Schizophrenia is a chronic mental disorder characterized by delusions, auditory hallucinations, and paranoid thoughts. Its symptoms can be classified as “positive” or “negative”. “Positive symptoms” refer to those that are typical of people diagnosed with schizophrenia. These can include hallucinations, delusions, and disturbed thoughts. “Negative symptoms”, on the other hand, are disruptions of normal behaviors, such as apparently emotionless demeanor (known as “flat affect”), who no longer enjoy hitherto pleasurable activities, or who have difficulty performing various activities. According to the National Institute of Mental Health, risk factors for schizophrenia range from genetic and environmental factors to chemical imbalances in the brain. Currently, treatments for schizophrenia include antipsychotic medications, psychosocial treatments (teaching people diagnosed with the disorder how to cope with a social environment), and a more complex approach called “coordinated specialist care,” which involves both drug prescriptions and a broad range. of therapies focused on coping and integration.
But understanding the metabolic, not just neurochemical, alterations underlying the problem could provide therapeutic possibilities based on natural molecules and metabolites. A new study by researchers from the University of California, Irvine, has now uncovered another possible cause of the disorder, offering new hope for the development of more effective therapies and preventative approaches. A study published in 2018 in the journal Molecular Psychiatry already focused on the role of excess methionine in the bodies of pregnant women. Methionine is an amino acid that cannot be synthesized by the body, yet it is crucial for the DNA methylation process, which is a mechanism that drives gene expression. It enters the structure of the enzymatic cofactor SAM, which is used by dozens of enzymes to transfer carbon units to proteins and nucleic acids. Some methionine-rich foods include cheese and other dairy products, eggs, some meats, beans, and various seeds and nuts. The study concluded that excess methionine in the mother’s system can lead to defective brain development of the fetus, which can, in turn, lead to the onset of schizophrenia.
The research has been spurred on by older studies, dating back to the 1960s, which have intuited the role played by methionine overload in the development of the disorder. Methionine is essential for the metabolism of carbon units, it is the amino acid that regulates methylation. Researchers have learned that schizophrenia is a multigenic, developmental, and epigenetic disorder. Methylation is critical to all of these processes. Studies have shown that methionine administration exacerbates schizophrenic symptoms, leading researchers to conduct their own in vivo experiments, which revealed that methionine intake caused schizophrenia-like behavioral deficits in adult mice. To test the consistency of their hypothesis, the researchers designed the current study, in which they tested methionine on pregnant mice during the third week of pregnancy at the time of brain development. Pregnant rats were given methionine equivalent to doubling their daily intake, during the last week of gestation.
Their offspring (MET mice) had schizophrenia-like social deficits, cognitive impairments and elevated stereotypy, decreased neurogenesis, and synaptic plasticity. The expression of the neural transcript of a single gene, coding for the transcription factor NPAS4, was more than doubled in MET mice. This protein is one of the regulators of gene expression associated with sleep-wake cycles (circadian rhythms). Surprisingly, NPAS4-like downregulation occurred in the prefrontal cortex of human patients with schizophrenia. Finally, the therapeutic actions of typical (haloperidol) and atypical (clozapine) antipsychotics in MET mice mimicked the effects in patients with human schizophrenia. These findings have significant clinical implications. The homeostasis of carbon units during a woman’s gestation is precisely regulated by the interaction between dietary factors (vitamin B12, folic acid, methionine and other amino acids) and genetics. The intake of methionine in the human diet has dramatically increased over the past few decades. In pregnant women, this can involve particular risks, considering the alterations in nutritional requirements during the different stages of gestation and development.
But methionine isn’t the only amino acid that could play a role in schizophrenia. And if methionine is able to make it worse, D-serine could do the opposite. D-Serine has long been known to be a co-agonist of the NMDA receptor (a receptor for glutamate in the brain), which can occupy the glycine binding site. D-serine is created by the serine racemase enzyme by converting L-serine to D-serine, which is metabolized by D-amino acid oxidase (DAAO). There is a growing body of evidence that D-serine protects against schizophrenia and that its loss reduces the activation of NMDA receptors, causing schizophrenic symptoms. In fact, numerous studies have found that giving schizophrenic patients high doses of D-serine mitigates the negative symptoms of schizophrenia. This is important because it has recently been shown that D-serine levels are significantly lower in humans with schizophrenia, possibly caused by blunt expression of serine racemase.
Another amino acid, among the many studied in this regard, is also D-tryptophan. The role D-tryptophan plays in the brain has been largely ignored, but work has been done in recent years on its role as a metabolic substrate and the role of a related compound in reversing ketamine-induced schizophrenia called kynurenic acid. This has several neural activities including anticonvulsant and acts as a non-competitive antagonist at the glycine binding site of NMDA receptors. Kynurenic acid is also known to trigger interleukin-6 expression through the aryl hydrocarbon receptor (AhR), making it an inflammatory signaling molecule. This pathway has been implicated in a number of diseases including cancer and schizophrenia. It is therefore not surprising that kynurenic acid levels are elevated in patients with schizophrenia and that 1-methyl-D-tryptophan reverses physiological markers of ketamine-induced schizophrenia by acting as an inhibitor of indoleamine 2,3-dioxygenase, the enzyme that generates kynurenic acid from both L- and D-tryptophan.
This research is part of a growing body of literature that treats schizophrenia as an autoimmune disease, whereby interleukin-6 is activated by the kynurenic acid pathway and contributes significantly to the symptoms of schizophrenia. This confirms what was said initially, of a biological complexity of schizophrenia that could hold further surprises in the future.
Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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