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1.  Allopregnanolone Levels are Reduced in Temporal Cortex in Patients with Alzheimer’s Disease Compared to Cognitively Intact Control Subjects 
Biochimica et biophysica acta  2010;1801(8):951-959.
Background
The neurosteroid allopregnanolone has pronounced neuroprotective actions, increases myelination, and enhances neurogenesis. Evidence suggests that allopregnanolone dysregulation may play a role in the pathophysiology of Alzheimer’s disease (AD) and other neurodegenerative disorders. Our prior data demonstrate that allopregnanolone is reduced in prefrontal cortex in male patients with AD compared to male cognitively intact control subjects, and inversely correlated with neuropathological disease stage (Braak and Braak). We therefore determined if allopregnanolone levels are also reduced in AD patients compared to control subjects in temporal cortex, utilizing a larger set of samples from both male and female patients. In addition, we investigated if neurosteroids are altered in subjects who are APOE4 allele carriers.
Methods
Allopregnanolone, dehydroepiandrosterone (DHEA), and pregnenolone levels were determined in temporal cortex postmortem samples by gas chromatography/mass spectrometry, preceded by high performance liquid chromatography (40 subjects with AD/41 cognitively intact control subjects).
Results
Allopregnanolone levels are reduced in temporal cortex in patients with AD (median 2.68 ng/g, n= 40) compared to control subjects (median 5.64 ng/g, n=41), Mann-Whitney p=0.0002, and inversely correlated with Braak and Braak neuropathological disease stage (Spearman r= −0.38, p=0.0004). DHEA and pregnenolone are increased in patients with AD compared to control subjects. Patients carrying an APOE4 allele demonstrate reduced allopregnanolone levels in temporal cortex (Mann-Whitney p=0.04).
Conclusions
Neurosteroids are altered in temporal cortex in patients with AD and related to neuropathological disease stage. The APOE4 allele is associated with reduced allopregnanolone levels. Neurosteroids may be relevant to the neurobiology and therapeutics of AD.
doi:10.1016/j.bbalip.2010.05.006
PMCID: PMC2907131  PMID: 20488256
2.  Allopregnanolone Elevations Following Pregnenolone Administration are Associated with Enhanced Activation of Emotion Regulation Neurocircuits 
Biological psychiatry  2013;73(11):1045-1053.
Background
The neurosteroid allopregnanolone is a potent allosteric modulator of the GABA(A) receptor with anxiolytic properties. Exogenous administration of allopregnanolone reduces anxiety, and allopregnanolone blockade impairs social and affective functioning. However, the neural mechanism whereby allopregnanolone improves mood and reduces anxiety is unknown. In particular, brain imaging has not been used to link neurosteroid effects to emotion regulation neurocircuitry.
Methods
To investigate the brain basis of allopregnanolone’s impact on emotion regulation, participants were administered 400mg of pregnenolone (N=16) or placebo (N=15) and underwent 3T fMRI while performing the Shifted-Attention Emotion Appraisal Task (SEAT), which probes emotional processing and regulation.
Results
Compared to placebo, allopregnanolone was associated with reduced activity in the amygdala and insula across all conditions. During the appraisal condition, allopregnanolone increased activity in the dorsal medial prefrontal cortex and enhanced connectivity between the amygdala and dorsal medial prefrontal cortex, an effect that was associated with reduced self-reported anxiety.
Conclusions
These results demonstrate that in response to emotional stimuli, allopregnanolone reduces activity in regions associated with generation of negative emotion. Furthermore, allopregnanolone may enhance activity in regions linked to regulatory processes. Aberrant activity in these regions has been linked to anxiety psychopathology. These results thus provide initial neuroimaging evidence that allopregnanolone may be a target for pharmacological intervention in the treatment of anxiety disorders, and suggest potential future directions for research into neurosteroid effects on emotion regulation neurocircuitry.
doi:10.1016/j.biopsych.2012.12.008
PMCID: PMC3648625  PMID: 23348009
Allopregnanolone; neuroactive steroid; fMRI; pharmaco-fMRI; emotion regulation; anxiety; pregnenolone
3.  The association of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) with anxiety sensitivity and electronic diary negative affect among smokers with and without posttraumatic stress disorder 
Posttraumatic stress disorder (PTSD) is associated with increased smoking initiation, maintenance and relapse. Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are neurosteroids that have been associated with mood measures as well as smoking status, and nicotine is associated with increased DHEA and DHEAS levels. Given the difficulties with mood experienced by smokers with PTSD, the purpose of the current study was to evaluate the association between negative affect and anxiety sensitivity with DHEA and DHEAS levels. Ninety-six smokers with and without PTSD provided blood samples for neurosteroid analyses, and completed self-report measures of anxiety sensitivity and electronic diary ratings of negative affect. As expected, PTSD smokers reported higher levels of anxiety sensitivity (F[1,94]=20.67, partial η2= 0.18, p<.0001) and negative affect (F[1,91]=7.98, partial η2= .08, p=.006). After accounting for age and gender, DHEAS was significantly inversely associated with both anxiety sensitivity (F[3,92]=6.97, partial η2= 0.07, p=.01) and negative affect (F[3,87]=10.52, partial η2= 0.11, p=.002) across groups. Effect sizes indicated that these effects are moderate to high. No significant interactions of diagnosis and DHEA(S) levels with mood measures were detected. Given that nicotine is known to elevate DHEA(S) levels, these results suggest that DHEAS may serve as a biomarker of the association between mood and nicotine among smokers. Implications for the results include 1) the use of DHEAS measurement across time and across quit attempts; and 2) the potential for careful use of DHEA supplementation to facilitate abstinence during smoking cessation.
