Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signalingby Clare J. Wilhelm, Joel G. Hashimoto, Melissa L. Roberts, Shelley H. Bloom, Douglas K. Beard, Kristine M. Wiren

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Research Report

Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signaling

Clare J. Wilhelma,b,n, Joel G. H

Shelley H. Blooma, Douglas K aVA Portland Health Care System, Portland, O bDepartment of Psychiatry, Oregon Health & cDepartment of Behavioral Neuroscience, Oreg rticularly among ingosine kinase 1 ith inflammatory ealed activation of n studies showed anterior cingulate cortex (ACC). By contrast, EtOH exposure lead to a significant reduction in cell death in

GABA, gamma amino-butyric acid; H&E, hematoxylin and eosin; HPA, hypothalamic-pituitary-adrenal axis; IL-6, interleukin 6; b r a i n r e s e a r c h 1 6 0 1 ( 2 0 1 5 ) 1 0 2 – 1 1 6E-mail address: wilhelmc@ohsu.edu (C.J. Wilhelm).http://dx.doi.org/10.1016/j.brainres.2015.01.002 0006-8993/Published by Elsevier B.V.

IPA, Ingenuity Pathway Analysis; LPS, lipopolysaccharide; PRRs, pattern recognition receptors; mPFC, medial prefrontal cortex;

MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Pyz, pyrazole;

S1P, sphingosine-1-phosphate; TGFβ1, transforming growth factor β1; TLR-4, toll-like receptor 4 (TLR-4); TNF-α, tumor necrosis factor-α; WSP, Withdrawal Seizure-Prone; WSR, Withdrawal Seizure-Resistant nCorrespondence to: Portland VA Medical Center, R & D 17, 3710 SW US Veterans Hospital Rd., Portland, OR 97239, USA.Abbreviations: ACC, anterior cingulate cortex; ANOVA, Analysis of Variance; BEC, blood alcohol concentration; CNS, central nervous system; Con, control; CORT, corticosterone; ELISA, enzyme-linked immunosorbent assay; EtOH, alcohol/ethanol;animals. Glucocorticoid signaling characterized using focused qPCR a sexually dimorphic response in the mPFC during withdrawal, pa astrocyte-enriched genes. These genes include aquaporin-1 (Aqp1), sph (Sphk1) and connective tissue growth factor (Ctgf); genes associated w signaling, and tissue damage and repair. Bioinformatic analysis also rev inflammatory signaling and cell death pathways in females. Confirmatio that female mice exhibited significant neuronal degeneration within theAstrocyte while control males but not females exhibited higher CORT concentrations than naive rrays identified aNeurodegeneration

Glucocorticoid signaling

NeurotoxicityAlcohol at peak withdrawal that is associated with cell damage. Given that glucocorticoids can function as anti-inflammatories, are known to increase with EtOH exposure, and influencea r t i c l e i n f o

Article history:

Accepted 1 January 2015

Available online 16 January 2015

Keywords:ashimotoa,c, Melissa L. Robertsa, . Bearda, Kristine M. Wirena,c

R 97239, USA

Science University, Portland, OR 97239, USA on Health & Science University, Portland, OR 97239, USA a b s t r a c t

Women are more sensitive to the harmful effects of alcohol (EtOH) abuse than men, yet the underlying mechanisms remain poorly understood. Previous gene expression analysis of the medial prefrontal cortex (mPFC) following a chronic intoxication paradigm using continuous 72 h vapor inhalation found that females, but not males, exhibit an inflammatory response neurotoxicity, we hypothesized that males and females may exhibit an altered corticosterone (CORT) response following chronic intoxication. Analysis of serum CORT levels revealed the expected increase during withdrawal with no difference between males and females, t g ity, e to mune disease, and sepsis (Lam et al., 201 2014; Lutalo et al., 2014). Glucocorticoid m employed in the treatment of centrally including for multiple sclerosis particularly relapse (Myhr and Mellgren, 2009) and for ed brain tumors (Dietrich et al., 2011). Nota associated with hypothalamic-pituitar 6 0as asthma, autoim3; Barnes and Ulrik, edications are also -mediated diseases, during active phase ema associated with ciated with EtOH abuse in male vs. female alcoholics remains poorly characterized.

Given a lifetime of chronic abuse, nutritional deficits, family discord and poor health choices, it can be difficult to develop a more mechanistic understanding of neurotoxicity in the EtOH dependent individual. Thus, models of vulnerability to theSapolsky, 2007), and therapeutically, glucocorticoids are used to suppress inflammation in conditions such characterization of neuroinflammation and neurotoxicity asso-males. Thus, distinc dimorphic neurotoxic particularly vulnerabl 1. Introduction

Alcohol (ethanol; EtOH) abuse has well recognized detrimental health consequences and was responsible for approximately 3.3 million deaths in 2012, nearly 6% of the total global death rate (World Health Organization, 2014). Chronic EtOH abuse increases rates of injury, cardiovascular-, digestive-, respiratory- and endocrine disease, cancer, and mental disorders (Centers for

Disease Control and Prevention, 2014). The brain is also a target of EtOH effects (Zahr et al., 2011), as neurotoxicity is observed within the frontal cortex of alcoholics (Kril et al., 1997) along with cognitive impairment (Fein et al., 1990). The frontal cortex is involved in executive function and inhibitory control, and dysfunction here contributes to the EtOH addiction cycle (Koob and

Volkow, 2010) making this region particularly important for study. However, the mechanism(s) of neuronal damage and neurodegeneration associated with EtOH abuse in the central nervous system (CNS) remain unclear.

Neurodegeneration may either be a consequence or the cause of neuroinflammation, but the impact of EtOH exposure on inflammatory signaling and cell death in the CNS are poorly described. The hippocampus is one region of EtOH-induced inflammation (He and Crews, 2008), but little is known about the relationship between EtOH-induced inflammation and neurodamage. Overall, the immunological consequences of EtOH abuse are complex and likely target-organ dependent. For example, EtOH consumption can induce immunosuppression associated with increased infection rates in some tissues, and in contrast inflammation and cell death in other tissues (Cook, 1998). Consistent with an immune compromised state, alcoholics exhibit increased rates and severity of infectious diseases, particularly those with lung involvement such as pneumonia and tuberculosis (MacGregor and Louria, 1997). Alcoholic liver disease however, is characterized by infiltration of immune cells, an inflammatory response associated with toll-like receptor 4 (TLR-4) signaling, tumor necrosis factor-α (TNF-α) production, and cell death (Albano, 2008). With the exception of the hippocampus, associations between EtOH abuse and neuroinflammation are only recently being characterized (Liu et al., 2007;