaptive responses that involve numerous neural circuits and effector molecules to adapt to the current and future demands. A maladaptive stress response has been linked to the etiology of a variety of disorders, such as anxiety and mood disorders, eating disorders, and the metabolic syndrome. The neuropeptide corticotropin-releasing factor (CRF) and its relatives, the urocortins 1-3, in concert with their receptors (CRFR1, CRFR2), have emerged as central components of the physiological stress response. This central peptidergic system impinges on a broad spectrum of physiological processes that are the basis for successful adaptation and concomitantly integrate autonomic, neuroendocrine, and behavioral stress responses. This review focuses on the physiology of CRF-related peptides and their cognate receptors with the aim of providing a comprehensive up-to-date overview of the field. We describe the major molecular features covering aspects of gene expression and regulation, structural properties, and molecular interactions, as well as mechanisms of signal transduction and their surveillance. In addition, we discuss the large body of published experimental studies focusing on state-of-the-art genetic approaches with high temporal and spatial precision, which collectively aimed to dissect the contribution of CRF-related ligands and receptors to different levels of the stress response. We discuss the controversies in the field and unravel knowledge gaps that might pave the way for future research directions and open up novel opportunities for therapeutic intervention.

The Corticotropin-Releasing Factor Family: Physiology of the Stress Response.

Dr. Athina Markou sought treatments for a common neural substrate shared by depression and drug dependence. Antagonists of corticotropin-releasing factor (CRF) receptors, a target of interest to her, have not reached the clinic despite strong preclinical rationale and sustained translational efforts. We explore potential causes for the failure of CRF1 antagonists and review recent findings concerning CRF-CRF1 systems in psychopathology. Potential causes for negative outcomes include (1) poor safety and efficacy of initial drug candidates due to bad pharmacokinetic and physicochemical properties, (2) specificity problems with preclinical screens, (3) the acute nature of screens vs. late-presenting patients, (4) positive preclinical results limited to certain models and conditions with dynamic CRF-CRF1 activation not homologous to tested patients, (5) repeated CRF1 activation-induced plasticity that reduces the importance of ongoing CRF1 agonist stimulation, and (6) therapeutic silencing which may need to address CRF2 receptor or CRF-binding protein molecules, constitutive CRF1 activity, or molecules that influence agonist-independent activity or to target structural regions other than the allosteric site bound by all drug candidates. We describe potential markers of activation towards individualized treatment, human genetic, and functional data that still implicate CRF1 systems in emotional disturbance, sex differences, and suggestive clinical findings for CRF1 antagonists in food craving and CRF-driven HPA-axis overactivation. The therapeutic scope of selective CRF1 antagonists now appears narrower than had been hoped. Yet, much remains to be learned about CRF’s role in the neurobiology of dysphoria and addiction and the potential for novel anti-CRF therapies therein.

/pdf/don-t-stress-about-crf-assessing-the-translational-failures-469mqaxl9s.pdf

Don't stress about CRF: assessing the translational failures of CRF 1 antagonists.

G-protein-coupled receptors (GPCRs) are the largest class of signaling receptors that are most frequently targeted by therapeutic drugs. Allosteric modulators bound to GPCRs at allosteric sites provide the potential for differential selectivity and improved safety compared with traditional orthosteric ligands. The recent breakthroughs in GPCR structural biology have made structures of GPCRs from classes A, B, C, and F complexed with small-molecule allosteric modulators available. Knowledge of the detailed receptor–modulator interactions at the allosteric sites is useful for structure-based GPCR drug design of novel therapeutics. This Perspective comprehensively summarizes the current status of structural complexes between GPCRs and their small-molecule allosteric modulators, particularly the key receptor–modulator interactions at the allosteric sites. Then, the structural diversity of allosteric sites across four GPCR subfamilies is compared. This study is expected to contribute to the design of GPCR allo...

Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug-Target Interactions.

As a severe and highly contagious infectious disease, coronavirus disease 2019 (COVID-19) has caused a global pandemic. Several case reports have demonstrated that the respiratory system is the main target in patients with COVID-19, but the disease is not limited to the respiratory system. Case analysis indicated that the nervous system can be invaded by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and that 36.4% of COVID-19 patients had neurological symptoms. Importantly, the involvement of the CNS may be associated with poor prognosis and disease worsening. Here, we discussed the symptoms and evidence of nervous system involvement (directly and indirectly) caused by SARS-CoV-2 infection and possible mechanisms. CNS symptoms could be a potential indicator of poor prognosis; therefore, the prevention and treatment of CNS symptoms are also crucial for the recovery of COVID-19 patients.

/pdf/involvement-of-the-nervous-system-in-sars-cov-2-infection-4p9lelhoqq.pdf

Jeff Sanders

Papers

Trauma exposure and PTSD symptoms associate with violence in inner city civilians

The CRF System as a Therapeutic Target for Neuropsychiatric Disorders