doi:10.1097/JCP.0b013e3182968962
PMCID: PMC3896952  PMID: 23771199
4.  GABAergic neuroactive steroids: a new frontier in bipolar disorders? 
Neurosteroids are synthesized in the brain and modulate brain excitability. There is increasing evidence of their sedative, anesthetic and antiseizure properties, as well as their influence on mood. Currently neurosteroids are classified as pregnane neurosteroids (allopregnanolone and allotetrahydrodeoxycorticosterone), androstane neurosteroids (androstanediol and etiocholanone) or sulfated neurosteroids (pregnenolone sulfate and dehydroepiandrosterone sulfate). Both preclinical and clinical findings indicate that progesterone derivative neurosteroids such as allopregnanolone and allotetrahydrodeoxycorticosterone play a role in mood disorders. Clozapine and olanzapine, which were shown to be effective in stabilizing bipolar disorder, elevate pregnenolone levels in rat hippocampus, cerebral cortex, and serum. In lithium-treated mice, the blood levels of allopregnanolone and pregnenolone were elevated compared to control levels. Women diagnosed with bipolar disorder typically show symptomatic exacerbation in relation to the menstrual cycle, and show vulnerability to the onset or recurrence of mood disorders immediately after giving birth, when the levels of neurosteroid derivatives of progesterone drop. Whereas in women who had recovered from bipolar disorder, the plasma concentration of allopregnanolone was elevated compared to either healthy controls or women with major depressive disorder during the premenstrual period. During depressive episodes, blood level of allopregnanolone is low. Treatment with fluoxetine tends to stabilize the levels of neurosteroids in depression. These findings converge to suggest that these steroids have significant mood-stabilizing effect. This hypothesis is consistent with the observation that a number of anticonvulsants are effective therapies for bipolar disorder, a finding also consistent with the antiseizure properties of neurosteroids. Further exploration of action of neuroactive steroids is likely to open new frontiers in the investigation of the etiology and treatment of mood disorders, particularly bipolar disorders.
doi:10.1186/1744-9081-8-61
PMCID: PMC3573983  PMID: 23253178
5.  Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia 
The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n = 9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change = 10.38) compared with patients receiving placebo (mean change = 2.33), p = 0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (rs = 0.81, p = 0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs = 0.74, p = 0.046). In addition, baseline pregnenolone (rs = −0.76, p = 0.037), pregnenolone sulfate (rs = − 0.83, p = 0.015), and allopregnanolone levels (rs = −0.83, p = 0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs = 0.74, p <0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.
doi:10.1038/npp.2009.26
PMCID: PMC3427920  PMID: 19339966
schizophrenia; negative symptoms; cognitive symptoms; neurosteroid; pregnenolone; allopregnanolone
6.  Patterns and Correlates of Prescription Opioid Use in OEF/OIF Veterans with Chronic Non-Cancer Pain 
Pain medicine (Malden, Mass.)  2011;12(10):1502-1509.
Objectives
Little is known about the treatment Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans receive for chronic non-cancer pain (CNCP). We sought to describe the prevalence of prescription opioid use, types and doses of opioids received, and identify correlates of receiving prescription opioids for CNCP among OEF/OIF veterans.
Design
Retrospective review of VA administrative data.
Setting
Ambulatory clinics within a VA regional healthcare network.
Patients
OEF/OIF veterans who had at least 3 elevated pain screening scores within a 12-month period in 2008. Within this group, those prescribed opioids (n=485) over the next 12 months were compared to those not prescribed opioids (n=277). In addition, patients receiving opioids short term (<90 days, n=284) were compared to patients receiving them long-term (≥90 consecutive days, n=201).
Results
Of 762 OEF/OIF veterans with CNCP, 64% were prescribed at least one opioid medication over the 12 months following their index dates. Of those prescribed an opioid, 59% were prescribed opioids short-term and 41% were prescribed opioids long-term. The average morphine-equivalent opioid dose for short-term users was 23.7 mg (SD=20.5) compared with 40.8 mg (SD=36.1) for long-term users (p<0.001). Fifty-one percent of long-term opioid users were prescribed short-acting opioids only and one-third were also prescribed sedative-hypnotics. In adjusted analyses, diagnoses of low back pain, migraine headache, post-traumatic stress disorder, and nicotine use disorder were associated with an increased likelihood of receiving an opioid prescription.
Conclusion
Prescription opioid use is common among OEF/OIF veterans with CNCP and is associated with several pain diagnoses and medical conditions.
doi:10.1111/j.1526-4637.2011.01226.x
PMCID: PMC3724513  PMID: 21899715
Chronic pain; Opioids; Veteran; Pain/drug therapy
7.  Gender Differences in Rates of Depression, PTSD, Pain, Obesity, and Military Sexual Trauma Among Connecticut War Veterans of Iraq and Afghanistan 
Journal of Women's Health  2010;19(2):267-271.
Abstract
Purpose
The current wars in Iraq and Afghanistan have led to an increasing number of female veterans seeking medical and mental healthcare in the Department of Veterans Affairs (VA) healthcare system. To better understand gender differences in healthcare needs among recently returned veterans, we examined the prevalence of positive screenings for depression, posttraumatic stress disorder (PTSD), military sexual trauma (MST), obesity, and chronic pain among female and male veterans of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) receiving care at the VA Connecticut Healthcare System.
Methods
We performed a retrospective, cross-sectional data analysis of OEF/OIF veterans at VA Connecticut who received services in either Primary Care or the Women's Health Clinic between 2001 and 2006.
Results
In this study, 1129 electronic medical records (1032 men, 197 women) were examined. Female veterans were more likely to screen positive for MST (14% vs. 1%, p < 0.001) and depression (48% vs. 39%, p = 0.01) and less likely to screen positive for PTSD (21% vs. 33%, p = 0.002). There was no significant gender difference in clinically significant pain scores. Men were more likely than women to have body mass index (BMI) >30 kg/m2 (21% vs. 13%, p = 0.008).
