Level Of Central Nervous System Research Articles

Intrathecal baclofen therapy as treatment for spasticity and dystonia: Review of cases in a pediatric palliative care unit

IntroductionPatients managed in the Pediatric Palliative Care Integral Unit (PPCIU) have serious neurological conditions that involve significant damage at central nervous system level. The movement disorder is a very common clinical problem and for the patients where an adequate control of muscle tone is not achieved with usual techniques or drugs, intrathecal baclofen therapy (IBT) should be considered. Materials and methodsDescriptive retrospective study based on the review of clinical records of patients who received IBT being followed by the PPCIU of Madrid Autonomous Region in the timeframe between September 2012 and February 2021. ResultsIBT was implanted in 8 patients affected by infantile cerebral palsy (ICP) with a Gross Motor Function Scale (GMFCS) IV–V, 3 patients was a Pantothenate kinase deficit-associated neurodegeneration (PKAN), 2 had Acquired Brain Damage, and the remaining 3 had, respectively, 2 glutaric aciduria type I (GA-1), and poly-malformative syndrome. In all patients we observed a period of clinical stability after IBT, we call this period “honeymoon”. Two patients died while in the honeymoon period, at 24.9 and 19.6 months from implantation of the pump; the median of duration of the honeymoon period in the remaining 14 was 14.4 months (IQ: 8.3–25.8). ConclusionsIBT was not only used in patients with non-progressive diseases, but also in the group of patients with neurodegenerative or progressive diseases. In all of them, after implantation of the device, we have objectified a period of clinical stability and a better control of muscle tone disorders.

Melatonin as an Anti-Aging Therapy for Age-Related Cardiovascular and Neurodegenerative Diseases.

The concept of “aging” is defined as the set of gradual and progressive changes in an organism that leads to an increased risk of weakness, disease, and death. This process may occur at the cellular and organ level, as well as in the entire organism of any living being. During aging, there is a decrease in biological functions and in the ability to adapt to metabolic stress. General effects of aging include mitochondrial, cellular, and organic dysfunction, immune impairment or inflammaging, oxidative stress, cognitive and cardiovascular alterations, among others. Therefore, one of the main harmful consequences of aging is the development and progression of multiple diseases related to these processes, especially at the cardiovascular and central nervous system levels. Both cardiovascular and neurodegenerative pathologies are highly disabling and, in many cases, lethal. In this context, melatonin, an endogenous compound naturally synthesized not only by the pineal gland but also by many cell types, may have a key role in the modulation of multiple mechanisms associated with aging. Additionally, this indoleamine is also a therapeutic agent, which may be administered exogenously with a high degree of safety. For this reason, melatonin could become an attractive and low-cost alternative for slowing the processes of aging and its associated diseases, including cardiovascular and neurodegenerative disorders.

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

Motor imagery and the muscle system

Many studies have investigated the activation of cortical areas and corticospinal excitability during motor imagery (MI) in relation to motor execution. Similar activation of cortical areas during imagined and executed bodily movements and increased corticospinal excitability while imagining movements has been demonstrated. Despite these similarities on the central nervous system level, there is no overt movement during MI. This suggests that centrally generated signals must be inhibited at some level. Second, even in the absence of movement, some studies find behavioral effects of MI interventions. Most of the studies have investigated the role of MI on the cortical or spinal level, but less is known about the peripheral level, such as the muscle system. Testing muscular excitability during MI will give further hints whether and how low-threshold motor commands during MI reach the muscular system. Furthermore, the extent of the shown effects during imagery depends considerably on type of imagery, available proprioceptive information, and imagery ability. Therefore, this study investigates muscular excitability of the biceps brachii muscle manipulating imagery mode (MI vs. visual imagery) and proprioceptive information (with or without muscle effort). 40 participants were included in the analysis. The mechanical response of the muscle after a single electrical stimulus was assessed via tensiomyography. The corresponding variables maximal displacement, delay time, and contraction velocity were used to calculate 2 × 2 ANOVAs with repeated measurements. The absence of interaction effects shows that possible imagery effects on the muscle system are not increased by effort. MI altered time to contraction with lower delay time compared to control condition. Velocity and maximal displacement of the muscle belly during contraction did not differ between imagery conditions. This indicates that MI might impact on the initiation of muscle contraction but does not change the contraction itself. Thus, neuronal factors are moving further into focus in the context of MI research.

