Mayasah Al-Nema, an Iraqi pharmaceutical chemist, has identified a drug target that might lead to better treatments for schizophrenia patients.
In her Ph.D. research, published in the Journal of Molecular Liquids, Al-Nema identified a compound that can inhibit two brain enzymes associated with schizophrenia, and found that it helped ameliorate symptoms in rat models of schizophrenia. The research got a merit award at the virtual Malaysia Technology Expo in October 2021.
Al-Nema, who was born in Baghdad, got inspired to focus on schizophrenia drugs after she won a scholarship to pursue a master’s degree in pharmaceutical chemistry at Malaysia’s UCSI University in 2016.
“I wanted to study pharmaceutical technology, but the course was not available that semester,” she told Al-Fanar Media in a recent interview via Zoom. “I was never passionate about chemistry, but I had no choice.”
Her eureka moment came when a lecturer mentioned molecular docking, a technique that employs software to predict how a target compound will behave in various situations and thus help identify possible new drugs. “That was what I wanted to do,” she said.
For the next two years, Al-Nema worked on identifying a compound that could treat the symptoms of schizophrenia better than the antipsychotic drugs commonly used now. In 2018, she got her M.Sc. degree and won a Ph.D. scholarship at the same university.
New Treatment Approach
Schizophrenia is a neuropsychiatric disorder characterised by three types of symptoms. These are classified as positive symptoms (such as hallucinations, delusions, and movement disorders), negative symptoms (such as lack of interest, diminished emotional expression, and social withdrawal), and cognitive symptoms (disorganized thinking, impaired ability to communicate, etc.).
“I wanted to study pharmaceutical technology, but the course was not available that semester. I was never passionate about chemistry, but I had no choice.”Mayasah Al-Nema
Research has not identified a single cause of schizophrenia, but scientists suspect a combination of genetic and environmental factors may lead to the disorder. Dopamine system dysfunction in different parts of the brain is also strongly implicated as a cause of schizophrenia.
Positive symptoms of the disorder develop when dopamine increases in the nucleus accumbens, a brain region concerned with motivation, reward and addiction, Al-Nema explained. At the same time, dopamine decreases in the prefrontal cortex, leading to cognitive impairment.
The antipsychotic drugs currently used to treat schizophrenia decrease the high level of dopamine in the nucleus accumbens and treat the positive symptoms, she said. “Yet they decrease the already decreased dopamine in the prefrontal cortex, worsening the negative and cognitive symptoms,” she added.
These drugs also affect the brain region concerned with voluntary movement control, leading to “involuntary movements, tremors, and Parkinson-like symptoms, which usually pushes patients to stop using the medication,” she said.
Six Million Possibilities
Al-Nema’s plan was to find a drug that could treat all the disorder’s symptoms. Her research focused on two enzymes in the phosphodiesterase (PDE) family, PDE1B and PDE10A, which are abundant in brain regions involved in schizophrenia.
“We found that if we inhibit the PDE1B enzyme in the prefrontal cortex, it can increase the deficient dopamine and improve the cognitive symptoms,” Al-Nema said.
Al-Nema’s hypothesis was to identify a compound that inhibits both PDE1B and PDE10A, and thus could treat all three categories of symptoms of schizophrenia.
Using computer-aided drug discovery, Al-Nema identified three possible inhibitors out of six million compounds in a virtual library called the ZINC database. In further tests, the team found one possible inhibitor of both enzymes. A company synthesised the compound for the team, so they could study it in animals.
Promising Results on Rats
To test the effectiveness of the compound, the team induced symptoms similar to those of schizophrenia in rats by injecting them with ketamine.
One dose of ketamine induces hyperactivity and excitation in rats, mimicking the positive symptoms of schizophrenia in humans. The compound proved effective in decreasing such symptoms.
“The drug caused no sedative and motor impairment symptoms,” Al-Nema said. “It is possibly not going to produce such side effects. However, we need more studies” to confirm that.
“The two enzymes I worked on are getting a lot of attention now. In the future, maybe 10 years or more, our compound can be a target for a new drug.”Mayasah Al-Nema
Rats injected with ketamine for 10 days mimicked the negative symptoms of schizophrenia. They chose empty cages and showed signs of social withdrawal. “With the new drug, the rat started to socialize again and invite other rats to play,” Al-Nema said.
The team studied cognitive symptoms by testing the rats’ ability to recognise objects in their boxes.
“We put in identical objects like bottles. Curious rats start to explore,” Al-Nema said. “On the second day, we change one of the items, placing a cube, for example. Normally, the rat should explore the new item. If it has a cognitive problem, it will not recognise anything and might spend more time exploring the same old object. The drug also helped treat this symptom.”
In conclusion, Al-Nema found that the compound proved highly effective and much better than risperidone, a standard atypical anti-psychotic currently used to treat the disease.
Her supervisor, Anand Gaurav, an assistant professor and head of research at UCSI’s Faculty of Pharmaceutical Sciences, agreed. When fully developed, he said, a compound that inhibits both PDE1B and PDE10A will help in overcoming the drawbacks of current medications. “The present antipsychotic drugs have minimal to no effect on negative and cognitive symptoms,” he said.
From Conflict Zones to Malaysia
After leaving war-torn Baghdad, Al-Nema studied pharmacy at the Arab International University in Syria. As she reached the programme’s fifth and final year in 2012, the security situation in Syria worsened, forcing her to move back to Iraq.
“I could not join my family that moved to Malaysia, as I would have needed to repeat my studies from zero,” she said. “In Iraq, they placed me back in the third year because of differences in the curricula. It was tragic to me. I finished pharmacy in seven years rather than five.”
She graduated from Al-Yarmok University College, a private university in Baghdad, ranking first.
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In Malaysia, she got an advanced diploma in baking from the Academy of Pastry Arts and started an online bakery in 2016. “However, I said I should not waste my degree in pharmacy,” she said. “A bursary from UCSI helped me achieve my dream.”
Al-Nema is grateful for both the financial aid and the mentorship she received.
“The project was fully funded by the university,” she said. “My supervisor also helped me improve my writing style. Now, I am a reviewer in some journals.”
Similarly, Gaurav praised Al-Nema’s abilities. “She proved to be very quick in understanding and grasping theoretical concepts, learning the elements of experimental design and learning new laboratory techniques,” he said. “Her views have always been non-conventional, involving a lot of creativity.”
All medicines used in schizophrenia patients only treat the symptoms and cannot cure the disease. Al-Nema hopes to conduct more research on the compound she identified in a postdoctoral position.
“We still have to do a lot of experiments, but this is not unexpected,” she said. “The two enzymes I worked on are getting a lot of attention now. In the future, maybe 10 years or more, our compound can be a target for a new drug.”
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