SNP intravenously improves symptoms within hours

Even if AIDS is taken into consideration, schizophrenia may still be the most severely affected disease in humans. "This statement appeared in 1988. Today, schizophrenia remains one of the major medical challenges. Although more and more drugs are available for our selection, 60% of patients are still unable to generate adequate treatment responses." In recent years, a new treatment for schizophrenia has been proposed, namely the regulation of the nitric oxide (NO) pathway. In a preclinical trial, intravenous infusion of sodium nitroprusside (SNP) successfully eliminated phenylcycloheximide. Pipoid (PCP) induced psychotic behavior and brain c-fos expression in rats.Afterwards, we designed a transformation experiment to evaluate the therapeutic effect of SNP, a nitric oxide donor, in schizophrenic patients. The results showed that intravenous administration of SNPs improved the subject's symptoms within a few hours (JAMA Psychiatry. 2013 Jul;70(7):668-76.).

This study builds on the glutamatergic hypothesis of schizophrenia: NMDA receptor blockers, including ketamine and PCP, can induce positive/negative symptoms like schizophrenia, thinking disorders, and cognitive symptoms. NMDA receptors are activated by a complex series of interactions between glutamate and the co-agonists D-serine and glycine, a process that causes the influx of calcium ions. Calcium ion binds calmodulin and stimulates neuronal NO synthase, which in turn generates NO in the central nervous system. NO can activate guanylate cyclase and increase the production of cyclic guanosine monophosphate (cGMP), which in turn can affect the kinase cascade, mRNA stability and translation, transcription factors, and major gene products. Blocking NMDA receptors with ketamine and PCP reduces NO production.

Recently, we studied the effects of SNPs on the day-night rhythm of mice. These mice have ketamine-induced psychotic symptoms. The results showed that for the ketamine- or saline-treated mice, we can delineate the standard sleep-wake cycle state maps, in which the regular potential cluster distributions of wakefulness, rapid eye movement sleep (REM) and slow wave sleep (SWS) appear. mode. However, for the SNP mice, we were unable to separate the cluster distributions, and there was a sporadic disruption in the sleep-wake cycle model, as shown above.

Previously Dzirasa et al. reported that a similar sleep-wake cycle pattern disruption occurred in DAT-KO (dopamine transporter knockout) transgenic mice treated with &alPHa;-methyl-L-tyrosine (&alPHa; MT). . &alPHa; MT is a tyrosine hydroxylase inhibitor that inhibits DA production in vivo. Since DAT-KO mice cannot recover DA, their DA levels are completely dependent on the amount of new synthesis. The use of αMT inhibits the synthesis of DA in mice, so that the level of DA in the striatum is only 0.2% of that of normal homologs. These animals were subsequently treated with the dopamine precursor levodopa and their potential cluster pattern of REM sleep was repaired.

Therefore, the question now is: as a NO donor, whether SNP can affect dopaminergic neurotransmission produces similar sleep-wake cycle pattern destruction as occurs in DA-deprived animals.

Researchers have described the relationship between dopamine and NO. Lee and colleagues reported that serum levels of NO in patients with schizophrenia were lower than controls and that 6-week dopamine receptor antagonist risperidone increased NO levels, a process that also accompanies Improvement of mental symptoms. A recent meta-analysis showed that patients taking antipsychotics had higher levels of plasma/serum NO compared with controls (Effects g = 0.663, 95%CI = 0.365-0.961, p<0.001). There are also studies showing that cGMP levels in cerebrospinal fluid are elevated in patients with schizophrenia after antipsychotic treatment. In fact, it has been speculated that NO has a regulatory inhibitory effect on dopamine receptors, which can correct the decline in DA activity in the prefrontal cortex and provide feedback loops for repairing excessive dopaminergic activity in the nucleus accumbens and striatum. Interestingly, Issy et al. reported this year that SNPs attenuate amphetamine-induced changes in prepulse inhibition (PPI) similar to schizophrenia, which is precisely a dopaminergic agonist.

The anti-psychotic mechanism of SNP is not yet clear. This effect may be faster than conventional antipsychotic drugs because SNPs can modulate NMDA-NO-cGMP. If the effect of SNPs on the dopamine pathway is confirmed by well-designed institutes in the future, this effect may imply an exciting correlation between glutamate and dopamine, both of which are currently studied in the field of schizophrenia. The most extensive neurotransmitter. For the development of more effective antipsychotic drugs, the above findings can also provide important clues.