Treatment prevents symptoms of schizophrenia in tests with rats

Brazilian researchers carried out studies in animal model that mimics condition in children and adolescents considered at risk for development of the disease in adulthood.

By Peter Moon  |  Agência FAPESP – Researchers at the Federal University of São Paulo (UNIFESP) in Brazil have tested a treatment with sodium nitroprusside in a strain of rats that spontaneously develop some of the symptoms associated with schizophrenia. 

The results obtained with a group of adolescent animals suggest that preventive treatment of the disease may be possible in future for young people considered at risk owing to cases of schizophrenia in their family history. 

The research was supported by FAPESP. The principal investigator was Vanessa Costhek Abílio, a professor in the Pharmacology Department of UNIFESP’s Medical School (Escola Paulista de Medicina). The findings have been published in the journal CNS Neuroscience & Therapeutics. 

Sodium nitroprusside is a salt that acts as a significant donor of nitric oxide, a powerful vasodilator. For this reason, it has been prescribed since the 1920s for severe hypertension. More recently, evidence has been found that it might also benefit patients with schizophrenia.

An important study by Brazilian researchers published in 2013 in JAMA Psychiatry, a journal produced by the American Medical Association, reported the discovery that administration of sodium nitroprusside has therapeutic effects on the symptoms of patients with severe schizophrenia.

The study was led by Jaime Eduardo Cecilio Hallak, a researcher in the Neuroscience & Behavioral Science Department of the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP) and principal investigator of the National Science & Technology Institute (INCT) for Translational Medicine, one of the INCTs supported by FAPESP in São Paulo State in partnership with the National Council for Scientific & Technological Development (CNPq). 

Its main contribution was to show that a single intravenous injection of sodium nitroprusside produced rapid improvements in positive symptoms (such as hallucinations), negative symptoms (such blunted affect), anxiety and depression in patients with severe schizophrenia.

“Hallak’s study showed that a single injection of sodium nitroprusside led to a global and lasting improvement in the symptoms experienced by 20 inpatients undergoing treatment for severe schizophrenia,” Abílio said.

The discovery led to a number of other studies, and there is now strong evidence for the beneficial effects of sodium nitroprusside on patients with schizophrenia. “We decided to investigate whether the drug also had a preventive effect on schizophrenia. To do so, we treated the animals before they displayed manifestations of the disease,” Abílio said.

Early treatment

Schizophrenia is an incurable neuropsychiatric disorder that typically develops in late adolescence or early adulthood. Several genetic, biochemical and environmental factors are known to contribute to its onset. 

In children and adolescents considered at risk for schizophrenia, such as those with cases in their family history (15%-30% develop the disease), physicians tend to detect early signs such as attention deficit, introspection, agitation, and living in an imaginary world.

“What if we could develop a safe preventive treatment for these children so as to avert development of schizophrenia in adulthood?” Abílio wondered.

The symptoms of schizophrenia typically fall into three categories. Agitated body movements, thought disorders, hallucinations and delusions are called positive symptoms. Blunted or flat affect (reduced expression of emotions), poor social interaction, loss of capacity to feel pleasure (anhedonia) and lack of motivation are termed negative symptoms. Cognitive symptoms include difficulty paying attention and problems with working memory.

“To study the drug’s preventive effects, we set out to mimic these three classes of symptoms in the animal model,” Abílio said. 

The experiment used rats that spontaneously become hypertensive, a strain selected in Japan in the 1960s and used since then in animal models of hypertension and cardiovascular problems. These rats also display behavioral alterations.

“In 2007, we began performing studies to show that rats of this strain display cognitive problems, poor social interaction and hyperlocomotion – behavioral alterations that model the symptoms of schizophrenia. Our goal was to demonstrate this similarity so that spontaneously hypertensive rats could be used to study schizophrenia,” Abílio said.

“Of course, we can’t know if a rat is hallucinating, but we attempted to identify other symptoms that also appear in schizophrenia. We performed several tests to evaluate the animals’ cognitive capacity and social behavior.” 

The occurrence of hallucinations in schizophrenic patients is known to be associated with an increase in levels of the neurotransmitter dopamine in a specific brain region. Higher levels of dopamine are associated with hyperlocomotion in rats. 

“All this neurochemistry is well known, so that in preclinical models, when animals display increased locomotion, this is considered evidence of higher levels of dopamine in the limbic region, which is also associated with delusions and hallucinations in schizophrenia,” Abílio said.

The investigation into the possible preventive effects of sodium nitroprusside in the animal model of schizophrenia was conducted by the first two authors of the paper, biomedical scientists Mariana Cepollaro Diana and Fernanda Fiel Peres, both of whom are engaged in research supervised by Abílio. Laboratory rats considered healthy and rats of the spontaneously hypertensive strain were submitted to two different types of treatment. 

A single injection of sodium nitroprusside was administered to adult animals (more than 90 days old). Approximately 24 hours later, behavioral tests were performed to verify the occurrence of symptoms such as cognitive impairment, social interaction deficit, and locomotion alterations. 

Young animals (aged 30-60 days) were treated with daily doses of sodium nitroprusside for 30 days, followed by a one-month interval until they reached 90 days old and were considered adults. Behavioral testing began at this point.

The spontaneously hypertensive adult rats used in the experiment displayed hyperlocomotion, diminished social interaction, and emotional memory deficit. No behavioral changes were observed following administration of a single dose of sodium nitroprusside. 

The most important results of the experiment were observed in the young rats that received the longer-term treatment. The behavioral tests that began 30 days after the injections of sodium nitroprusside ended, when the animals were 90 days old and hence adult, showed that while the treatment had no visible effects on the healthy rats, the spontaneously hypertensive rats failed to display the behavioral alterations in adulthood associated with the symptoms of schizophrenia.

In other words, treatment with sodium nitroprusside prevented the appearance of the behavioral disorders that would have been inevitable without it.

“We don’t yet know how sodium nitroprusside acts to prevent the development of symptoms,” Abílio said. “That’s what we’ve set out to discover in the new stage of the research. What we do know is that sodium nitroprusside has an effect on the organism’s nitrergic system [neuronal communication mediated by nitric oxide]. Sodium nitroprusside is a donor of nitric oxide, which is a neurotransmitter, a chemical that transmits signals between neurons. Nitrergic neurotransmission is altered in schizophrenia and modulates other neurotransmission systems associated with the physiopathology of the disease. In addition, nitric oxide participates in neurodevelopment-related processes that are altered in schizophrenia.” 

The administration of sodium nitroprusside in the adolescent stage of spontaneously hypertensive rats somehow had a beneficial influence on this entire chain of neurochemical relationships, preventing the appearance of behavioral alterations when the animals reached adulthood. 

According to the authors, new studies are needed to investigate whether therapeutic possibilities such as sodium nitroprusside could be used to prevent or attenuate the development of schizophrenia.

The article “Sodium nitroprusside is effective in preventing and/or reversing the development of schizophrenia-related behaviors in an animal model: The SHR strain” (https://doi.org/10.1111/cns.12852) by Mariana C. Diana, Fernanda F. Peres, Veronica Justi, Rodrigo A. Bressan, Acioly L. T. Lacerda, José Alexandre Crippa, Jaime E. C. Hallak and Vanessa Costhek Abilio can be retrieved from: onlinelibrary.wiley.com/doi/abs/10.1111/cns.12852.