Conclusions
These results suggest that important gender differences exist in the prevalence of positive screenings for MST, depression, obesity, and PTSD. As the VA continues to review and improve its services for women veterans, clinicians, researchers, and senior leaders should consider innovative ways to ensure that female veterans receive the health services they need within the VA system.
doi:10.1089/jwh.2008.1262
PMCID: PMC3052274  PMID: 20109115
8.  Neurosteroids Reduce Social Isolation-Induced Behavioral Deficits: A Proposed Link with Neurosteroid-Mediated Upregulation of BDNF Expression 
The pharmacological action of selective serotonin reuptake inhibitor antidepressants may include a normalization of the decreased brain levels of the brain-derived neurotrophic factor (BDNF) and of neurosteroids such as the progesterone metabolite allopregnanolone, which are decreased in patients with depression and posttraumatic stress disorders (PTSD). The allopregnanolone and BDNF level decrease in PTSD and depressed patients is associated with behavioral symptom severity. Antidepressant treatment upregulates both allopregnanolone levels and the expression of BDNF in a manner that significantly correlates with improved symptomatology, which suggests that neurosteroid biosynthesis and BDNF expression may be interrelated. Preclinical studies using the socially isolated mouse as an animal model of behavioral deficits, which resemble some of the symptoms observed in PTSD patients, have shown that fluoxetine and derivatives improve anxiety-like behavior, fear responses and aggressive behavior by elevating the corticolimbic levels of allopregnanolone and BDNF mRNA expression. These actions appeared to be independent and more selective than the action of these drugs on serotonin reuptake inhibition. Hence, this review addresses the hypothesis that in PTSD or depressed patients, brain allopregnanolone levels, and BDNF expression upregulation may be mechanisms at least partially involved in the beneficial actions of antidepressants or other selective brain steroidogenic stimulant molecules.
doi:10.3389/fendo.2011.00073
PMCID: PMC3355888  PMID: 22649384
allopregnanolone; 5α-reductase type I; selective brain steroidogenic stimulants; GABAA receptors; BDNF; anxiety; aggressive behavior; PTSD
9.  Analgesic strategies aimed at stimulating the endogenous production of allopregnanolone 
A growing number of studies indicate that 3-alpha reduced neurosteroids are remarkable analgesics in various pain states. This is the case for allopregnanolone (AP), one of the most potent endogenous positive allosteric modulators of GABAA receptor function. From the pioneering work of Hans Selye, who described the sedative properties of steroids, synthetic compounds resembling the progesterone metabolite AP have been developed. If some of them have been used as anesthetics, it seems difficult to propose them as a therapeutic option for pain since they display several adverse side effects such as sedation, amnesia and functional tolerance. An alternative strategy, chosen by few laboratories around the world, is aimed at stimulating the local production of 3-alpha reduced neurosteroids in order to limit these well-known side effects. This pharmacological approach has the advantage of targeting specific structures, fully equipped with the necessary biosynthetic enzymatic machinery, where neurosteroids already act as endogenous pain modulators. The various pharmacological trials which attempted to treat pain symptoms by stimulating the production of 3-alpha reduced neurosteroids are reviewed here, as well as novel neurotransmitter systems possibly regulating their endogenous production.
doi:10.3389/fncel.2014.00174
PMCID: PMC4060572  PMID: 24987335
allodynia; hyperalgesia; nociception; pain; neurosteroids; etifoxine
10.  In a mouse model relevant for PTSD, selective brain steroidogenic stimulants (SBSSs) improve behavioral deficits by normalizing allopregnanolone biosynthesis 
Behavioural pharmacology  2010;21(5-6):438-450.
The pathophysiological role of the neurosteroid 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) in neuropsychiatric disorders has been highlighted in several recent investigations. For instance, allopregnanolone levels are decreased in the cerebrospinal fluid (CSF) of patients with posttraumatic stress disorder (PTSD) and major unipolar depression. Neurosteroidogenic antidepressants, including fluoxetine and analogs, correct this decrease in a manner that correlates with improved depressive symptoms.
PTSD-like behavioral dysfunctions, including heightened aggression, exaggerated fear, and anxiety-like behavior associated with a decrease in corticolimbic allopregnanolone content are modeled in mice by protracted social isolation stress. Allopregnanolone is not only synthesized by principal glutamatergic and GABAergic neurons but also locally, potently, positively, and allosterically modulates GABA action at post- and extra-synaptic GABAA receptors. Hence, this paper will review preclinical studies which show that in socially-isolated mice, rather than SSRI mechanisms, allopregnanolone biosynthesis in glutamatergic corticolimbic neurons offers a non-traditional target for fluoxetine to decrease signs of aggression, normalize fear responses, and decrease anxiety-like behavior. At low SSRI-inactive doses, fluoxetine and related congeners potently increase allopregnanolone levels by acting as potent selective brain steroidogenic stimulants (SBSSs), thereby facilitating GABAA receptor neurotransmission and improving behavioral dysfunctions.
Although the precise molecular mechanisms that underlie the action of these drugs are not fully understood, findings from socially-isolated mice may ultimately generate insights into novel drug targets for the treatment of psychiatric disorders, such as anxiety and panic disorders, depression, and PTSD.
doi:10.1097/FBP.0b013e32833d8ba0
PMCID: PMC2942072  PMID: 20716970
Allopregnanolone; 5α-reductase type I; selective brain steroidogenic stimulants (SBSSs); aggressive behavior; GABAA receptors; social isolation; anxiety; PTSD; mouse
11.  Excitability Changes Related to GABAA Receptor Plasticity during Pregnancy 
Alterations in GABAA receptor (GABAAR) expression and function, similar to those we described previously during pregnancy in the mouse dentate gyrus, may also occur in other brain regions. Here we show, using immunohistochemical techniques, a decreased δ subunit-containing GABAAR (δGABAAR) expression in the dentate gyrus, hippocampal CA1 region, thalamus, and striatum but not in the cerebral cortex. In the face of the highly elevated neurosteroid levels during pregnancy, which can act on δGABAARs, it may be beneficial to decrease the number of neurosteroid-sensitive receptors to maintain a steady-state level of neuronal excitability throughout pregnancy. Consistent with this hypothesis, the synaptic input/output (I/O) relationship in the dentate gyrus molecular layer in response to lateral perforant path stimulation was shifted to the left in hippocampal slices from pregnant compared with virgin mice. The addition of allopregnanolone, at levels comparable with those found during pregnancy (100 nM), shifted the I/O curves in pregnant mice back to virgin levels. There was a decreased threshold to induce epileptiform local field potentials in slices from pregnant mice compared with virgin, but allopregnanolone reverted the threshold for inducing epileptiform activity to virgin levels. According to these data, neuronal excitability is increased in pregnant mice in the absence of allopregnanolone attributable to brain region-specific downregulation of δGABAAR expression. In brain regions, such as the cortex, that do not exhibit alterations in δGABAAR expression, there were no changes in the I/O relationship during pregnancy. Similarly, no changes in network excitability were detected in pregnant Gabrd−/− mice that lack δGABAARs, suggesting that changes in neuronal excitability during pregnancy are attributable to alterations in the expression of these receptors. Our findings indicate that alterations in δGABAAR expression during pregnancy result in brain region-specific increases in neuronal excitability that are restored by the high levels of allopregnanolone under normal conditions but under pathological conditions may result in neurological and psychiatric disorders associated with pregnancy and postpartum.
doi:10.1523/JNEUROSCI.2162-09.2009
PMCID: PMC2875247  PMID: 19641122
12.  A retrospective cohort study of U.S. service members returning from Afghanistan and Iraq: is physical health worsening over time? 