Management of Oligoprogression in Patients with Metastatic NSCLC Harboring ALK Rearrangements.

Simple SummaryThe growing efficacy and availability of new targeted systemic therapies have markedly improved the prognosis of metastatic lung cancer patients harboring ALK rearrangements. The use of effective targeted therapies capable of maintaining a prolonged control of disease, for as long as possible, is paramount to ensure the best survival outcomes. In this regard, in cases of oligoprogression, “beyond progression” systemic treatment added to local ablative therapies is considered a feasible option in an attempt to improve the quality and quantity of patients’ lives, even if based on retrospective data. Certainly, treatment of ALK rearranged lung cancer patients with oligoprogressive disease must be individualized and based on multidisciplinary decisions. Above all, when further molecular targeted therapies are available, options must always be evaluated, especially in case of cerebral progression. In this review, we provide an updated and comprehensive overview of the main treatment strategies in cases of ALK rearranged oligoprogression.Personalized treatment based on driver molecular alterations, such as ALK rearrangement, has revolutionized the therapeutic management of advanced oncogene-addicted NSCLC patients. Multiple effective ALK tyrosine kinase inhibitors (TKIs), with the amelioration of the activity at central nervous system level, are now available, leading to substantial prognosis improvement. The exposure to TKIs triggers resistance mechanisms and the sequential administration of other TKIs and chemotherapy is, for the most part, not targeted. In this context, extending the benefit deriving from precision medicine is paramount, above all, when disease progression occurs in a limited number of sites. Retrospective data indicate that, in oligoprogressive disease, targeted therapy beyond progression combined with definitive local treatment of the progressing site(s) is an effective alternative. In these cases, a multidisciplinary approach becomes essential for an integrated treatment strategy, depending on the site of disease progression, in order to improve not only survival, but also quality of life. In this review we provide an updated and comprehensive overview of the main treatment strategies in cases of ALK rearranged oligoprogression, including systemic treatment as well as local therapy, and report a real-world clinical story, with the final aim of identifying the most promising management for this subset of patients.

Exploring Neurofilament Light Chain and Exosomes in the Genetic Forms of Frontotemporal Dementia.

Differential diagnosis of neurological disorders and their subtype classification are challenging without specific biomarkers. Genetic forms of these disorders, typified by an autosomal dominant family history, could offer a window to identify potential biomarkers by exploring the presymptomatic stages of the disease. Frontotemporal dementia (FTD) is the second cause of dementia with an age of onset < 65, and its most common mutations are in GRN, C9orf72, and MAPT genes. Several studies have demonstrated that the main proteins involved in FTD pathogenesis can be secreted in exosomes, a specific subtype of extracellular vesicles able to transfer biomolecules between cells avoiding cell-to-cell contact. Neurofilament light chain (NfL) levels in central nervous system have been advocated as biomarkers of axonal injury. NfL concentrations have been found increased in FTD and have been related to disease severity and prognosis. Little information on the relationship between NfL and exosomes in FTD has been collected, deriving mainly from traumatic brain injury. Current review deals with this matter in the attempt to provide an updated discussion of the role of NfL and exosomes as biomarkers of genetic forms of FTD.

Ion Mobility Mass Spectrometry Reveals Rare Sialylated Glycosphingolipid Structures in Human Cerebrospinal Fluid.

