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Abstract: The effects of intrahippocampal administration of nicotine and the neurosteroids pregnenolone sulfate and allopregnanolone on acquiring the lever-press response and extinction in a Skinner box were examined using voluntary alcohol-drinking rats. A free-choice drinking procedure that implies early availability of the alcoholic solution (10% ethanol v/v+3% glucose w/v in distilled water) was used. Alcohol and control rats were deprived of food and assigned at random to six groups. Each group received two consecutive intrahippocampal (dorsal CA1) injections immediately after 1-h of drinking ethanol and before the free lever-press response shaping and extinction session. The groups were: saline–saline; saline–pregnenolone sulfate (5 ng, 24μM); saline–allopregnanolone (0.2μg, 1.26μM); nicotine (4.6μg, 20mM)–saline; nicotine–pregnenolone sulfate; nicotine–allopregnanolone. Blood alcohol concentrations were assessed the day before conditioning. The combination of the oral self-administration of ethanol and the intrahippocampal injection of nicotine deteriorated the ability to acquire the lever-press response. This effect was neutralized by intrahippocampal pregnenolone sulfate (negative modulator of the GABAA receptor complex), and it was not affected by intrahippocampal allopregnanolone (positive GABA receptor complex A modulator). Pregnenolone sulfate and allopregnanolone had no effects per se on lever-press acquisition, neither in alcohol-drinking rats nor in controls. Alcohol consumption facilitated operant extinction just as anxiolytics that act as positive modulators of the GABA receptor complex A receptors do, possibly reducing the anxiety or aversion related to non-reinforcement. This effect was increased by intrahippocampal nicotine. [Copyright &y& Elsevier]

Mutations in mitochondrial energy-producing genes lead to a heterogeneous group of untreatable disorders known as primary mitochondrial diseases (MD). Leigh syndrome (LS) is the most common pediatric MD and is characterized by progressive neuromuscular affectation and premature death. Here, we show that daily cannabidiol (CBD) administration significantly extends lifespan and ameliorates pathology in two LS mouse models, and improves cellular function in fibroblasts from LS patients. CBD delays motor decline and neurodegenerative signs, improves social deficits and breathing abnormalities, decreases thermally induced seizures, and improves neuropathology in affected brain regions. Mechanistically, we identify peroxisome proliferator-activated receptor gamma (PPARγ) as a key nuclear receptor mediating CBD's beneficial effects, while also providing proof of dysregulated PPARγ expression and activity as a common feature in both mouse neurons and fibroblasts from LS patients. Taken together, our results provide the first evidence for CBD as a potential treatment for LS., (© 2024. The Author(s).)

Purpose: Trocar site incisional hernia (TSIH) is a common complication of laparoscopic surgery. In the scientific literature there are few descriptions of methods or tools for its prevention. The aim of this report was to assess the effectiveness and safety of a prophylactic measure designed to lower rates of TSIH., Methods: A multicenter randomized double-blinded clinical trial was performed in high-risk patients (diabetes mellitus and/or age ≥ 70 years and/or BMI ≥ 30 kg/m 2 and/or extended incision for specimen retrieval) who underwent either elective or emergency laparoscopic cholecystectomy. Patients were assigned to prophylactic onlay polypropylene mesh fixation (intervention) or to standard trocar closure (control). The main aim was to analyze the efficacy of the intervention, taking occurrence of TSIH as the primary outcome. Clinical and radiological follow up lasted at least one year after surgery. Secondary endpoints were technique-related complications (surgical site occurrences)., Results: One hundred and forty-three patients were randomized and finally 116 were analyzed (64 in the intervention arm and 52 in the control arm). Groups were homogeneous. Mean [SD] age, 65 [18] years; 86 (60.6%) were women. The cumulative TSIH incidence was lower in the intervention group although the differences did not reach statistical significance, assessed either radiologically (16 [25.4%] vs 17 [31.5%], p = 0.538) or clinically (9 [16.1%] vs 9 [20], p = 0.613). No differences in surgical site infection, hematoma or seroma were detected. Mean follow-up was 670 days (range 223-1294)., Conclusion: Our results show that, when properly assessed, the overall TSIH incidence is extremely high. Although polypropylene onlay mesh placement is safe, it does not appear to be effective in reducing the TSIH incidence rate. Radiological evaluation may be more accurate., Trial Registration: ClinicalTrials.org NCT03495557. Date of registration: April 12, 2018., (© 2024. The Author(s).)

