Serotonin (5-hydroxytryptamine, 5-HT) receptor agonists have recently emerged as promising new treatment options for a variety of disorders. The recent success of these agonists, also known as psychedelics, like psilocybin for the treatment of anxiety, depression, obsessive-compulsive disorder (OCD), and addiction, has ushered in a renaissance in the way these compounds are perceived in the medical community and populace at large. One emerging therapeutic area that holds significant promise is their use as anti-inflammatory agents. Activation of 5-HT receptors produces potent anti-inflammatory effects in animal models of human inflammatory disorders at sub-behavioural levels. This review discusses the role of the 5-HT receptor in the inflammatory response, as well as highlight studies using the 5-HT agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] to treat inflammation in cellular and animal models. It also examines potential mechanisms by which 5-HT agonists produce their therapeutic effects. Overall, psychedelics regulate inflammatory pathways via novel mechanisms, and may represent a new and exciting treatment strategy for several inflammatory disorders.
Psychedelic drugs
can exert potent anti-inflammatory effects. However,
anti-inflammatory effects do not appear to correlate with behavioral
activity, suggesting different underlying mechanisms. We hypothesized
that the distinct structural features of psychedelics underlie functionally
selective mechanisms at the target 5-HT2A receptor to elicit
maximal anti-inflammatory effects. In order to test this hypothesis,
we developed a new rat-based screening platform for allergic asthma.
Next, we investigated 21 agonists at the 5-HT2A receptor
from the three primary chemotypes (phenylalkylamine, ergoline, and
tryptamine) for their ability to prevent airways hyperresponsiveness as a measure of pulmonary
inflammation. Furthermore, we assessed each drug for in vitro activation of the canonical signaling pathway, calcium mobilization,
from the 5-HT2A receptor. We find that the drug 2,5-dimethoxyphenethylamine
(2C-H) represents the pharmacophore for anti-inflammatory activity
and identify structural modifications that are either permissive or
detrimental to anti-inflammatory activity. Additionally, there is
no correlation between the ability of a particular psychedelic to
activate intracellular calcium mobilization and to prevent the symptoms
of asthma or with behavioral potencies. Our results support the notions
that specific structural features mediate functional selectivity underlying
anti-inflammatory activity and that relevant receptor activated pathways
necessary for anti-inflammatory activity are different from canonical
signaling pathways. Our results inform on the nature of interactions
between ligands at the 5-HT2A receptor as they relate to
anti-inflammatory activity and are crucial for the development of
new 5-HT2A receptor agonists for anti-inflammatory therapeutics
in the clinic that may be devoid of behavioral activity.
The H1 or linker histones bind dynamically to chromatin in living cells via a process that involves transient association with the nucleosome near the DNA entry/exit site followed by dissociation, translocation to a new location, and rebinding. The mean residency time of H1 on any given nucleosome is about a minute, which is much shorter than that of most core histones but considerably longer than that of most other chromatin-binding proteins, including transcription factors. Here we review recent advances in understanding the kinetic pathway of H1 binding and how it relates to linker histone structure and function. We also describe potential mechanisms by which the dynamic binding of H1 might contribute directly to the regulation of gene expression and discuss several situations for which there is experimental evidence to support these mechanisms. Finally, we review the evidence for the participation of linker histone chaperones in mediating H1 exchange.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.