Day: February 18, 2023

Receptor Location is Key when Rebuilding Neural Connections with Psychedelic Drugs

Source: Pixabay CC0

When using psychedelic drugs to treat mental illness, it’s all down to location when rapidly rebuilding connections between nerve cells. In their paper published in Science, scientists show that engaging serotonin 2A receptors inside neurons promotes growth of new connections – but engaging the same receptor on the surface of nerve cells does not.

The findings will help guide efforts to discover new drugs for depression, PTSD and other disorders, according to senior author David E. Olson, associate professor at the University of California, Davis.

Drugs such as LSD, MDMA and psilocybin show great promise for treating a wide range of mental disorders that are characterised by a loss of neural connections. In laboratory studies, a single dose of these drugs can cause rapid growth of new dendrites from nerve cells, and formation of new spines on those dendrites.

Olson calls this group of drugs “psychoplastogens” because of their ability to regrow and remodel connections in the brain.

Earlier work from Olson’s and other labs showed that psychedelic drugs work by engaging the serotonin 2A receptor (5-HT2AR). But other drugs that engage the same receptor, including serotonin, do not have the same growth effects.

Maxemiliano Vargas, a graduate student in Olson’s lab, Olson and colleagues experimented with chemically tweaking drugs and using transporters to make it easier or harder for compounds to slip across cell membranes. Serotonin itself is polar, meaning it dissolves well in water but does not easily cross the lipid membranes that surround cells. The psychedelics, on the other hand, are much less polar and can easily enter the interior of a cell.

They found that the growth-promoting ability of compounds was correlated with the ability to cross cell membranes.

Drug receptors are usually thought of as being located on the cell membrane, facing out. But the researchers found that in nerve cells, serotonin 2A receptors were concentrated inside cells, mostly around a structure called the Golgi body, with some receptors on the cell surface. Other types of signalling receptors in the same class were on the surface.

The results show that there is a location bias in how these drugs work, Olson said. Engaging the serotonin 2A receptor when it is inside a cell produces a different effect from triggering it when it is on the outside.

“It gives us deeper mechanistic insight into how the receptor promotes plasticity, and allows us to design better drugs,” Olson said.

Source: University of California – Davis

Promising Results for Immunotherapy Drug Nivolumab in Advanced Skin Cancer

Female scientist in laboratory
Photo by Gustavo Fring on Pexels

A phase II clinical trial has demonstrated that patients with advanced cutaneous squamous cell carcinoma can benefit from the immune checkpoint inhibitor nivolumab. The findings were published in the journal CANCER

Two other immune checkpoint inhibitors, cemiplimab and pembrolizumab, have been approved by the US Food and Drug Administration for the treatment of advanced cutaneous squamous cell carcinoma in recent years. This new study is the first to report clinical trial results for nivolumab. 

The single-arm trial included 24 patients who received nivolumab at 3mg/kg every two weeks until they experienced cancer progression, developed unacceptable toxicity, or had received 12 months of treatment.  

During the trial, 14 patients (58.3%) benefited from the treatment, with their cancers demonstrating a response. Treatment-related adverse events of any grade occurred in 21 patients (87.5%) and, for and grade ≥ 3, in six patients (25%). One patient discontinued nivolumab due to toxicities. Prior radiotherapy exposure was associated with a worse response. 

“This is the first study to investigate nivolumab in this patient population, and it provides further evidence supporting the use of immune checkpoint blockers as standard therapies in cutaneous squamous cell carcinoma,” said lead author Rodrigo R. Munhoz, MD, of the Hospital Sírio-Libanês, in Brazil. 

An accompanying editorial notes that although the trial was small, its results were similar to those reported with pembrolizumab and cemiplimab. “In addition to providing more assurance to the clinical activity of different [immune checkpoint] inhibitors in this disease, this replicated data may permit a more widespread utilisation of these agents in managing a common disease with global implications,” the authors wrote. 

Source: Wiley

Self-stigma Linked to Worse Blood Glucose Control in Type 1 Diabetes

Diabetes - person measures blood glucose
Photo by Photomix Company from Pexels

Because of their illness, patients with chronic medical conditions may experience self-stigma, or negative beliefs, emotional reactions, and behaviours towards themselves. New research published in the Journal of Diabetes Investigation found a link between self-stigma and glycated haemoglobin (HbA1c) in adults with type 1 diabetes.

The study included 109 adults in Japan with type 1 diabetes who completed questionnaires that generated scores based on a self-stigma scale. Although the findings support a link between self-stigma and sub-optimal HbA1c, additional studies are needed to show whether this is a causal relationship.

“We focused on this issue through clinical experiences with people with type 1 diabetes, whose glycaemic management improved markedly by social supports of eliminating diabetes-related stigma. Although the finding of an association between self-stigma and HbA1c is significant, further longitudinal research is required to determine whether self-stigma leads to sub-optimal HbA1c,” said corresponding author Yukiko Onishi MD, PhD, of the Institute of Medical Science, Asahi Life Foundation, in Tokyo. “This research does support and highlight the importance of eliminating self-stigma when treating people with type 1 diabetes.”

Source: Wiley

Some Dipeptides Found in Meat are Potent Antioxidants

Photo by Jose Ignacio Pompe on Unsplash

Imidazole dipeptides (IDPs), which are abundant in meat and fish, have been reported to be effective in relieving fatigue and preventing dementia. Researchers have discovered that most of these IDPs identified in beef, chicken and pork also have remarkably high antioxidant activity. They detailed their findings in the journal Antioxidants.

Professor Hideshi Ihara from the Osaka Metropolitan University Graduate School of Science led a research team that was the first to discover 2-oxo-imidazole-containing dipeptides (2-oxo-IDPs), which have one more oxygen atom than normal IDPs. Found at concentrations of  0.015–0.11% that of normal IDPs, these were also shown to be potent antioxidants.

In their study, the researchers came up with a method for selective and highly sensitive detection of five types of 2-oxo-IDPs using mass spectrometry, which enables quantitative detection of trace 2-oxo-IDPs in living organisms. Using this method, they revealed for the first time that beef, pork, chicken, and other meats contain antioxidants, not only IDPs but a variety of different 2-oxo-IDPs.

“We hope that this research method, which enables advanced analysis of 2-oxo-IDPs, will be applied not only to basic biology but also to medicine, agriculture, and pharmacy, where it will help improve peoples’ health and prevent diseases,” concluded Professor Ihara.

Source: Osaka Metropolitan University