Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies.

Aggression and deficient cognitive control problems are widespread in psychiatric disorders, including major depressive disorder (MDD). These abnormalities are known to contribute significantly to the accompanying functional impairment and the global burden of disease. Progress in the development of targeted treatments of excessive aggression and accompanying symptoms has been limited, and there exists a major unmet need to develop more efficacious treatments for depressed patients. Due to the complex nature and the clinical heterogeneity of MDD and the lack of precise knowledge regarding its pathophysiology, effective management is challenging. Nonetheless, the aetiology and pathophysiology of MDD has been the subject of extensive research and there is a vast body of the latest literature that points to new mechanisms for this disorder. Here, we overview the key mechanisms, which include neuroinflammation, oxidative stress, insulin receptor signalling and abnormal myelination. We discuss the hypotheses that have been proposed to unify these processes, as many of these pathways are integrated for the neurobiology of MDD. We also describe the current translational approaches in modelling depression, including the recent advances in stress models of MDD, and emerging novel therapies, including novel approaches to management of excessive aggression, such as anti-diabetic drugs, antioxidant treatment and herbal compositions.

Immunomodulatory effects of new phytotherapy on human macrophages and TLR4- and TLR7/8-mediated viral-like inflammation in mice.

Background: While all efforts have been undertaken to propagate the vaccination and develop remedies against SARS-CoV-2, no satisfactory management of this infection is available yet. Moreover, poor availability of any preventive and treatment measures of SARS-CoV-2 in economically disadvantageous communities aggravates the course of the pandemic. Here, we studied a new immunomodulatory phytotherapy (IP), an extract of blackberry, chamomile, garlic, cloves, and elderberry as a potential low-cost solution for these problems given the reported efficacy of herbal medicine during the previous SARS virus outbreak. Methods: The key feature of SARS-CoV-2 infection, excessive inflammation, was studied in in vitro and in vivo assays under the application of the IP. First, changes in tumor-necrosis factor (TNF) and lnteurleukin-1 beta (IL-1ß) concentrations were measured in a culture of human macrophages following the lipopolysaccharide (LPS) challenge and treatment with IP or prednisolone. Second, chronically IP-pre-treated CD-1 mice received an agonist of Toll-like receptors (TLR)-7/8 resiquimod and were examined for lung and spleen expression of pro-inflammatory cytokines and blood formula. Finally, chronically IP-pre-treated mice challenged with LPS injection were studied for "sickness" behavior. Additionally, the IP was analyzed using high-potency-liquid chromatography (HPLC)-high-resolution-mass-spectrometry (HRMS). Results: LPS-induced in vitro release of TNF and IL-1ß was reduced by both treatments. The IP-treated mice displayed blunted over-expression of SAA-2, ACE-2, CXCL1, and CXCL10 and decreased changes in blood formula in response to an injection with resiquimod. The IP-treated mice injected with LPS showed normalized locomotion, anxiety, and exploration behaviors but not abnormal forced swimming. Isoquercitrin, choline, leucine, chlorogenic acid, and other constituents were identified by HPLC-HRMS and likely underlie the IP immunomodulatory effects. Conclusions: Herbal IP-therapy decreases inflammation and, partly, "sickness behavior," suggesting its potency to combat SARS-CoV-2 infection first of all via its preventive effects.

Increased Oxidative Stress in the Prefrontal Cortex as a Shared Feature of Depressive- and PTSD-Like Syndromes: Effects of a Standardized Herbal Antioxidant.

