CENTRAL AND PERIPHERAL EFFECT OF MPTP VIA DOSE-DEPENDENT MAGNESIUM MODULATION.

Background: Recent studies suggested that MPTP could cause gastrointestinal motility deficits additionally to its nonconclusive and controverted effects on the CNS (behavior and brain oxidative stress) in rats. A possible interaction between MPTP typical impairments and magnesium modulatory potential was previously suggested, as magnesium role was described in neuroprotection, gastrointestinal function, and oxidative stress. Aim: To investigate the possible modulatory effect of several magnesium intake formulations (via drinking water) in MPTP neurotoxicity and functional gastrointestinal impairment induction. Materials and Methods: Adult male Wistar rats were subjected to 3-week magnesium intake-controlled diets (magnesium depleted food and magnesium enriched drinking water) previously to acute subcutaneous MPTP treatment (30 mg/ kg body weight). Gastrointestinal motility (one hour stool collection test), and behavioral patterns (Y maze task, elevated plus maze test, open field test, forced swim test) were evaluated. Followingly, brain and bowel samples were collected, and oxidative stress was evaluated (glutathione peroxidase activity, malondial-dehyde concentrations). Results: MPTP could lead to magnesium intake-dependent constipation-like gastrointestinal motility impairments, anxiety- and depressive-like affective behavior changes, and mild pain tolerance defects. Also, we found similar brain and intestinal patterns in magnesium-dependent oxidative stress. Conclusion: While the MPTP effects in normal magnesium intake could be regarded as not fully relevant in rat models and limited to the current experimental conditions, the abnormalities observed in the affective behavior, gastrointestinal status, pain tolerance, peripheric and central oxidative status could be indicative of the extent of the systemic effects of MPTP that are not restricted to the CNS level, but also to gastro-intestinal system.

Preclinical Considerations about Affective Disorders and Pain: A Broadly Intertwined, yet Often Under-Explored, Relationship Having Major Clinical Implications.

Background: Pain, a distinctive undesirable experience, encompasses several different and fluctuating presentations across varying mood disorders. Therefore, the present narrative review aimed to shed further light on the matter, accounting for both experimental animal models and clinical observations about major depressive disorder (MDD) pathology. Method: Major databases were inquired from inception until April 2016 for records about MDD and pain. Results: Pain and MDD are tightly associated with each other in a bi-directional fashion. Several cross-sectional and retrospective studies indicated a high presence of pain in the context of mood disorders, including MDD (up to 65%), but also increased prevalence rates in the case of mood disorders documented among people with a primary diagnosis of either psychological or somatic pain (prevalence rates exceeding 45%). The clinical implications of these observations suggest the need to account for mood and pain manifestations as a whole rather than distinct entities in order to deliver more effective interventions. Limitations: Narrative review, lack of systematic control groups (e.g., people with the primary diagnosis at review, but not the associated comorbidity as a study) to allow reliable comparisons. Prevalence rates and clinical features associated with pain varied across different studies as corresponding operational definitions did. Conclusions: Pain may have a detrimental effect on the course of mood disorders-the opposite holds. Promoting a timely recognition and management of such an often neglected comorbidity would therefore represent a primary goal toward the delivery of effective, multi-disciplinary care.

Oxytocin Differentiated Effects According to the Administration Route in a Prenatal Valproic Acid-Induced Rat Model of Autism.

Background and objectives: The hormone oxytocin (OXT) has already been reported in both human and animal studies for its promising therapeutic potential in autism spectrum disorder (ASD), but the comparative effectiveness of various administration routes, whether central or peripheral has been insufficiently studied. In the present study, we examined the effects of intranasal (IN) vs. intraperitoneal (IP) oxytocin in a valproic-acid (VPA) autistic rat model, focusing on cognitive and mood behavioral disturbances, gastrointestinal transit and central oxidative stress status. Materials and Methods: VPA prenatally-exposed rats (500 mg/kg; age 90 days) in small groups of 5 (n = 20 total) were given OXT by IP injection (10 mg/kg) for 8 days consecutively or by an adapted IN pipetting protocol (12 IU/kg, 20 µL/day) for 4 consecutive days. Behavioral tests were performed during the last three days of OXT treatment, and OXT was administrated 20 minutes before each behavioral testing for each rat. Biochemical determination of oxidative stress markers in the temporal area included superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA). A brief quantitative assessment of fecal discharge over a period of 24 hours was performed at the end of the OXT treatment to determine differences in intestinal transit. Results: OXT improved behavioral and oxidative stress status in both routes of administration, but IN treatment had significantly better outcome in improving short-term memory, alleviating depressive manifestations and mitigating lipid peroxidation in the temporal lobes. Significant correlations were also found between behavioral parameters and oxidative stress status in rats after OXT administration. The quantitative evaluation of the gastrointestinal (GI) transit indicated lower fecal pellet counts in the VPA group and homogenous average values for the control and both OXT treated groups. Conclusions: The data from the present study suggest OXT IN administration to be more efficient than IP injections in alleviating autistic cognitive and mood dysfunctions in a VPA-induced rat model. OXT effects on the cognitive and mood behavior of autistic rats may be associated with its effects on oxidative stress. Additionally, present results provide preliminary evidence that OXT may have a balancing effect on gastrointestinal motility.