BMC Public Health  2012;12:1124.
Background
High rates of mental health disorders have been reported in veterans returning from deployment to Afghanistan (Operation Enduring Freedom: OEF) and Iraq (Operation Iraqi Freedom: OIF); however, less is known about physical health functioning and its temporal course post-deployment. Therefore, our goal is to study physical health functioning in OEF/OIF veterans after deployment.
Methods
We analyzed self-reported physical health functioning as physical component summary (PCS) scores on the Veterans version of the Short Form 36 health survey in 679 OEF/OIF veterans clinically evaluated at a post-deployment health clinic. Veterans were stratified into four groups based on time post-deployment: (1Yr) 0 – 365 days; (2Yr) 366 – 730 days; (3Yr) 731 – 1095 days; and (4Yr+) > 1095 days. To assess the possibility that our effect was specific to a treatment-seeking sample, we also analyzed PCS scores from a separate military community sample of 768 OEF/OIF veterans evaluated pre-deployment and up to one-year post-deployment.
Results
In veterans evaluated at our clinic, we observed significantly lower PCS scores as time post-deployment increased (p = 0.018) after adjusting for probable post-traumatic stress disorder (PTSD). We similarly observed in our community sample that PCS scores were lower both immediately after and one year after return from deployment (p < 0.001) relative to pre-deployment PCS. Further, PCS scores obtained 1-year post-deployment were significantly lower than scores obtained immediately post-deployment (p = 0.02).
Conclusion
In our clinical sample, the longer the duration between return from deployment and their visit to our clinic, the worse the Veteran’s physical health even after adjusting for PTSD. Additionally, a decline is also present in a military community sample of OEF/OIF veterans. These data suggest that, as time since deployment length increases, physical health may deteriorate for some veterans.
doi:10.1186/1471-2458-12-1124
PMCID: PMC3543837  PMID: 23272950
Veterans; Military personnel; Veterans health; Quality of life; Operation enduring freedom; Operation iraqi freedom; Health surveys
13.  Neurosteroids in the context of stress: Implications for depressive disorders 
Pharmacology & therapeutics  2007;116(1):125-139.
Animal models indicate that the neuroactive steroids 3α,5α-THP (allopregnanolone) and 3α,5α-THDOC (allotetrahydroDOC) are stress responsive, serving as homeostatic mechanisms in restoring normal GABAergic and hypothalamic-pituitary-adrenal (HPA) function following stress. While neurosteroid increases to stress are adaptive in the short term, animal models of chronic stress and depression find lower brain and plasma neurosteroid concentrations and alterations in neurosteroid responses to acute stressors. It has been suggested that disruption in this homeostatic mechanism may play a pathogenic role in some psychiatric disorders related to stress. In humans, neurosteroid depletion is consistently documented in patients with current depression and may reflect their greater chronic stress. Women with the depressive disorder, premenstrual dysphoric disorder (PMDD), have greater daily stress and a greater rate of traumatic stress. While results on baseline concentrations of neuroactive steroids in PMDD are mixed, PMDD women have diminished functional sensitivity of GABAA receptors and our laboratory has found blunted allopregnanolone responses to mental stress relative to non-PMDD controls. Similarly, euthymic women with histories of clinical depression, which may represent a large proportion of PMDD women, show more severe dysphoric mood symptoms and blunted allopregnanolone responses to stress versus never-depressed women. It is suggested that failure to mount an appropriate allopregnanolone response to stress may reflect the price of repeated biological adaptations to the increased life stress that is well documented in depressive disorders and altered allopregnanolone stress responsivity may also contribute to the dysregulation seen in HPA axis function in depression.
doi:10.1016/j.pharmthera.2007.05.006
PMCID: PMC2650267  PMID: 17597217
Neurosteroids; Allopregnanolone; Stress; Premenstrual dysphoric disorder; Depressive disorders
14.  Pregnenolone and ganaxolone reduce operant ethanol self-administration in alcohol-preferring P rats 
Background
Neuroactive steroids modulate ethanol intake in several self-administration models with variable effects. The purpose of this work was to examine the effects of the long-acting synthetic GABAergic neurosteroid ganaxalone and the endogenous neurosteroid pregnenolone, a precursor of all GABAergic neuroactive steroids, on the maintenance of ethanol self-administration in an animal model of elevated drinking – the alcohol preferring (P) rats.
Methods
P rats were trained to self-administer ethanol (15% v/v) vs. water on a concurrent schedule of reinforcement, and the effects of ganaxolone (0 – 30 mg/kg, SC) and pregnenolone (0 – 75 mg/kg, IP) were evaluated on the maintenance of ethanol self-administration. After completion of self-administration testing, doses of the neuroactive steroids that altered ethanol self-administration were assessed on spontaneous locomotor activity. Finally, the effect of pregnenolone administration on cerebral cortical levels of the GABAergic neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone, 3α,5α-THP) was determined in both ethanol experienced and inexperienced P rats since pregnenolone is a precursor of these steroids.
Results
Ganaxolone produced a dose-dependent biphasic effect on ethanol reinforcement, as the lowest dose (1 mg/kg) increased and the highest dose (30 mg/kg) decreased ethanol-reinforced responding. However, the highest ganaxolone dose also produced a nonspecific reduction in locomotor activity. Pregnenolone treatment significantly reduced ethanol self-administration (50 and 75 mg/kg), without altering locomotor activity. Pregnenolone (50 mg/kg) produced a significant increase in cerebral cortical allopregnanolone levels. This increase was observed in the self-administration trained animals, but not in ethanol naïve P rats.