Major depression (MD) and posttraumatic stress disorder (PTSD) share common brain mechanisms and treatment strategies. Nowadays, the dramatically developing COVID-19 situation unavoidably results in stress, psychological trauma, and high incidence of MD and PTSD. Hence, the importance of the development of new treatments for these disorders cannot be overstated. Herbal medicine appears to be an effective and safe treatment with fewer side effects than classic pharmaca and that is affordable in low-income countries. Currently, oxidative stress and neuroinflammation attract increasing attention as important mechanisms of MD and PTSD. We investigated the effects of a standardized herbal cocktail (SHC), an extract of clove, bell pepper, basil, pomegranate, nettle, and other plants, that was designed as an antioxidant treatment in mouse models of MD and PTSD. In the MD model of "emotional" ultrasound stress (US), mice were subjected to ultrasound frequencies of 16-20 kHz, mimicking rodent sounds of anxiety/despair and "neutral" frequencies of 25-45 kHz, for three weeks and concomitantly treated with SHC. US-exposed mice showed elevated concentrations of oxidative stress markers malondialdehyde and protein carbonyl, increased gene and protein expression of pro-inflammatory cytokines interleukin (IL)-1ß and IL-6 and other molecular changes in the prefrontal cortex as well as weight loss, helplessness, anxiety-like behavior, and neophobia that were ameliorated by the SHC treatment. In the PTSD model of the modified forced swim test (modFST), in which a 2-day swim is followed by an additional swim on day 5, mice were pretreated with SHC for 16 days. Increases in the floating behavior and oxidative stress markers malondialdehyde and protein carbonyl in the prefrontal cortex of modFST-mice were prevented by the administration of SHC. Chromatography mass spectrometry revealed bioactive constituents of SHC, including D-ribofuranose, beta-D-lactose, malic, glyceric, and citric acids that can modulate oxidative stress, immunity, and gut and microbiome functions and, thus, are likely to be active antistress elements underlying the beneficial effects of SHC. Significant correlations of malondialdehyde concentration in the prefrontal cortex with altered measures of behavioral despair and anxiety-like behavior suggest that the accumulation of oxidative stress markers are a common biological feature of MD and PTSD that can be equally effectively targeted therapeutically with antioxidant therapy, such as the SHC investigated here.

Ultrasound stress compromises the correlates of emotional-like states and brain AMPAR expression in mice: effects of antioxidant and anti-inflammatory herbal treatment.

The modern lifestyle is associated with exposure to "psychological" or "emotional" stress. A growing portion of the population is exposed to emotional stress that results in a high incidence of anxiety disorders, a serious social problem. With this rise, there is a need for understanding the neurobiological causes of stress-induced anxiety and to offer safe remedies for this condition. Side effects of existing pharmaceuticals necessitate the search for alternatives. Having fewer adverse effects than classic remedies, natural extract-based therapies can be a promising solution. Here, we applied a model of emotional stress in BALB/c mice using ultrasound exposure to evoke the signs of anxiety-like behavior. We examined the behavioral and molecular impact of ultrasound and administration of herbal antioxidant/anti-inflammatory treatment (HAT) on AMPA receptor expression, markers of plasticity, inflammation and oxidative stress. A 3-week ultrasound exposure increased scores of anxiety-like behaviors in the standard tests and altered hippocampal expression as well as internalization of AMPA receptor subunits GluA1-A3. Concomitant treatment with HAT has prevented increases of anxiety-like behaviors and other behavioral changes, normalized hippocampal malondialdehyde content, GSK3ß and pro-inflammatory cytokines Il-1ß and Il-6, and the number of Ki67-positive cells. Levels of malondialdehyde, a common measure of oxidative stress, significantly correlated with the investigated end-points in stressed, but not in non-stressed animals. Our results emphasize the role of oxidative stress in neurobiological abnormalities associated with experimentally induced condition mimicking emotional stress in rodents and highlight the potential therapeutic use of anti-oxidants like herbal compositions for management of stress-related emotional disturbances within the community.

Ultrasound of alternating frequencies and variable emotional impact evokes depressive syndrome in mice and rats.

