Schizophrenia is a chronic mental disorder, which very commonly needs lifelong treatment. Frequently patients present the paranoid form of schizophrenia, in which positive symptoms, like hallucinations and delusions, as well negative symptoms, including memory impairment can be observed.
Despite continuous progress in psychiatric pharmacotherapy, negative symptoms of schizophrenia remain a great therapeutic challenge. This specifically applies to cognitive dysfunction, apathy and lack of motivation. For many years, decreased dopaminergic neurotransmission along with glutamatergic signaling hypofunction in the prefrontal cortex was the leading explanation for memory impairment observed in patients with schizophrenia. However, current antipsychotic drugs, which affect mainly dopaminergic and serotoninergic neurotransmission, are not fully effective in the treatment of the negative symptoms of schizophrenia. Recently, other factors including disturbance in kynurenic acid (KYNA) biosynthesis, are considered to be involved in schizophrenia pathogenesis.
KYNA is an endogenous substance produced widely in the body, including the brain, where it is synthesized by the kynurenine aminotransferases (KATs). KAT II is the main isoenzyme responsible for brain KYNA synthesis. KYNA is a potent free radical scavenger and an antagonist of ionotropic glutamate receptors, thus it is generally considered as a neuroprotective agent. However, the occurrence of negative symptoms and cognitive decline in schizophrenia was linked with elevated brain levels of KYNA and attenuated glutamatergic neurotransmission in the mesocortical pathway. Thus, it has been hypothesized that suppression of KYNA production may generate an improvement in negative schizophrenia symptoms treatment. This is why KAT II inhibitors are currently being tested as a potential adjunct therapy for memory impairment, especially in schizophrenia patients.
Angiotensin II type 1 receptor blockers (ARBs) are antagonists of angiotensin II type 1 receptor antagonists. Vasodilation and prevention of tissue remodeling are their main cardiovascular effects. Through decreasing organ damage in diabetes mellitus or kidney failure patients, ARBs became one of the most recommended antihypertensive agents. Except peripheral hypotensive properties ARBs have also been shown to abolish glutamate’s central pressor effects. Neuroprotective effects of ARBs were repeatedly reported.
Since KYNA is a glutamate receptor antagonist, we analyzed the effect of three ARBs: irbesartan, losartan and telmisartan on KYNA production in rat brain cortex in vitro. The experiments were carried out on rat brain cortical slices and brain homogenates in the presence of KYNA precursor kynurenine and analyzed ARBs. The incubation of rat tissue with tested compounds lasted 2 hours. Results of our experiments showed that ARBs decreased KYNA production and KAT II activity in a dose-dependent manner. Microarray data mining revealed that there is no experimental evidence indicating that ARBs affect the expression of KAT-coding genes. However, our molecular docking results strongly suggested that ARBs could bind to the active site of KAT II, competing with kynurenine, the natural substrate of the enzyme. This means that the observed attenuation of KYNA production occurred due to the direct enzyme inhibition by ARBs. In summary, we postulate that ARBs may be considered as potential supportive agents in the management of cognitive decline and negative schizophrenia symptoms, as they efficiently suppress KYNA production.
These findings are described in the article entitled Angiotensin II Type 1 Receptor Blockers Inhibit KAT II Activity in the Brain-Its Possible Clinical Applications, published in the journal Neurotoxicity Research. This work was led by Izabela Zakrocka & Artur Wnorowski from the Medical University of Lublin.