Conclusions
These results indicate that pregnenolone dose-dependently reduces operant ethanol self-administration in P rats without locomotor impairment, suggesting it may have potential as a novel therapeutic for reducing chronic alcohol drinking in individuals that abuse alcohol.
doi:10.1111/j.1530-0277.2010.01300.x
PMCID: PMC2988984  PMID: 20946297
ethanol self-administration; GABA; neuroactive steroids; ganaxolone; pregnenolone
15.  Reduced Amygdala Volume Is Associated with Deficits in Inhibitory Control: A Voxel- and Surface-Based Morphometric Analysis of Comorbid PTSD/Mild TBI 
BioMed Research International  2014;2014:691505.
A significant portion of previously deployed combat Veterans from Operation Enduring Freedom and Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) are affected by comorbid posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI). Despite this fact, neuroimaging studies investigating the neural correlates of cognitive dysfunction within this population are almost nonexistent, with the exception of research examining the neural correlates of diagnostic PTSD or TBI. The current study used both voxel-based and surface-based morphometry to determine whether comorbid PTSD/mTBI is characterized by altered brain structure in the same regions as observed in singular diagnostic PTSD or TBI. Furthermore, we assessed whether alterations in brain structures in these regions were associated with behavioral measures related to inhibitory control, as assessed by the Go/No-go task, self-reports of impulsivity, and/or PTSD or mTBI symptoms. Results indicate volumetric reductions in the bilateral anterior amygdala in our comorbid PTSD/mTBI sample as compared to a control sample of OEF/OIF Veterans with no history of mTBI and/or PTSD. Moreover, increased volume reduction in the amygdala predicted poorer inhibitory control as measured by performance on the Go/No-go task, increased self-reported impulsivity, and greater symptoms associated with PTSD. These findings suggest that alterations in brain anatomy in OEF/OIF/OND Veterans with comorbid PTSD/mTBI are associated with both cognitive deficits and trauma symptoms related to PTSD.
doi:10.1155/2014/691505
PMCID: PMC3958771  PMID: 24724093
16.  Psychiatric Diagnoses and Neurobehavioral Symptom Severity Among OEF/OIF VA Patients with Deployment-Related Traumatic Brain Injury: A Gender Comparison 
Background
Traumatic brain injury (TBI) has substantial negative implications for the post-deployment adjustment of Veterans who served in Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF); however, most research on Veterans has focused on males. This study investigated gender differences in psychiatric diagnoses and neurobehavioral symptom severity among OEF/OIF Veterans with deployment-related TBI.
Methods
This population-based study examined psychiatric diagnoses and self-reported neurobehavioral symptom severity from administrative records for 12,605 United States OEF/OIF Veterans evaluated as having deployment-related TBI. Men (n = 11,951) and women (n = 654) who were evaluated to have deployment-related TBI during a standardized comprehensive TBI evaluation in Department of Veterans Affairs (VA) facilities were compared on the presence of psychiatric diagnoses and severity of neurobehavioral symptoms.
Findings
Posttraumatic stress disorder (PTSD) was the most common psychiatric condition for both genders, although women were less likely than men to have a PTSD diagnosis. In contrast, relative to men, women were 2 times more likely to have a depression diagnosis, 1.3 times more likely to have a non-PTSD anxiety disorder, and 1.5 times more likely to have PTSD with comorbid depression. Multivariate analyses indicated that blast exposure during deployment may account for some of these differences. Additionally, women reported significantly more severe symptoms across a range of neurobehavioral domains.
Conclusions
Although PTSD was the most common condition for both men and women, it is also critical for providers to identify and treat other conditions, especially depression and neurobehavioral symptoms, among women Veterans with deployment-related TBI.
doi:10.1016/j.whi.2011.04.019
PMCID: PMC3132395  PMID: 21724143
traumatic brain injury; Veterans; women; gender; psychiatric conditions; neurobehavioral symptoms; post-deployment adjustment
17.  Pain in veterans of the Gulf War of 1991: a systematic review 
Background
Veterans of the Persian Gulf War of 1991 have reported a range of adverse health symptoms. This systematic review aims to identify all studies that have compared the prevalence of symptoms of pain in veterans of the Gulf War to that in a non-Gulf military comparison group, and to determine whether Gulf War veterans are at increased risk of reporting pain.
Methods
Studies published between January 1990 and May 2004 were identified by searching a large number of electronic databases. Reference lists and websites were also searched and key researchers were contacted. Studies were included if they reported the prevalence of any symptom or condition that included the word "pain" in Gulf War veterans and in a comparison group of non-Gulf veterans. 2401 abstracts were independently reviewed by two authors.
Results
Twenty studies fulfilled the inclusion criteria. Five main sites of pain were identified (muscle, joint, chest/heart, back and abdominal pain) and separate meta-analyses were performed to summarise the results related to each site. A greater proportion of Gulf veterans reported symptoms at each site of pain when compared to a non-Gulf military group. Gulf deployment was most strongly associated with abdominal pain, with Gulf veterans being more than three times more likely to report such pain than a comparison group (OR 3.23; 95%CI 2.31–4.51). Statistical heterogeneity between study estimates was significant, probably due to variation in measured periods of prevalence and symptom measurement methods.
Conclusion
A higher proportion of veterans of the Persian Gulf War of 1991 reported symptoms of pain than military comparison groups. This is consistent with previously demonstrated increased reporting of more general symptoms (fatigue, multiple chemical sensitivity, post traumatic stress disorder) in these veterans compared with non-Gulf military groups. However, the primary studies were heterogeneous and varied greatly in quality.
doi:10.1186/1471-2474-7-74
PMCID: PMC1592094  PMID: 16987407
18.  Allopregnanolone suppresses diabetes-induced neuropathic pain and motor deficit through inhibition of GABAA receptor down-regulation in the spinal cord of diabetic rats 
Objective(s):
Painful diabetic neuropathy is associated with hyperexcitability and hyperactivity of spinal cord neurons. However, its underlying pathophysiological mechanisms have not been fully clarified. Induction of excitatory/inhibitory neurotransmission imbalance at the spinal cord seems to account for the abnormal neuronal activity in diabetes. Protective properties of neurosteroids have been demonstrated in numerous cellular and animal models of neurodegeneration.