Early postnatal neuroactive steroids (NAS) play a significant role in the neurodevelopment. Their alteration can modify adult behavior, such as anxiety or learning. For this reason, we set out to observe if neonatal NAS levels alteration affects two types of learning implying low or high levels of emotional content, such as recognition memory and aversive learning respectively. Thus, we tested allopregnanolone or finasteride administered from postnatal days 5-9. In adulthood, recognition memory was assessed using the object recognition test, as well as aversive learning throughout the passive avoidance test (PA). Because of the important emotional component of PA, which can be influencing learning, we evaluated anxiety-like behavior by means of the open field test (OF). The results indicated that those animals administered with finasteride showed higher recognition levels of a familiar object. On the other hand, they showed an impairment in a stressful learning, such as PA. However, no effects of finasteride were observed on anxiety-like behavior in OF, despite it has been reported that neonatal finasteride treatment can promote an anxiety-like profile in the elevated plus-maze test in adulthood. Regarding neonatal allopregnanolone, animals showed higher levels in OF exploration only when they were already familiar with the apparatus. Furthermore, neonatal allopregnanolone did not affect recognition memory or aversive learning. In conclusion, the neonatal NAS manipulation by means of finasteride differently affected two types of learning implying distinct stress levels. Altogether, the results show the importance of the emotional content to explain the effects of neonatal NAS manipulation on learning., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Several studies have highlighted the role that early postnatal levels of allopregnanolone play in the development of the CNS and adult behavior. Changes in allopregnanolone levels related to stress have been observed during early postnatal periods, and perinatal stress has been linked to neuropsychiatric disorders. The alteration of early postnatal allopregnanolone levels in the first weeks of life has been proven to affect adult behaviors, such as anxiety-related behaviors and the processing of sensory inputs. This review focuses on the first studies about the possible relationship between the early postnatal allopregnanolone levels and the vulnerability to abuse of drugs such as alcohol in adulthood, given that (1) changes in neonatal allopregnanolone levels affect novelty exploration and novelty seeking has been linked to vulnerability to drug abuse; (2) early postnatal administration of progesterone, the main allopregnanolone precursor, affects the maturation of dopaminergic meso-striatal systems, which have been related to novelty seeking and drug abuse; and (3) alcohol consumption increases plasma and brain allopregnanolone levels in animals and humans. Manipulating neonatal allopregnanolone by administering finasteride, an inhibitor of the 5α-reductase enzyme that participates in allopregnanolone synthesis, increases alcohol consumption and decreases the locomotor stimulant effects of low alcohol doses. At a molecular level, finasteride decreases dopamine and serotonin in ventral striatum and dopamine release in nucleus accumbens. Preliminary results suggest that serotonin 5HT3 receptors could also be affected. Although an in-depth study is necessary, evidence suggests that there is a relation between early postnatal allopregnanolone and vulnerability to drug use/abuse., (© 2019 Published by Elsevier Inc.)

Planarians are remarkable organisms that can regenerate their entire body from a tiny portion thereof. This capability is made possible by the persistence throughout the lifespan of these animals of a population of pluripotent stem cells known as neoblasts. Planarian neoblasts include both pluripotent stem cells and specialized lineage-committed progenitors that give rise to all mature cell types during regeneration and homeostatic cell turnover. However, little is known about the mechanisms that regulate neoblast differentiation. A recent study demonstrated that Smed-egfr-1, a homologue of the epidermal growth factor receptor (EGFR) family, is required for final differentiation, but not specification, of gut progenitor cells into mature cells. Given the expression by planarians of several EGFR homologues, it has been proposed that these homologues may have diverged functionally to regulate the differentiation of distinct cell types in these animals. In this study, we investigated the role of Smed-egfr-4 in eye regeneration. Compared with controls, animals in which this gene was silenced by RNA interference (RNAi) regenerated smaller eyes. Moreover, the numbers of both mature eye cell types, photoreceptor neurons and cells of the pigment cup, were significantly reduced in Smed-egfr-4(RNAi) animals. By contrast, these animals exhibited an increase in the numbers of eye progenitor cells expressing the specific markers Smed-ovo and Smed-sp6-9. These results suggest that Smed-egfr-4 is required not for the specification of eye progenitor cells but for their final differentiation, and support the view that in planarians the EGFR pathway might play a general role in regulating the differentiation of lineage-committed progenitors.