Emotional stress is primarily triggered by the cognitive processing of negative input; it is regarded as a serious pathogenetic factor of depression that is challenging to model in animals. While available stress paradigms achieve considerable face and construct validity in modelling depressive disorders, broader use of naturalistic stressors instead of the more prevalent models with artificial challenges inducing physical discomfort or pain may substantially contribute to the development of novel antidepressants. Here, we investigated whether a 3-week exposure of Wistar rats and Balb/c mice to unpredictably alternating frequencies of ultrasound between the ranges of 20-25 and 25-45kHz, which are known to correspond with an emotionally negative and with a neutral emotional state, respectively, for small rodents in nature, can induce behavioural and molecular depressive-like changes. Both rats and mice displayed decreased sucrose preference, elevated "despair" behaviour in a swim test, reduced locomotion and social exploration. Rats showed an increased expression of SERT and 5-HT2A receptor, a decreased expression of 5-HT1A receptor in the prefrontal cortex and hippocampus, diminished BDNF on gene and protein levels in the hippocampus. Fluoxetine, administered to rats at the dose of 10mg/kg, largely precluded behavioural depressive-like changes. Thus, the here applied paradigm of emotional stress is generating an experimental depressive state in rodents, which is not related to any physical stressors or pain. In essence, this ultrasound stress model, besides enhancing animal welfare, is likely to provide improved validity in the modelling of clinical depression and may help advance translational research and drug discovery for this disorder.

Altered emotionality, hippocampus-dependent performance and expression of NMDA receptor subunit mRNAs in chronically stressed mice.

N-Methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission in the hippocampus is implicated in cognitive and emotional disturbances during stress-related disorders. Here, using quantitative RT-PCR, we investigated the hippocampal expression of NR2A, NR2B and NR1 subunit mRNAs in a mouse stress paradigm that mimics clinically relevant conditions of simultaneously affected emotionality and hippocampus-dependent functions. A 2-week stress procedure, which comprised ethologically valid stressors, exposure to a rat and social defeat, was applied to male C57BL/6J mice. For predation stress, mice were introduced into transparent containers that were placed in a rat home cage during the night; social defeat was applied during the daytime using aggressive CD1 mice. This treatment impaired hippocampus-dependent performance during contextual fear conditioning. A correlation between this behavior and food displacement performance was demonstrated, suggesting that burrowing behavior is affected by the stress procedure and is hippocampus-dependent. Stressed mice (n = 22) showed behavioral invigoration and anomalous anxiolytic-like profiles in the O-maze and brightly illuminated open field, unaltered short-term memory in the step-down avoidance task and enhanced aggressive traits, as compared to non-stressed mice (n = 10). Stressed mice showed increased basal serum corticosterone concentrations, hippocampal mRNA expression for the NR2A subunit of the NMDAR and in the NR2A/NR2B ratio; mRNA expression of NR2B and NR1 was unchanged. Thus, stress-induced aberrations in both hippocampal-dependent performance and emotional abnormalities are associated with alterations in hippocampal mRNA NR2A levels and the NR2A/NR2B ratio and not with mRNA expression of NR2B or NR1.

Hippocampal gene expression of deiodinases 2 and 3 and effects of 3,5-diiodo-L-thyronine T2 in mouse depression paradigms.

Central thyroid hormone signaling is important in brain function/dysfunction, including affective disorders and depression. In contrast to 3,3',5-triiodo-L-thyronine (T3), the role of 3,5-diiodo-L-thyronine (T2), which until recently was considered an inactive metabolite of T3, has not been studied in these pathologies. However, both T3 and T2 stimulate mitochondrial respiration, a factor counteracting the pathogenesis of depressive disorder, but the cellular origins in the CNS, mechanisms, and kinetics of the cellular action for these two hormones are distinct and independent of each other. Here, Illumina and RT PCR assays showed that hippocampal gene expression of deiodinases 2 and 3, enzymes involved in thyroid hormone regulation, is increased in resilience to stress-induced depressive syndrome and after antidepressant treatment in mice that might suggest elevated T2 and T3 turnover in these phenotypes. In a separate experiment, bolus administration of T2 at the doses 750 and 1,500 mcg/kg but not 250 mcg/kg in naive mice reduced immobility in a two-day tail suspension test in various settings without changing locomotion or anxiety. This demonstrates an antidepressant-like effect of T2 that could be exploited clinically. In a wider context, the current study suggests important central functions of T2, whose biological role only lately is becoming to be elucidated.

Blond hair removal using ELOS systems.