Materials and Methods:
Here, the protective effects of allopregnanolone, a neurosteroid were investigated in an in vivo model of diabetic neuropathy. The tail-flick test was used to assess the nociceptive threshold. Diabetes was induced by injection of 50 mg/kg (IP) streptozotocin. Seven weeks after the induction of diabetes, the dorsal half of the lumbar spinal cord was assayed for the expression of γ2 subunit of GABAA receptor using semiquantitative RT-PCR.
Results:
The data shows that allopregnanolone (5 and 20 mg/kg) markedly ameliorated diabetes-induced thermal hyperalgesia and motor deficit. The weights of diabetic rats that received 5 and 20 mg/kg allopregnanolone did not significantly reduce during the time course of study. Furthermore, this neurosteroid could inhibit GABAA receptor down-regulation induced by diabetes in the rat spinal cord.
Conclusion:
The data revealed that allopregnanolone has preventive effects against hyperglycemic-induced neuropathic pain and motor deficit which are related to the inhibition of GABAA receptor down-regulation.
PMCID: PMC4069843  PMID: 24967058
Allopregnanolone; Diabetic neuropathy; GABAA receptor; Hyperalgesia; Rats
19.  A case–control study examining whether neurological deficits and PTSD in combat veterans are related to episodes of mild TBI 
BMJ Open  2012;2(2):e000312.
Background
Mild traumatic brain injury (mTBI) is a common injury among military personnel serving in Iraq or Afghanistan. The impact of repeated episodes of combat mTBI is unknown.
Objective
To evaluate relationships among mTBI, post-traumatic stress disorder (PTSD) and neurological deficits (NDs) in US veterans who served in Iraq or Afghanistan.
Methods
This was a case–control study. From 2091 veterans screened for traumatic brain injury, the authors studied 126 who sustained mTBI with one or more episodes of loss of consciousness (LOC) in combat. Comparison groups: 21 combat veterans who had definite or possible episodes of mTBI without LOC and 21 veterans who sustained mTBI with LOC as civilians.
Results
Among combat veterans with mTBI, 52% had NDs, 66% had PTSD and 50% had PTSD and an ND. Impaired olfaction was the most common ND, found in 65 veterans. The prevalence of an ND or PTSD correlated with the number of mTBI exposures with LOC. The prevalence of an ND or PTSD was >90% for more than five episodes of LOC. Severity of PTSD and impairment of olfaction increased with number of LOC episodes. The prevalence of an ND for the 34 combat veterans with one episode of LOC (4/34=11.8%) was similar to that of the 21 veterans of similar age and educational background who sustained civilian mTBI with one episode of LOC (2/21=9.5%, p-NS).
Conclusions
Impaired olfaction was the most frequently recognised ND. Repeated episodes of combat mTBI were associated with increased likelihood of PTSD and an ND. Combat setting may not increase the likelihood of an ND. Two possible connections between mTBI and PTSD are (1) that circumstances leading to combat mTBI likely involve severe psychological trauma and (2) that altered cerebral functioning following mTBI may increase the likelihood that a traumatic event results in PTSD.
Article summary
Article focus
Case–control study of mTBI associated with LOC among US veterans who were deployed to Iraq or Afghanistan during Operations Iraqi Freedom and Enduring Freedom.
Three study groups: (1) 126 veterans who had mTBI with LOC, (2) 21 OIF/OEF veterans who did not suffer mTBI with LOC and (3) 21 veterans who sustained mTBI with LOC in a civilian setting.
Evaluated NDs including a quantitative test of olfaction, PTSD with severity assessed using the PCL-M instrument and a cognitive function using the Montreal Cognitive Assessment Test.
Key messages
Olfaction was a sensitive test for neurological injury associated with mTBI with LOC.
More episodes of mTBI with LOC were associated with higher prevalence rates of NDs or of PTSD.
The severity of PTSD and extent of olfactory impairment increased with the number of episodes of LOC; cognitive function performance was inversely related to the number of episodes of LOC.
Strengths and limitations of this study
Case–control study of US combat veterans with mTBI who were assessed for NDs, PTSD and cognitive function.
Subjects and comparison groups had detailed assessments for NDs, and combat veterans were also assessed for PTSD.
The findings should be relevant to other groups of military personnel with combat mTBI.
The neurological examination was not blinded.
The selection of veterans in this study may be biased because veterans who do not have health issues may not seek care from the Department of Veterans Affairs.
The comparison groups were small.
The findings in veterans with mTBI with LOC may not apply to people with mTBI without LOC.
doi:10.1136/bmjopen-2011-000312
PMCID: PMC3312078  PMID: 22431700
20.  Health Risk Behaviors of Afghanistan and Iraq War Veterans Attending College 
Purpose
The population military veterans attending college is rapidly growing as veterans return from Operations Enduring Freedom and Iraqi Freedom (OEF/OIF). We sought to describe patterns of student veterans’ health-related behaviors and how they might differ from their non-veteran peers.
Design
We analyzed data from the 2008 Boynton College Student Health Survey (CSHS).
Setting
CSHS participants completed an anonymous online survey.
Subjects
The CSHS sampled students (n=8,651) attending public, private, two-, and four-year postsecondary educational institutions in Minnesota.
Measures
The CSHS included items on substance use (including alcohol and tobacco), safety, nutrition, and physical activity.
Analysis
We described demographics of OEF/OIF veteran, non-OEF/OIF veteran, and non-veteran students and used poisson regression to compute adjusted relative risks (ARR) with 95% confidence intervals to characterize associations between veteran status and health behaviors.
Results
After controlling for demographics, veteran students reported more safety-, tobacco-, and alcohol-related risk behaviors compared to non-veteran students. For instance, compared to the non-veteran reference group, the ARR for past year smokeless tobacco use and physical fighting among for OEF/OIF veterans was 1.76 [CI: 1.31–2.35] and 1.48 [CI: 1.22–1.79] respectively. Veteran and non-veteran students display similar weight-related behaviors, though OEF/OIF veteran students were more likely to engage in strengthening exercises.
