β‐Endorphin Neuronal Cell Transplant Reduces Corticotropin Releasing Hormone Hyperresponse to Lipopolysaccharide and Eliminates Natural Killer Cell Functional Deficiencies in Fetal Alcohol Exposed Rats

Abstract

Background Natural killer (NK) cell dysfunction is associated with hyperresponse of corticotropin releasing hormone (CRH) to immune challenge and with a loss of β-endorphin (BEP) neurons in fetal alcohol exposed animals. Recently, we established a method to differentiate neural stem cells into BEP neurons using cyclic adenosine monophosphate (cAMP)-elevating agents in cultures. Hence, we determined whether in vitro differentiated BEP neurons could be used for reversing the compromised stress response and immune function in fetal alcohol exposed rats. Methods To determine the effect of BEP neuron transplants on NK cell function, we implanted in vitro differentiated BEP neurons into the paraventricular nucleus of pubertal and adult male rats exposed to ethanol or control in utero. The functionality of transplanted BEP neurons was determined by measuring proopiomelanocortin (POMC) gene expression in these cells and their effects on CRH gene expression under basal and after lipopolysaccaride (LPS) challenge. In addition, the effectiveness of BEP neurons in activating NK cell functions is determined by measuring NK cell cytolytic activity and interferon-γ (IFN-γ) production in the spleen and in the peripheral blood mononuclear cell (PBMC) following cell transplantation. Results We showed here that when these in vitro differentiated BEP neurons were transplanted into the hypothalamus, they maintain biological functions by producing POMC and reducing the CRH neuronal response to the LPS challenge. BEP neuronal transplants significantly increased NK cell cytolytic activity in the spleen and in the PBMC and increased plasma levels of IFN-γ in control and fetal alcohol exposed rats. Conclusions These data further establish the BEP neuronal regulatory role in the control of CRH and NK cell cytolytic function and identify a possible novel therapy to treat stress hyper-response and immune deficiency in fetal alcohol exposed subjects.

β‐Endorphin Neuronal Transplantation Into the Hypothalamus Alters Anxiety‐Like Behaviors in Prenatal Alcohol‐Exposed Rats and Alcohol‐Non‐Preferring and Alcohol‐Preferring Rats

“…In the current study, we investigated whether β-EP neuronal transplantation could attenuate the elevated anxiety-like behavior and the corticosterone response to acute restraint stress in fetal alcohol exposed rats. Previously, we have shown that β-EP neuronal transplantation into the PVN of the hypothalamus reduces the response of hypothalamic CRH neurons to an immune stressor and modulates the peripheral stress response during and following a stressor (Boyadjieva et al, 2009; Sarkar and Zhang, 2013). …”

Fetal Alcohol Programming of Hypothalamic Proopiomelanocortin System by Epigenetic Mechanisms and Later Life Vulnerability to Stress

“…Alteration in feedback inhibition of the HPA axis by glucocorticoids (GCs) or β-endorphin (β-EP) at the level of the PVN (Hellemans et al, 2010; Boyadjieva et al, 2009)…”

Epigenetic mechanisms: A possible link between autism spectrum disorders and fetal alcohol spectrum disorders

“…These effects of ethanol on the Pomc gene were associated with some functional and behavioral abnormalities in FASD patients [139,140,141] (Fig. 1).…”