Preliminary Data on Some Behavioral Changes Induced by Short-Term Intraperitoneal Oxytocin Administration in Aged Rats.

INTRODUCTION: Oxytocin (OT) is a well-known neuropeptides which together with vasopressin, melatonin, insulin and other hormones can alter both behavior and physiological or neuronal functions. This growing interest on OT roles is also based on the demonstrated beneficial effects as a stress reliever and a social bonding agent. The association between old age and OT was only vaguely studied. Little or few is known on the effect of the OT hormone on the old body. Hereby, we present our preliminary results in the research on behavioral changes regarding the intraperitoneal administration of OT in aged rats. SUBJECTS AND METHODS: OT was administered for 8 days in Wistar aged rats in parallel with saline administration for control group. Behavioral markers were assessed in some specific behavioral tasks, such as the Y-Maze test for short-term working memory, Open Field test, Elevated Plus Maze, and Forced Swim test for anxious and depressive behavior assessment, and Three-chambered Maze test for sociability assessment. RESULTS: Increased mobility and decreased anxiety behaviors were reported for the aged intraperitoneal OT-treated animals, as compared with controls, during FST and OFT, and respectively FST, EPM, and OFT. Also, decreased depressive-like behaviors were observed in the same animal group during FST and ST. Moreover, a decrease in anxiolytic behavior was observed as exposed to stressful stimuli (such as grooming behavior in OFT, and forced grooming behavior in ST), and as exposed to social stimuli (such as grooming behavior in TCT). Similarly, significant differences were obtained regarding the social behavior of the intraperitoneal OT-treated animal as compared to control group, the animals showing increased sociability and social preference for the stranger animal in TCT. However, no significant effects on the working memory (assessed as spontaneous alternation in YMT) were observed. CONCLUSIONS: Intraperitoneal administration of OT in aged rats has clear effects on anxious and depressive behavior, but no significant effects on the working memory. Also, several beneficial effects of OT on social preferences and sociability were observed.

Ficus sycomorus extract reversed behavioral impairment and brain oxidative stress induced by unpredictable chronic mild stress in rats.

BACKGROUND: Stress, regardless of its nature is nowadays recognized as one of the major risk factors for neuropsychiatric diseases, such as mood and anxiety disorders. The brain compared with other organs is more vulnerable to oxidative damage mainly due to its high rate of oxygen consumption, abundant lipid content, and relative insufficiency of antioxidant enzymes. Thus, the identification of neural mechanisms underlying resistance and vulnerability to stress is of crucial importance in understanding the pathophysiology of neuropsychiatric disorders and in developing new treatments, since the existing ones are for several reasons subject to increasing limitations. This study was aimed to assess the effects of hydromethanolic extract of Ficus sycomorus stem bark on depression, anxiety and memory impairment induced by unpredictable chronic mild stress (UCMS) in rats. METHODS: These effects were studied using anxiety-related behavior, depression-related behavior, anhedonia-like behavior and the Y maze task. Sucrose test was performed twice (before and after UCMS) to assess anhedonia in rats. Liquid chromatography-mass spectrometry analysis of the extract were performed. The antioxidant activities of the extract were assessed using total glutathione (GSH) content and malondialdehyde (MDA) level (lipid peroxidation) in the rat temporal lobe homogenates. RESULTS: The extract of F. sycomorus in a dose of 100 mg/kg significantly increased the sucrose consumption and the swimming time which had been reduced by the unpredictable chronic mild stress (p < 0.001). The extract also significantly reduced (p < 0.01) the latency time in the novelty-suppressed feeding test. In the elevated plus-maze, the extract (100 and 200 mg/kg) significantly reduced (p < 0.01) the time and the number of entries into the closed arms. The treatment with the extracts also significantly increased alternation in the Y-maze (p < 0.01 for 100 mg/kg). The extract significantly increased the total GSH content and reduced MDA level in rat temporal lobe. For the LC-MS analysis, the major compound in the extract was a flavonoid with formula C22H28O14. CONCLUSIONS: F. sycomorus reversed the harmful effects of UCMS on mood and behaviors in rats and it possesses an antidepressant property that is at least in part mediated through the oxidative pathway.

Correction to: Ficus sycomorus extract reversed behavioral impairment and brain oxidative stress induced by unpredictable chronic mild stress in rats.

CORRECTION: After the publication of this article [1] it came to our attention that Harquin Simplice Foyet was incorrectly included as Harquin Simplice Harquin Foyet. The corrected name is included in the author list. The original article was updated.

Pain manifestations in schizophrenia - clinical and experimental aspects in human patients and animal models.