Neuroactive steroids (NS) such as allopregnanolone are crucial for brain development and adult behaviour. Early post-natal alterations of NS by administering finasteride induce a decrease in the sensitivity to stimulant effects of low alcohol doses, an increase in alcohol consumption, and a decrease in ventrostriatal dopamine and serotonin levels. The aim of the present study is to observe if the effects of the 5HT3 receptor antagonist ondansetron on initial alcohol consumption are modulated by post-natal NS manipulation. For this purpose, allopregnanolone, finasteride, or vehicle was injected from day 5 to 9. In adulthood, a novel object preference test was carried out in order to detect a possible novelty-seeking pattern in our animals, which has been related to vulnerability to drug abuse. The subjects then had access to two bottles (alcohol or control solutions) one hour daily for two consecutive weeks. Ondansetron (0.01 mg/kg, 0.1 mg/kg or vehicle) was administered before the hour of consumption in the initial phase (days 1, 2, 3) of the procedure, and after prolonged alcohol intake (days 11, 12, 13). Results indicated that finasteride animals showed a higher preference to explore the new object, as well as a higher alcohol consumption than the rest of the groups. Moreover, 0.1 mg/kg of ondansetron decreased alcohol consumption, but only in the post-natal finasteride group, suggesting a possible increase in 5HT3 receptor sensitivity in these animals. In conclusion, NS manipulation in crucial stages of development, such as early post-natal periods, seems to play an important role on the effects of ondansetron on alcohol intake and in the vulnerability to develop drug use or abuse., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Urban Health Equity Assessment and Response Tool (HEART) is a tool developed by the World Health Organization whose objective is to provide evidence on urban health inequalities so as to help to decide the best interventions aimed to promote urban health equity. The aim of this paper is to describe the experience of implementing Urban HEART in Barcelona city, both the adaptation of Urban HEART to the city of Barcelona, its use as a means of identifying and monitoring health inequalities among city neighbourhoods, and the difficulties and barriers encountered throughout the process. Although ASPB public health technicians participated in the Urban HEART Advisory Group, had large experience in health inequalities analysis and research and showed interest in implementing the tool, it was not until 2015, when the city council was governed by a new left-wing party for which reducing health inequalities was a priority that Urban HEART could be used. A provisional matrix was developed, including both health and health determinant indicators, which allowed to show how some neighbourhoods in the city systematically fare worse for most of the indicators while others systematically fare better. It also allowed to identify 18 neighbourhoods-those which fared worse in most indicators-which were considered a priority for intervention, which entered the Health in the Barcelona Neighbourhoods programme and the Neighbourhoods Plan. This provisional version was reviewed and improved by the Urban HEART Barcelona Working Group. Technicians with experience in public health and/or in indicator and database management were asked to indicate suitability and relevance from a list of potential indicators. The definitive Urban HEART Barcelona version included 15 indicators from the five Urban HEART domains and improved the previous version in several requirements. Several barriers were encountered, such as having to estimate indicators in scarcely populated areas or finding adequate indicators for the physical context domain. In conclusion, the Urban HEART tool allowed to identify urban inequalities in the city of Barcelona and to include health inequalities in the public debate. It also allowed to reinforce the community health programme Health in the Barcelona Neighbourhoods as well as other city programmes aimed at reducing health inequalities. A strong political will is essential to place health inequalities in the political agenda and implement policies to tackle them.

