New treatment for Major Depression

Modulators of Synaptogenesis and Neurogenesis for the treatment of Major Depression

Advantages:

A novel biological system has been found altered in brain samples from Depressive patients.

The alteration of a particular cytokine, has been associated with depressive/anxious behavior in a transgenic mouse model over-expressing this target specifically in the brain.

Lead compounds acting on some of this specific cytokine receptors are available.

BRC Target

ALTERATIONS IN:

BRAIN PLASTICITYHPA AXIS NEUROTRANSMISSIONBEHAVIOR & COGNITION

(HPA: Hypothalamic‐PituitaryAdrenal)

DEPRESSION

Background:

Studying post-mortem brain samples (right prefrontal cortex) by genomic and proteomic methods, BRAINco has found a significant over-expression of a particular cytokine in depressive suicides compared to controls. Hypothesis:

BRAINco has set up a Drug Discovery Program focused on this new therapeutic target, which is potentially implicated in the biological bases of Depression through its effects on neuroplasticity and cognition.

Targeting specific cell signaling pathways modulated by BRAINco target, could render new antidepressant drugs.

 

 

ANIMAL MODEL

BRAINco has generated a transgenic (TG) animal model that over-expresses the specific cytokine in the brain (Fig.1). Its comprehensive characterization has pointed it out as a good model for the development of new antidepressant drugs with novel mechanisms of action.

Behavioral features:

At basal conditions… TG mice showed a consistent anxious phenotype (Fig.2), not attributable to locomotion impairment. No differences were found in tests classically used to determine antidepressant efficacy (such as tail suspension and forced swimming test). In addition, the over-expression of the candidate induced a decrease in long term potentiation as well as deficits in the T-Maze test (Fig.3), being both results associated with a cognitive impairment.

After an aversive stimulus…

TG mice presented important indications of a depressive-like behavior as assessed by Anhedonia test, after being exposed to different aversive stimulus (chronic unpredictable mild stress and olfactory bulbectomy) (Fig.3). These results suggest that TG mice show a higher sensitivity to develop depression after a stressful situation, than wild-types.

After pharmacological treatment…

TG mice exhibited a higher sensitivity to chronic Fluoxetine treatment, measured in normal conditions, as well as after Olfactory Bulbectomy (Fig.4).

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 Figure 3. Sucrose preference in WT and TG mice with and without olfactory bulbectomy (O).

 Figure 1. Target expression in WT and TG mice, measured by in situ hybridization.  

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 Figure 4. Chronic Fluoxetine treatment in WT and TG animals (A) under basal conditions (measure by NSF (Novelty Supressed Feeding) test) and (B) in bulbectomized animals (measuring sucrose preference or anhedonia).

  Development Stage: Target Validation

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Figure 2. Anxiety-like responses (top) and cognition analysis (botton) of TG animals and WT siblings. OF: Open Field; EPM: Elevated Plus Maze; LDB: Light-Dark Box.

 

 

   

Biochemical characterization:

TG mice overexpressing the target showed important alterations in phosphoproteins implicated in dendrite formation, synaptogenesis and regulation of actin cytoskeleton.

The over-expression of BRAINco target in hippocampus, induced significant changes in proteins previously found altered in Depression such as, Wnt, BDNF, CREB and β-catenin (Fig.5).

All these data showed the implication of BRAINco target in crucial biological processes found altered in Depression.

FINDING OF NEW CHEMICAL ENTITIES   

Characterization of Neurogenesis:

The overexpression of BRAINco target, induced a decrease in both, cell proliferation (measured by BrdU incorporation) and neurogenesis (Dcx labeled cells). Interestingly, KO mice for this target, showed a significant increase in hippocampal cell proliferation (Fig.6). 

BIOMARKERS

BRAINco therapeutic target is a secreted cytokine measurable in human serum. A biomarker discovery program is being set up in order to investigate the alteration of target expression levels in non-invasive samples of the animal model, as well as in Depressive patients. The final purpose is to use this biomarker as patient selection criteria.

  Figure 5. Cell signaling pathways affected in BRAINco TG model.

TG mice exhibit several features similar to those observed in human Depressive patients. Therefore, BRAINco TG mice could be considered as a novel animal model to study Depression and to test the

effectiveness of new drugs as well as existing compounds modulating the system. 

The main objective of this project is the development of a novel therapy for Depression by finding new drugs directed to a new target found altered in human specimens. For this purpose, we tested the effect of BRAINco target in different cellular systems in order to set up assays suitable for High-Throughput Screening.

Different assays including cell proliferation, migration, differentiation and survival of new neurons are being set up, using human neural progenitor cells.

 Figure 6. BrdU positive cells in TG and KO mouse models, compared to the respective WT animals.

Development Stage: Target Validation

 

 

  

Summary

Depression is a devastating disorder with high prevalence and mortality, resulting in massive socioeconomic burden (200 Millions in 2010). Current antidepressant treatments are limited by their efficacy and delay onset of action. Therefore, new therapies based on novel mechanisms of action are urgently needed.

In 2008, BRAINco discovered that a specific cytokine was significantly over-expressed in the prefrontal cortex of depressive patients, which became a novel promising therapeutic target for drug discovery.

With the purpose of functionally validate the target, a transgenic mouse which over-expressed the cytokine in the brain was generated. A comprehensive characterization of this mouse showed a consistent anxious-like behavior and cognitive impairment in basal conditions, combined with a depressive-like phenotype after a stressful event, which was reversed by chronic antidepressant treatment. Therefore, this transgenic mouse could be considered as a non-classical animal model of Depression, which may be a very valuable tool for the development of new antidepressants with novel mechanisms of action.

BRAINco team is also developing a cell based High Throughput Screening program with human neuronal progenitor cells, to look for new chemical entities targeting the system.

In addition, a biomarker program is ongoing. The objective is to identify non-invasive biomarkers specific to the mechanism of action of BRAINco compounds and that could be used for patient selection.

BRAINco has already filed a Patent application on these results.

BRAINco Biopharma S.LEdificio 504. Parque tecnológico de Vizcaya | 48160 Derio (Bilbao). Vizcaya. Spain | Telf: +34 94 4064525 | Fax: +34 94 406 4526 jmasse@brainco.es | www.brainco.es