Conclusions
There are specific health risk behaviors which are particularly relevant for veterans attending postsecondary institutions. As veterans enroll in postsecondary education there is a unique window of opportunity for health promotion in this population.
doi:10.4278/ajhp.090826-QUAN-278
PMCID: PMC3579508  PMID: 22040391
Veterans; Young Adult; Tobacco; Substance Abuse; Obesity; Safety
21.  Intrathecal neurosteroids and a neurosteroid antagonist: Effects on inflammation-evoked thermal hyperalgesia and tactile allodynia 
Neuroscience letters  2013;548:27-32.
Neurosteroids regulate neuronal excitability though binding sites associated with the ionotropic γ-aminobutyric acid (GABAA) receptor. We sought to characterize the spinal analgesic actions in rats of two 5α-reduced neurosteroids, allopregnanolone and alphaxalone, on nociceptive processing and to determine whether a putative neurosteroid antagonist attenuates this effect: (3α, 5α)-17-phenylandrost-16-en-3-ol (17PA). Intrathecal (IT) injection of allopregnanolone (1-30μg/10μL in 20%cyclodextrin) delivered through lumbar catheters produced a dose-dependent analgesia in rats as measured by thermal thresholds in the ipsilateral (inflamed by intraplantar carrageenan) and in the contralateral (un-inflamed paws). Similar observations were made with alphaxalone (30-60 μg in 20%cyclodextrin). Effective doses were not associated with suppressive effects on pinnae, blink or placing and stepping reflex. Effects of allopregnanolone (30μg) on the normal and hyperalgesic paw were completely prevented by IT 17PA (30μg). Reversal by IT 17PA of an equi-analgesic dose of alphaxalone occurred only at higher antagonist dosing. These results suggest that a spinal neurosteroid-binding site with which 17 PA interacts may regulate spinal nociceptive processing in normal and inflamed tissue. (NIDA DA02110) (171 words)
doi:10.1016/j.neulet.2013.05.027
PMCID: PMC3761066  PMID: 23707652
Neurosteroid; allopregnanolone; alphaxalone; hyperalgesia; Tactile allodynia; GABAA; intrathecal
22.  Oxidative Stress-Mediated Brain Dehydroepiandrosterone (DHEA) Formation in Alzheimer’s Disease Diagnosis 
Neurosteroids are steroids made by brain cells independently of peripheral steroidogenic sources. The biosynthesis of most neurosteroids is mediated by proteins and enzymes similar to those identified in the steroidogenic pathway of adrenal and gonadal cells. Dehydroepiandrosterone (DHEA) is a major neurosteroid identified in the brain. Over the years we have reported that, unlike other neurosteroids, DHEA biosynthesis in rat, bovine, and human brain is mediated by an oxidative stress-mediated mechanism, independent of the cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) enzyme activity found in the periphery. This alternative pathway is induced by pro-oxidant agents, such as Fe2+ and β-amyloid peptide. Neurosteroids are involved in many aspects of brain function, and as such, are involved in various neuropathologies, including Alzheimer’s disease (AD). AD is a progressive, yet irreversible neurodegenerative disease for which there are limited means for ante-mortem diagnosis. Using brain tissue specimens from control and AD patients, we provided evidence that DHEA is formed in the AD brain by the oxidative stress-mediated metabolism of an unidentified precursor, thus depleting levels of the precursor in the blood stream. We tested for the presence of this DHEA precursor in human serum using a Fe2+-based reaction and determined the amounts of DHEA formed. Fe2+ treatment of the serum resulted in a dramatic increase in DHEA levels in control patients, whereas only a moderate or no increase was observed in AD patients. The DHEA variation after oxidation correlated with the patients’ cognitive and mental status. In this review, we present the cumulative evidence for oxidative stress as a natural regulator of DHEA formation and the use of this concept to develop a blood-based diagnostic tool for neurodegenerative diseases linked to oxidative stress, such as AD.
doi:10.3389/fendo.2011.00069
PMCID: PMC3356139  PMID: 22654823
Alzheimer’s disease; dehydroepiandrosterone; diagnostic tool; neurosteroids
23.  Low back pain (acute) 
Clinical Evidence  2008;2008:1102.
Introduction
Low back pain (LBP) affects about 70% of people in resource-rich countries at some point. Acute low back pain is usually perceived as self-limiting; however, one year later, as many as 33% of people still have moderate-intensity pain and 15% have severe pain. It has a high recurrence rate; 75% of those with a first episode have a recurrence. Although acute episodes may resolve completely, they may also increase in severity and duration over time.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral drug treatments for low back pain? What are the effects of local injections for low back pain? What are the effects of non-drug treatments for low back pain? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 34 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, advice to stay active, analgesics (paracetamol, opioids), back exercises, back schools, bed rest, behavioural therapy, electromyographic biofeedback, epidural corticosteroid injections, lumbar supports, massage, multidisciplinary treatment programmes, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), spinal manipulation (in the short term), temperature treatments (short wave diathermy, ultrasound, ice, heat), traction, and transcutaneous electrical nerve stimulation (TENS).
Key Points
Low back pain is pain, muscle tension, or stiffness, localised below the costal margin and above the inferior gluteal folds, with or without referred or radicular leg pain (sciatica), and is defined as acute when pain persists for less than 12 weeks. Low back pain affects about 70% of people in resource-rich countries at some point.Acute low back pain is usually self-limiting, although 2-7% develop chronic pain. Acute low back pain has a high recurrence rate with less-painful symptoms recurring in 50-80% of people within a year; one year later, as high as 33% still experience moderate-intensity pain and 15% experience severe pain.
NSAIDs have been shown to effectively improve symptoms compared with placebo. However, their use is associated with gastrointestinal adverse effects. Muscle relaxants may also reduce pain and improve overall clinical assessment, but are associated with some severe adverse effects including drowsiness, dizziness, and nausea.The studies examining the effects of analgesics such as paracetamol or opioids were generally too small to detect any clinically important differences.
We found no studies examining the effectiveness of epidural injections of corticosteroids in treating people with acute low back pain.