Neonatal neuroactive steroids levels are crucial for brain development. Alterations of neonatal neuroactive steroids levels induce anxiolytic-like effects and improve exploration in novel environments in adulthood. These behavioural traits, i.e. sensation/novelty seeking, anxiety or impulsivity, are associated with vulnerability to drug use and abuse. Adolescence is also recognized as a particularly critical developmental phase to contribute to vulnerable phenotype. However, the influence of neuroactive steroids during development in the vulnerability to drug addiction has been poorly studied. The aim of the present experiment is to study the effect of early neonatal and adolescent manipulations of neuroactive steroids on the sensitivity to the stimulant effects of ethanol in adult male rats. Therefore, allopregnanolone or finasteride, an allopregnanolone synthesis inhibitor, were injected from postnatal day 5-9. In early adolescence, half of the subjects were injected with progesterone, the main allopregnanolone precursor, and the elevated plus-maze anxiety test was performed. Results indicated that early adolescent progesterone induced anxiolytic-like effects (increase in the percentage of entries and time in open arms). Neonatal finasteride administration decreased locomotor activity induced by ethanol in adolescent vehicle subjects. Interestingly, differences induced by neonatal treatments were not present in the animals that received progesterone in the early adolescence. In conclusion, neuroactive steroid manipulations in crucial stages of development could be playing an important role in behavioural effects of alcohol such as the sensitivity to locomotor stimulation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Endogenous levels of the neurosteroid (NS) allopregnanolone (AlloP) during neonatal stages are crucial for the correct development of the central nervous system (CNS). In a recent work we reported that the neonatal administration of AlloP or finasteride (Finas), an inhibitor of the enzyme 5α-reductase needed for AlloP synthesis, altered the voluntary consumption of ethanol and the ventrostriatal dopamine (DA) levels in adulthood, suggesting that neonatal NS manipulations can increase alcohol abuse vulnerability in adulthood. Moreover, other authors have associated neonatal NS alterations with diverse dopaminergic (DAergic) alterations. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP alter the DAergic response in the nucleus accumbens (NAcc) during alcohol intake in rats. We administered AlloP or Finas from postnatal day (PND) 5 to PND9. At PND98, we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 12 days. On the last day of consumption, we measured the DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in NAcc in response to ethanol intake. The samples were obtained by means of in vivo microdialysis in freely moving rats, and DA and DOPAC levels were determined by means of high-performance liquid chromatography analysis (HPLC). The results revealed that neonatal Finas increased ethanol consumption in some days of the consumption phase, and decreased the DA release in the NAcc in response to solutions (ethanol+glucose) and food presentation. Taken together, these results suggest that neonatal NS alterations can affect alcohol rewarding properties., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Changes in endogenous neonatal levels of the neurosteroid allopregnanolone (AlloP) as well as a single 24h period of early maternal separation (EMS) on postnatal day (PND) 9 affect the development of the central nervous system (CNS), causing adolescent/adult alterations including systems and behavioural traits that could be related to vulnerability to drug abuse. In rats, some behavioural alterations caused by EMS can be neutralised by previous administration of AlloP. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP could increase adult alcohol consumption, and if EMS could change these effects. We administered AlloP or finasteride, a 5α-reductase inhibitor, from PND5 to PND9, followed by 24h of EMS at PND9. At PND70 we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 15days. Ventral striatum samples were obtained to determine monoamine levels. Results revealed that neonatal finasteride increased both ethanol and glucose consumption, and AlloP increased alcohol intake compared with neonatal vehicle-injected animals. The differences between neonatal groups in alcohol consumption were not found in EMS animals. In accordance, both finasteride and AlloP animals that did not suffer EMS showed lower levels of dopamine and serotonin in ventral striatum. Taken together, these results reveal that neonatal neurosteroids alterations affect alcohol intake; an effect which can be modified by subsequent EMS. Thus, these data corroborate the importance of the relationship between neonatal neurosteroids and neonatal stress for the correct