Study suggests caffeine mitigates psychiatric side effects of cyclosporine

Life-saving medical treatments often come with heavy physiological costs that extend beyond the targeted organ or disease. New research suggests that caffeine might serve as an unexpected remedy for the severe mood changes associated with a common drug used to prevent organ rejection.

The study provides evidence that caffeine can reverse anxiety and depression symptoms in mice treated with cyclosporine, potentially by altering nitric oxide signaling in the brain. The findings were published recently in the journal Physiology & Behavior.

Cyclosporine is a powerful immunosuppressive medication utilized globally. Doctors prescribe it frequently to patients undergoing organ transplantation to ensure the body does not attack the new tissue. It is also used to treat certain autoimmune disorders.

While effective for the immune system, the drug is known to cause neurotoxicity. This toxicity often manifests as psychological side effects, including elevated anxiety and depressive states. These neuropsychiatric issues can severely impact the quality of life for transplant recipients.

The biological roots of these side effects are tied to how cyclosporine works. The drug inhibits a protein called calcineurin. This inhibition stops the activation of specific T-cells in the immune system. However, calcineurin is also present in the brain. When its activity is blocked there, it disrupts the release of neurotransmitters. Previous research indicates that this disruption leads to lower levels of serotonin and dopamine. These chemicals are essential for regulating mood and emotion.

Researchers are now looking for accessible ways to mitigate these adverse effects without stopping the life-saving treatment. Caffeine is a primary candidate due to its ability to modulate brain chemistry. It is structurally similar to adenosine, a brain chemical that promotes sleep and relaxation. By blocking adenosine receptors, caffeine increases alertness. It also interacts with dopamine and other neurotransmitter systems.

The investigation also focused on the role of nitric oxide. This is a gaseous signaling molecule involved in various physiological processes. It plays a role in immune function and the regulation of blood vessel width. In the brain, nitric oxide acts as a neurotransmitter. Abnormal levels of nitric oxide signaling are linked to both anxiety and depression. Since both cyclosporine and caffeine are known to influence nitric oxide pathways, the researchers hypothesized that this gas might be the missing link.

The study was led by Mohaddeseh Ebrahimi-Ghiri and Sakineh Alijanpour. They collaborated with researchers from the University of Zanjan, Gonbad Kavous University, and Tehran University of Medical Sciences in Iran. They sought to determine if acute caffeine consumption could counterbalance the psychiatric side effects of cyclosporine. They also aimed to identify if nitric oxide mechanisms were responsible for any observed protective effects.

To test their hypothesis, the team utilized adult male mice. The animals were housed in controlled conditions to ensure standard responses. The researchers employed two standard behavioral tests to measure mood in the rodents. The first was the Elevated Plus Maze. This apparatus consists of two open arms and two enclosed arms raised above the ground. Mice naturally prefer enclosed spaces due to safety but are also inquisitive. Anxious mice will spend most of their time in the dark, enclosed arms. Less anxious mice will venture out onto the open platforms.

The second assessment was the Forced Swim Test. This is a standard method for evaluating depressive-like behavior in rodents. Mice are placed in a cylinder of water. Initially, they struggle to escape. Eventually, they may stop struggling and float. This immobility is interpreted as a measure of behavioral despair or depression. Antidepressants typically reduce the amount of time the mice spend floating motionless.

The researchers first established the baseline effects of the immunosuppressant. They administered cyclosporine to the mice and tested them 24 hours later. The results confirmed that the drug induces negative mood states. Mice treated with a 60 mg/kg dose of cyclosporine spent about 63 percent less time in the open arms of the maze compared to the control group. This indicates a heightened state of anxiety. In the swim test, these mice spent roughly 43 percent more time immobile. This suggests a significant increase in depressive-like behavior.

In the next phase, the team investigated the impact of caffeine. They found that caffeine by itself did not alter the behavior of healthy mice at the doses used. However, the results changed when caffeine was given to mice treated with cyclosporine. The researchers administered caffeine 40 minutes before the behavioral tests.

Lower doses of caffeine proved effective against anxiety. Pre-treatment with 0.1 and 0.5 mg/kg of caffeine prevented the anxiety-like behaviors usually caused by cyclosporine. The mice returned to exploring the open arms of the maze. However, the highest dose of caffeine tested did not produce this anti-anxiety effect. This aligns with known properties of caffeine, where low doses can calm but high doses may induce jitters or anxiety.

Different doses were required to address the depressive symptoms. The lowest dose of caffeine had no effect on the immobility time in the swim test. Conversely, the moderate and high doses effectively reversed the depressive-like behaviors. The mice treated with these amounts of caffeine spent more time swimming and struggling, similar to the healthy control group.

The final set of experiments explored the chemical mechanism behind these changes. The researchers wanted to know if nitric oxide was the driver. They used two chemical agents to manipulate nitric oxide levels. The first was L-arginine, a precursor that the body uses to create more nitric oxide. The second was L-NAME, a compound that inhibits the enzyme responsible for making nitric oxide.

The addition of L-arginine changed the outcome of the swim test. When researchers increased nitric oxide potential using L-arginine, caffeine lost its ability to reduce depression in the cyclosporine-treated mice. This suggests that the antidepressant effect of caffeine might depend on keeping nitric oxide levels in check. Excess nitric oxide appeared to counteract the benefit.

The inhibitor L-NAME had a different interaction, specifically in the anxiety test. When the researchers blocked nitric oxide production, it enhanced the protective effect of caffeine. Even at doses where caffeine alone might not have been fully effective, the addition of the inhibitor helped reduce anxiety. This reinforces the idea that modulating this gas is a key part of how caffeine influences mood in this context.

The authors noted that cyclosporine is known to increase nitric oxide activity in certain tissues. This increase may contribute to the negative mood symptoms. Caffeine appears to counteract this. It likely does so by blocking adenosine receptors, which in turn can lower nitric oxide production in specific brain areas.

There are limitations to this study that require consideration. The research was conducted on mice. Animal models provide essential insights but do not always perfectly predict human biological responses. The brain chemistry of humans is more elaborate. The psychological experience of depression and anxiety in humans involves complex cognitive processes that a swim test cannot fully capture.

Dosing is another variable. The study highlighted a biphasic effect of caffeine. This means the drug produces different effects at different quantities. Translating these specific milligram-per-kilogram doses from mice to humans requires careful calculation. What works as a therapeutic dose for a mouse could be ineffective or overstimulating for a person.

The role of nitric oxide is also intricate. It acts differently in various parts of the brain. In some regions, it might aid mood, while in others, it might worsen it. This study looked at systemic administration of drugs rather than targeting specific brain regions. Future research would need to pinpoint exactly where in the brain these interactions are happening.

The researchers suggest that understanding these mechanisms is vital for patient care. If these findings hold true in clinical settings, it could offer a simple strategy for managing side effects. Patients undergoing immunosuppressive therapy often have few options for managing mental health side effects. A regulated intake of caffeine could potentially offer a non-pharmaceutical adjunct to improve their well-being.

The study, “Caffeine attenuates anxiety- and depressive-like behavior following cyclosporine administration in mice, possibly via an NO pathway,” was authored by Mohaddeseh Ebrahimi-Ghiri, Fatemeh Khakpai, Sakineh Alijanpour, Seyed Parsa Golshani, Mohammad-Reza Zarrindast, and Mohammad-Reza Jafari.