With regard to non-drug treatments, advice to stay active (be it as a single treatment or in combination with other interventions such as back schools, a graded activity programme, or behavioural counselling) seems the most effective. Spinal manipulation (in the short term) also seems to reduce pain, but not functional outcomes, compared with sham treatments.We found insufficient evidence to judge the effectiveness of acupuncture, back schools, behavioural therapy, massage, multidisciplinary treatment programmes (for either acute or subacute low back pain), ortemperature treatments in treating people with acute low back pain.We found no evidence examining the effectiveness of electromyographic biofeedback, lumbar supports, traction, or TENS in the treatment of acute low back pain. Back exercises do not seem to increase recovery time compared with no treatment, although there is considerable heterogeneity among studies with regard to the definition of back exercise. There is also disparity among studies in the definition of generic and specific back exercise. Bed rest does not improve symptoms any more effectively than other treatments, but does produce a number of adverse effects including joint stiffness, muscle wasting, loss of bone mineral density, pressure sores, and venous thromboembolism.
PMCID: PMC2907975  PMID: 19445792
24.  Low back pain (acute) 
Clinical Evidence  2011;2011:1102.
Introduction
Low back pain affects about 70% of people in resource-rich countries at some point in their lives. Acute low back pain can be self-limiting; however, 1 year after an initial episode, as many as 33% of people still have moderate-intensity pain and 15% have severe pain. Acute low back pain has a high recurrence rate; 75% of those with a first episode have a recurrence. Although acute episodes may resolve completely, they may increase in severity and duration over time.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral drug treatments for acute low back pain? What are the effects of local injections for acute low back pain? What are the effects of non-drug treatments for acute low back pain? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 49 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, advice to stay active, analgesics (paracetamol, opioids), back exercises, back schools, bed rest, behavioural therapy, electromyographic biofeedback, epidural corticosteroid injections, lumbar supports, massage, multidisciplinary treatment programmes, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), spinal manipulation, temperature treatments (short-wave diathermy, ultrasound, ice, heat), traction, and transcutaneous electrical nerve stimulation (TENS).
Key Points
Low back pain is pain, muscle tension, or stiffness, localised below the costal margin and above the inferior gluteal folds, with or without referred or radicular leg pain (sciatica), and is defined as acute when pain persists for <12 weeks. Low back pain affects about 70% of people in resource-rich countries at some point in their lives.Acute low back pain may be self-limiting, although there is a high recurrence rate with less-painful symptoms recurring in 50% to 80% of people within 1 year of the initial episode; 1 year later, as many as 33% of people still experience moderate-intensity pain and 15% experience severe pain.
NSAIDs have been shown to effectively improve symptoms compared with placebo. However, their use is associated with gastrointestinal adverse effects. Muscle relaxants may also reduce pain and improve overall clinical assessment, but are associated with some severe adverse effects including drowsiness, dizziness, and nausea.The studies examining the effects of analgesics such as paracetamol or opioids were generally too small to detect any clinically important differences.
We found no studies examining the effectiveness of epidural injections of corticosteroids in treating people with acute low back pain.
With regard to non-drug treatments, advice to stay active (be it as a single treatment or in combination with other interventions such as back schools, a graded activity programme, or behavioural counselling) may be effective. We don't know whether spinal manipulation improves pain or function compared with sham treatments.We found insufficient evidence to judge the effectiveness of acupuncture, back schools, behavioural therapy, massage, multidisciplinary treatment programmes (for either acute or subacute low back pain), lumbar supports, TENS, or temperature treatments in treating people with acute low back pain.We found no evidence examining the effectiveness of electromyographic biofeedback or traction in the treatment of acute low back pain. Back exercises may decrease recovery time compared with no treatment, but there is considerable heterogeneity among studies with regard to the definition of back exercise. There is a large disparity among studies in the definition of generic versus specific back exercise. Bed rest does not improve symptoms any more effectively than other treatments, but does produce a number of adverse effects including joint stiffness, muscle wasting, loss of bone mineral density, pressure sores, and venous thromboembolism.
PMCID: PMC3217769  PMID: 21549023
25.  Impaired neurosteroid synthesis in multiple sclerosis 
Brain  2011;134(9):2703-2721.
High-throughput technologies have led to advances in the recognition of disease pathways and their underlying mechanisms. To investigate the impact of micro-RNAs on the disease process in multiple sclerosis, a prototypic inflammatory neurological disorder, we examined cerebral white matter from patients with or without the disease by micro-RNA profiling, together with confirmatory reverse transcription–polymerase chain reaction analysis, immunoblotting and gas chromatography-mass spectrometry. These observations were verified using the in vivo multiple sclerosis model, experimental autoimmune encephalomyelitis. Brains of patients with or without multiple sclerosis demonstrated differential expression of multiple micro-RNAs, but expression of three neurosteroid synthesis enzyme-specific micro-RNAs (miR-338, miR-155 and miR-491) showed a bias towards induction in patients with multiple sclerosis (P < 0.05). Analysis of the neurosteroidogenic pathways targeted by micro-RNAs revealed suppression of enzyme transcript and protein levels in the white matter of patients with multiple sclerosis (P < 0.05). This was confirmed by firefly/Renilla luciferase micro-RNA target knockdown experiments (P < 0.05) and detection of specific micro-RNAs by in situ hybridization in the brains of patients with or without multiple sclerosis. Levels of important neurosteroids, including allopregnanolone, were suppressed in the white matter of patients with multiple sclerosis (P < 0.05). Induction of the murine micro-RNAs, miR-338 and miR-155, accompanied by diminished expression of neurosteroidogenic enzymes and allopregnanolone, was also observed in the brains of mice with experimental autoimmune encephalomyelitis (P < 0.05). Allopregnanolone treatment of the experimental autoimmune encephalomyelitis mouse model limited the associated neuropathology, including neuroinflammation, myelin and axonal injury and reduced neurobehavioral deficits (P < 0.05). These multi-platform studies point to impaired neurosteroidogenesis in both multiple sclerosis and experimental autoimmune encephalomyelitis. The findings also indicate that allopregnanolone and perhaps other neurosteroid-like compounds might represent potential biomarkers or therapies for multiple sclerosis.
doi:10.1093/brain/awr200
PMCID: PMC4141444  PMID: 21908875
microRNA; multiple sclerosis; experimental autoimmune encephalomyelitis; neurosteroid

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