CNS development., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The maintenance of levels of endogenous neurosteroids (NS) across early postnatal development of the brain, particularly to the hippocampus, is crucial for their maturation. Allopregnanolone (Allop) is a NS that exerts its effect mainly through the modulation of the GABAA receptor (GABAAR). During early development, GABA, acting through GABAAR, that predominantly produces depolarization shifts to hyperpolarization in mature neurons, around the second postnatal week in rats. Several factors contribute to this change including the progressive increase of the neuron-specific K(+)/Cl(-) co-transporter 2 (KCC2) (a chloride exporter) levels. Thus, we aimed to analyze whether a different profile of NS levels during development is critical and can alter this natural progression of KCC2 stages. We administrated sustained Allop (20mg/kg) or Finasteride (5α-reductase inhibitor, 50mg/kg) from the 5th postnatal day (PD5) to PD9 and assessed changes in the hippocampal expression of KCC2 at transcript and protein levels as well as its active phosphorylated state in male rats. Taken together data indicated that manipulation of NS levels during early development influence KCC2 levels and point out the importance of neonatal NS levels for the hippocampal development., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Allopregnanolone is a neurosteroid that has been reported to fluctuate during early developmental stages. Previous experiments reported the importance of neonatal endogenous allopregnanolone levels for the maturation of the central nervous system and particularly for the hippocampus. Changes in neonatal allopregnanolone levels have been related to altered adult behaviour and with psychopathological susceptibility, including anxiety disorders, schizophrenia and drug abuse. However, the mechanism underlying these changes remains to be elucidated. In the present study we assessed changes in hippocampal expression of α4 and δ GABAA receptor (GABAAR) subunits as a consequence of neonatal finasteride (a 5-α reductase inhibitor) administration during early development (PD6 to PD15) in male rats. We observed that the treatment altered the temporal window of the natural peak in the expression of these subunits during development. Additionally, the level of these subunits were higher than in non-handled and control animals in the adult hippocampus. We observed that in adulthood, neonatal finasteride-treated animals presented an anxiogenic-like profile in response to progesterone administration which was absent in the rest of the groups. In conclusion, these results corroborate the relevance of neonatal maintenance of neurosteroid levels for behavioural anxiety responses in the adult, and point to some of the mechanisms involved in this alterations.

Diverse studies indicate that the alteration of the physiological levels of neurosteroids in early neonatal phases provokes alterations in the maturation of certain cerebral structures. Allopregnanolone (ALLO) has important modulatory effects in the hippocampus during the postnatal period where the adult pattern of inhibitory transmission is being established. In order to study whether endogenous neonatal ALLO levels would be a determinant parameter involved in mediating adult hippocampal GABAA system maturation, we investigated the effects of neonatal finasteride (50mg/kg, SC) treatment and ALLO (ALLO; 20mg/kg, SC) supplementation on an animal behavioural model with relevance to neurodevelopmental disorder, such as schizophrenia. Two sets of experiments were conducted. Neonatal treatment (from postnatal day (pnd) 5 to pnd9) was performed in 23 male Wistar rats and steroid quantification was performed in hippocampal homogenates at pnd9. A second group (n=127) underwent neonatal treatment (pnd5-pnd9) and were submitted to hippocampal surgery at 80d. The behavioural response to bilateral intrahippocampal neurosteroid administration (ALLO, 0.2μg/0.5μl per side or pregnenolone sulphate 5ng/0.5μl per side) on novelty-induced exploration activity and prepulse inhibition (PPI) was assessed at 95d. Results showed that neonatal ALLO and finasteride administration decreased novelty directed exploratory behaviour and impaired the prepulse inhibition of the acoustic startle response at 95 days of age. Moreover, intrahippocampal ALLO increased head-dipping behaviour independently of the neonatal treatment, while intrahippocampal ALLO decreased PPI only in finasteride and ALLO groups. The results obtained in the present study indicate the importance of neonatal neurosteroid levels in the development of hippocampal function and their relevance in a behavioural phenotype that some have likened to that present in schizophrenia., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Endogenous neurosteroid level fluctuations are related to several emotional and behavioral