OBJECTIVE: The aim of this study was to test blond hair removal using the ELOS system, which is optical energy and radio-frequency combined. METHODS: Seventeen patients with blond hair were randomly selected from the Department of Lasertherapy, Medical Centre Maastricht, The Netherlands. The mean age of the patients was 57.4 years. The mean energy used per patient was 23.2 J/cm2 and the mean radio-frequency was 18.6 J/cm2. RESULTS: A mean hair reduction of 57.4% was obtained with a mean of 8.5 treatments. There was a trend found between hair removal and the number of treatments. No correlation was found between the percentage of hair removal and age. Furthermore, there was no correlation between hair removal and the device's technical data. No major side effects were observed postoperatively. CONCLUSIONS: This study showed that ELOS can effectively be used for blond hair reduction.

Effective treatment of rosacea using intense pulsed light systems.

BACKGROUND: To date, a variety of lasers have been used for treating vascular skin lesions. Intense pulsed light (IPL) is a proven technology for vascular lesion management, such as rosacea. OBJECTIVES: The aim of this study was to test the effectiveness of IPL in treating vascular facial lesions in rosacea patients. METHODS: Sixty patients presenting with telangiectasia owing to facial rosacea were selected randomly from the patient population in the Department of Laser Therapy at the Medical Centre Maastricht, the Netherlands. Patients of various skin types (Fitzpatrick I-IV) were selected with an average age of 44.2 years. Five hundred eight sites were treated, with a mean of 4.1 treatments per site and an IPL spectrum ranging from 515 to 1,200 nm with different pulse durations between 4.3 and 6.5 milliseconds. The energy density varied from 25 to 35 J/cm2. RESULTS: Patients were assessed clinically and photographically. A mean clearance of 77.8% was achieved and was maintained for a follow-up period averaging 51.6 months (range 12-99 months). No correlation was found between the clearance of rosacea and patient-related or technical data. For approximately 3 years post-treatment, lesion recurrence was noted in 4 of the 508 treated facial sites. DISCUSSION: This study demonstrated that IPL treatment of facial rosacea is effective in obtaining clearance of 77.8%, with minimal side effects, and that treatment effects are maintained. CONCLUSION: The IPL system, with its broad range of technical variables, is an effective tool in achieving meaningful and lasting rosacea clearance.

Photodynamic therapy: new treatment for therapy-resistant plantar warts.

BACKGROUND: Plantar wart treatment remains a challenging one. Various treatment modalities have been previously used and are still in current use. The problem remains in the degree of response to these treatments and the side effects associated with them. OBJECTIVE: The aim of this study was to test a new treatment modality for therapy-resistant plantar warts. METHODS: Thirty-one patients with 48 plantar warts were randomly selected from the Department of Laser Therapy, Medical Centre Maastricht, The Netherlands. The mean age of the patients was 29 years (range 6-74 years). The mean incubation time was 6.8 hours, and the mean treatment time was 18.7 minutes per wart. Each wart was treated an average of 2.3 times, with a median fluence of 100 cm2. RESULTS: Forty-two of 48 (88%) warts showed a complete response. A trend was found between total clearance and size of the warts, age of the patient, and the mean treatment time. No significant side effects were seen postoperatively. CONCLUSION: This study showed that recalcitrant plantar warts were successfully treated with no significant side effects; however, the user needs sufficient experience for this new effective treatment application.

Hair reduction using intense pulsed light source.

BACKGROUND: Long-term hair removal in hirsute women remains a challenging issue. Various laser and laser-like devices are currently in use for hair removal, but little is known about the permanence of their results. This study deals with the permanence of hair removal using the intense pulsed light source (IPLS). OBJECTIVE: To test the effectiveness in long-term hair reduction. METHODS: Seventy female hirsute patients were selected in the Department of Laser Therapy at the Medical Center, Maastricht, the Netherlands. The average age of the mostly dark-haired patients of various skin types (Fitzpatrick I to V) was 41 years. They were subjected to a mean of 8 treatments (range of 2 to 23) followed for a mean period of 27.3 months. RESULTS: Using the IPLS, 87% hair removal was achieved, whereby the number of treatments correlated with the amount of hair lost. No correlation was found between hair removal and patient-related or technical data. Minimal side effects occurred in 10% of the patients. CONCLUSION: The IPLS system with its broad range of technical variables is effective in achieving long-term hair removal.