Pain is a subjective phenomenon, not fully understood, which is manifesting abnormally in most of the disorders. Also, in the case of schizophrenia, a psychiatric disorder marked by gross distortion from reality, disturbances in thinking, feeling and behavior, pain behaves in an unpredictable manner, just like the evolution of this mental disorder. In this way, findings on this matter are contradictory, some pleading for decreased pain perception in schizophrenia, others for increased pain sensitivity, while there are also reports stating no differences between healthy controls and schizophrenic patients. Still, it is now generally accepted that pain perception is impaired in various ways in schizophrenics. Nevertheless, pain is a very important clinical issue in this population that needs to be clarified. Throughout this paper, we are going to review these contradictory information regarding pain manifestations in the context of schizophrenia in both human patients and animal models, emphasizing the importance of determining pain mechanism, its particularities and evolution in the context of schizophrenic disease, so that this phenomenon could be evaluated, quantified and controlled with the intention of obtaining a superior management for this disorder and to possibly raise hopes of higher life quality and expectancy in patients suffering from schizophrenia. Also, we would like to raise awareness on this matter, making psychiatrists, general practitioners, and other medical specialists more conscious of the importance of this problem, so that medical care could improve for these patients in the future.

Minireview on the Connections between the Neuropsychiatric and Dental Disorders: Current Perspectives and the Possible Relevance of Oxidative Stress and Other Factors.

Although the connections between neuropsychiatric and dental disorders attracted the attention of some research groups for more than 50 years now, there is a general opinion in the literature that it remains a clearly understudied and underrated topic, with many unknowns and a multitude of challenges for the specialists working in both these areas of research. In this way, considering the previous experience of our groups in these individual matters which are combined here, we are summarizing in this minireport the current status of knowledge on the connections between neuropsychiatric and dental manifestations, as well as some general ideas on how oxidative stress, pain, music therapy or even irritable bowel syndrome-related manifestations could be relevant in this current context and summarize some current approaches in this matter.

Favorite Music Mediates Pain-related Responses in the Anterior Cingulate Cortex and Skin Pain Thresholds.

PURPOSE: Music therapy is widely used to enhance well-being, reduce pain, and distract patients from unpleasant symptoms in the clinical setting. However, the degree to which music modulates pain perception is unknown. The medial pain pathway including the limbic system is associated with emotion, but how music alters pathway activity is unclear. The aim of the study was to investigate pain thresholds and pain-related responses in the anterior cingulate cortex (ACC) and whether they were modulated when subjects listened to their favorite music genre. SUBJECTS AND METHODS: First, 30 subjects were examined for left forearm pain threshold using electrical stimulation with Pain Vision PS-2011N. The pain thresholds with and without music were compared. Second, when an 80-µA current from Pain Vision was applied to the left ankle of eight women, the pain-related responses of the ACC with and without music were observed with functional magnetic resonance device (fMRI). The changes in the pain-related activity in both parameters were discussed. RESULTS: The median pain threshold with favorite music was 38.9 µA, compared to 29.0 µA without, which was significantly different (p<0.0001). The men's thresholds were significantly higher than women's both with music (p<0.05) and without music (p<0.01). The pain threshold in women was more strongly affected by music than in men. The fMRI results showed that the pain-related response in the ACC in five of eight subjects was attenuated while they listened to their favorite music. No change was observed in the other three subjects. CONCLUSION: The present findings suggest that pain perception might be strongly affected by listening to favorite music, possibly through modulation of pain-related responses in the ACC.

Describing some behavioural animal models of anxiety and their mechanistics with special reference to oxidative stress and oxytocin relevance.

It is now generally accepted that animal studies are playing an important role in the understanding of anxiety disorders, since they contribute to the current knowledge regarding the mechanisms and possible therapeutic approaches in anxiety. In the present review we will detail some essential aspects of behavioral animal models of anxiety related to social defeat paradigm, elevated plus maze, elevated zero or T maze, light/dark box, social interaction test or tests based on predator models, considering the latest theories and methodological approaches in this area of research, as well as our previous studies focusing on anxiety manifestations in a variety of species including rats, zebrafish, dogs and pigs. Moreover, in this context, we will focus on the recent theories concerning oxidative stress, as well as importance of oxytocin administration (especially the intranasal route). This could be important considering that these two factors are currently being investigated as possible mechanisms (oxidative stress status) and related therapeutic target (both intranasal oxytocin and antioxidants) in the pathology of the anxiety disorders.

Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches.

The correlation between the affective disorders and the almost ubiquitous pathological oxidative stress can be described in a multifactorial way, as an important mechanism of central nervous system impairment. Whether the obvious changes which occur in oxidative balance of the affective disorders are a part of the constitutive mechanism or a collateral effect yet remains as an interesting question. However it is now clear that oxidative stress is a component of these disorders, being characterized by different aspects in a disease-dependent manner. Still, there are a lot of controversies regarding the relevance of the oxidative stress status in most of the affective disorders and despite the fact that most of the studies are showing that the affective disorders development can be correlated to increased oxidative levels, there are various studies stating that oxidative stress is not linked with the mood changing tendencies. Thus, in this minireview we decided to describe the way in which oxidative stress is involved in the affective disorders development, by focusing on the main oxidative stress markers that could be used mechanistically and therapeutically in these deficiencies, the genetic perspectives, some antioxidant approaches, and the relevance of some animal models studies in this context.