|M.Sc Student||Einoch Reef|
|Subject||The Involvement of BDNF-CREB Signaling Pathways in the|
Pharmacological Mechanism of Combined SSRI-
Antidepressants and Antipsychotics in
|Department||Department of Medicine||Supervisors||ASSOCIATE PROF. Henry Silver|
|PROFESSOR EMERITUS Moussa Youdim|
|DR. Orly Weinreb|
|Full Thesis text|
Schizophrenia responds only partially to antipsychotic treatment so development of new drugs to treat such resistant features as negative symptoms and cognitive impairments is of major importance. Clinical studies showed that adding selective serotonin reuptake inhibitor (SSRI) antidepressant can ameliorate negative symptoms resistant to antipsychotics alone. The biochemical mechanism cannot be explained by the known actions of the individual drugs. We hypothesized that SSRI-antipsychotic synergism involves dynamic changes in neuronal signaling pathways. Previous studies in our laboratory identified changes in the brain, unique to the SSRI-antipsychotic combination particularly in the γ-aminobutiryc acid (GABA)-A receptor and its modulators. This study examined the role of BDNF-cAMP response element binding (CREB) protein signaling pathways, including protein kinase B (AKT), glycogen synthase kinase (GSK)-3β and related molecules. We examined the molecular response to haloperidol, fluvoxamine, combined haloperidol-fluvoxamine and clozapine treatments in rat prefrontal cortex (PFC), hippocampus and primary cortical neuronal cultures and conducted cognitive behavioral tests on chronically treated rats. The effect of fluvoxamine augmentation on BDNF-CREB pathway elements in peripheral mononuclear cells (PMC's) of medicated schizophrenia patients was also studied.
Chronic haloperidol-fluvoxamine combined treatment (1 mg/kg, 10 mg/kg respectively) increased tyrosine kinase B (TrkB) mRNA expression and protein level in rat PFC and hippocampus. In the hippocampus TrkB receptor up-regulation was accompanied by a significant increase in BDNF protein levels. Haloperidol-fluvoxamine combined treatment significantly increased the phosphorylation of AKT and CREB in both brain regions and GSK-3β in the hippocampus, compared to the individual drugs. Similar results were seen in primary neuronal cultures following 30 minutes of combination treatment. Pretreatment with a selective PI3K inhibitor abolished haloperidol-fluvoxamine- induced phosphorylation of AKT and GSK-3β, but did not affect the up-regulation of CREB phosphorylation. Clozapine, which is also effective against resistant symptoms of schizophrenia, induced similar changes. Combined treatment improved cognitive function in rats as seen in Y-maze and novel object recognition tests, indicating the changes may have a role in clinical improvement.
PMC's of treated patients showed up-regulation of mRNA expression and protein levels of BDNF, CREB, AKT and related signaling molecules, including truncated TrkB receptor, disrupted in schizophrenia (DISC)-1 and serotonin transporter (SERT) consistent with preclinical findings. PMC genes and proteins showed significant inter-correlations and some correlated with improvement in negative and cognitive symptoms.
Our study provides new knowledge of the molecular mechanisms of symptom amelioration in schizophrenia and may advance development of new drugs for this disease and other neuropsychiatric disorders.