alterations. Neurosteroids also have important roles during neurodevelopment, with there being a relationship between modification of their levels in neurodevelopmental periods and behavioral alterations in adolescence and adulthood. Early maternal separation (EMS) is a stressful event that also alters neurodevelopment and adolescent and adult behaviors. The aim of the present study is to analyze the interaction between the effects of the neonatal alteration of allopregnanolone (AlloP), neurosteroid that increase its levels after acute stress presentation, and EMS on adolescent exploration and adult anxiety and sensorimotor gating in male rats. AlloP (10 mg/kg s.c.) was administrated between postnatal day 5 (PN5) and PN9, and a single 24-hour period of EMS was carried out on PN9. Exploration was analyzed at PN40 and PN60. At adult age (PN85), anxiety was tested by means of the elevated plus-maze test (EPM), and sensorimotor gating by means of prepulse inhibition test (PPI). PPI deterioration has been considered as a reliable indicator of diseases such as schizophrenia. Results showed that the previous neonatal AlloP administration neutralized the effects of EMS in the adolescent exploration (increase of traveled distance and decrease of head-dips). In adult age, an anxiolytic-like profile was observed as a consequence of EMS. Finally, EMS and neonatal AlloP disrupted PPI. Taken together, these data show the important role that physiological neonatal AlloP levels and stressful events play in neural development, adult behavior and vulnerability to neurodevelopmental disorders such as schizophrenia., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Neurosteroids (NS) are well known to exert modulatory effects on ionotropic receptors. Recent findings indicate that NS could also act as important factors during development. In this sense, neonatal modifications of Allopregnanolone (Allop) levels during critical periods have been demonstrate to alter the morphology of the hippocampus but also other brain structures. The aim of the present work is to screen whether the alterations of Allop levels modify adult CA1 hippocampal response to NS administration. For this purpose, pups were injected with Allop (20 mg/kg s.c.), Finasteride (5α-reductase inhibitor that impedes Allop synthesis) (50 mg/kg s.c.) or Vehicle from postnatal day 5 (P5) to postnatal day 9 (P9). NS levels were tested at P5. To test the behavioural hippocampal response to NS in adulthood, animals were implanted with a bilateral cannula into the CA1 hippocampus at 80 days old and injected with Allop (0.2 μg/0.5 μl), Pregnenolone sulphate (5 ng/0.5 μl) or Vehicle in each hippocampus. After injections animals were tested in the Boisser test to assess exploratory behaviour, the elevated plus maze to assess anxiety and the passive avoidance to test aversive learning. Results indicate that alteration of neonatal Allop or pregnenolone levels (by Allop and Finasteride administration, respectively) suppressed intrahippocampal Allop anxiolytic effect in the EPM. Moreover our results also indicate that manipulation of neonatal Allop levels (Allop and Finast administration) alters exploratory and anxiety-like behaviour and impairs aversive learning in the adulthood. These data point out the role of Allop in the maturation of hippocampal function and behaviour., (Copyright © 2012. Published by Elsevier B.V.)

The hippocampus is a brain structure that has traditionally been associated with the pathophysiology and neuropathology of schizophrenia. Also, one of the animal models of schizophrenia most widely accepted and validated is the deterioration of prepulse inhibition (PPI). The hippocampus (both dorsal and ventral) seems to be a brain structure important for the PPI since it appears to contribute to sensorimotor gating. A possible role of neurosteroids in schizophrenia has recently been suggested, as clozapine and olanzapine treatments increase brain and plasma levels of the neurosteroid allopregnanolone (AlloP). The aim of the present work is to investigate the effects of the intrahippocampal administration of neurosteroids on prepulse inhibition. For this purpose, we have bilaterally injected AlloP (0.2 μg/0.5 μl) and pregnenolone sulphate (PregS, 5 ng/0.5 μl) into the dorsal CA1 hippocampus, and we have evaluated PPI behavior. Results show that intrahippocampal AlloP increases PPI ability regardless of prepulse intensity (5, 10 or 15 db above background). Intrahippocampal PregS administration, at the dose tested, does not significantly affect PPI performance. The increase in PPI due to intrahippocampal AlloP administration points out the important role of the hippocampus in central sensorimotor gating mechanisms and on the effects of neurosteroids on this behavior. The present findings may contribute to the study of the neurobiological basis of schizophrenia., (Copyright © 2011 Elsevier Ltd. All rights reserved.)