Stem cell therapy: a new approach to the treatment of refractory depression

Yoshiyasu Kigawa,Wataru Ukai,Hanako Tsujino,Takao Ishii,Toshikazu Saito,Eri Hashimoto,Tomohiro Shirasaka,Kengo Furuse

doi:10.1007/s00702-014-1194-2

Abstract

To better understand the relationship of repeated exposure to adversity during early development as a risk factor for refractory depression, we exposed pregnant female rats to ethanol and the resulting pups to corticosterone during adolescence. A stressful forced swim test was then used to induce depression-like behavior. The adolescent rat brains were examined for the possible therapeutic benefit of a combination of sertraline, an antidepressant, and neural stem cells (NSCs) complexed with atelocollagen in relation to the level of GABAergic interneuron and synaptic protein density in different brain regions. The combined exposures of prenatal and adolescent stress resulted in a reduction in parvalbumin (PV)-positive phenotype of GABAergic interneurons and reduced postsynaptic density protein 95 (PSD-95) levels in the anterior cingulate cortex, amygdala, and hippocampus. Treatments with sertraline and NSCs reversed the reductions in PV-positive cells and PSD-95 levels. Furthermore, the combined treatment of sertraline and NSCs resulted in reduced depressive-like behaviors. These experiments underscore a potentially important role for synaptic remodeling and GABAergic interneuron genesis in the treatment of refractory depression and highlight the therapeutic potential of stem cell and pharmacological combination treatments for refractory depression.

Highlights

Repeated exposure to environmental adversity during development can cause treatment resistant, refractory depression
We found that intravenous neural stem cell (NSC) treatment reversed the reductions in the number of GABAergic interneurons and synaptic protein density in the brain decreased by prenatal ethanol exposure
We show here that aspects of depressive-like behavior resulting from a forced swim test (FST) are reversed by the combined treatment of an antidepressant and the intravenous administration of fetal rat brainderived NSCs with atelocollagen to reduce immune rejection and to potentiate effective migration of administrated cells into the brain

Summary

Introduction

Repeated exposure to environmental adversity during development can cause treatment resistant, refractory depression. Prenatal alcohol exposure has been identified as a potential risk factor for refractory depression and a high rate of comorbid depression has been reported in fetal alcohol spectrum disorder (FASD) patients (Famy et al 1998). The cortex, hippocampus, and amygdala are candidate brain regions since they have been implicated in the pathophysiology of FASD. These regions have been identified as key structures in memory and emotion (Archibald et al 2001; Miller 1996). In brain samples from schizophrenics, parvalbumin (PV)-positive interneurons (many of which display a fast-spiking firing pattern) were severely disrupted (Curley et al 2011; Gonzalez-Burgos et al 2010)

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