Gangliosides (GGs) represent an important class of biomolecules associated with the central nervous system (CNS). In view of their special role at a CNS level, GGs are valuable diagnostic markers and prospective therapeutic agents. By ion mobility separation mass spectrometry (IMS MS), recently implemented by us in the investigation of human CNS gangliosidome, we previously discovered a similarity between GG profiles in CSF and the brain. Based on these findings, we developed IMS tandem MS (MS/MS) to characterize rare human CSF glycoforms, with a potential biomarker role. To investigate the oligosaccharide and ceramide structures, the ions detected following IMS MS separation were submitted to structural analysis by collision-induced dissociation (CID) MS/MS in the transfer cell. The IMS evidence on only one mobility feature, together with the diagnostic fragment ions, allowed the unequivocal identification of isomers in the CSF. Hence, by IMS MS/MS, GalNAc-GD1c(d18:1/18:1) and GalNAc-GD1c(d18:1/18:0) having both Neu5Ac residues and GalNAc attached to the external galactose were for the first time discovered and structurally characterized. The present results demonstrate the high potential of IMS MS/MS for biomarker discovery and characterization in body fluids, and the perspectives of method implementation in clinical analyses targeting the early diagnosis of CNS diseases through molecular fingerprints.

Gut microbiota signatures and modulation in irritable bowel syndrome.

Irritable bowel syndrome (IBS) affects approximately one tenth of the general population and is characterized by abdominal pain associated with abnormalities in bowel habits. Visceral hypersensitivity, abnormal intestinal motor function, mucosal immune activation, and increased intestinal permeability concur to its pathophysiology. Psychological factors can influence symptom perception at the central nervous system level. In addition, recent evidence suggests that dysbiosis may be a key pathophysiological factor in patients with IBS. Increasing understanding of the pathophysiological mechanisms translates into new and more effective therapeutic approaches. Indeed, in line with this evidence, IBS therapies nowadays include agents able to modulate gut microbiota function and composition, such as diet, prebiotics, probiotics, and antibiotics. In addition, in the last decade, an increasing interest in fecal microbiota transplantation has been paid. An in-depth understanding of the intestinal microenvironment through accurate faucal microbiota and metabolite analysis may provide valuable insights into the pathophysiology of IBS, finally shaping new tailored IBS therapies.

NR4A1 agonist cytosporone B attenuates neuroinflammation in a mouse model of multiple sclerosis.

Nuclear receptor subfamily 4 group A1 (NR4A1) is an orphan nuclear receptor, which is expressed in the majority of cells. NR4A1 expression in peripheral blood mononuclear cells is low during the preclinical stage of multiple sclerosis. Knockout of the Nr4a1 gene in mice can aggravate the symptoms of experimental autoimmune encephalomyelitis (EAE), which is an animal model of multiple sclerosis. In this study, we intragastrically administered the NR4A1 agonist cytosporone B (Csn-B) to mice after inducing EAE. After treatment with Csn-B, the clinical symptoms in the EAE mice were substantially attenuated compared with that in PBS-treated control mice. The percentages of CD4+ T cells and F4/80+ cells in the central nervous system were decreased. In addition, interferon-γ and interleukin-17 production by proinflammatory Th1/Th17 cells in the central nervous system and interferon-γ levels in splenocytes were decreased after Csn-B treatment. These findings suggest that the NR4A1 agonist Csn-B can alleviate nerve injury after EAE induction, and, therefore, may be useful as a potential treatment for multiple sclerosis.

Puncture vine (Tribulus Terrestris L.) in control of health and reproduction.

Tribulus terrestris, L. (puncture vine) have been used as a folk medicine for five thousands of years, but its targets, effects, their mechanisms and application requires further studies. This paper reviews the provenance, constituents and properties of Tribulus terrestris, L., its general physiological and health effects, as well as the currently available knowledge concerning its influence on male and female reproductive processes and their dysfunctions. Analysis of the available publications demonstrated the influence of Tribulus terrestris on a wide spectrum of targets and physiological processe and disorders. In particular, Tribulus terrestris can be a stimulator of male and female reproductive processes at the level of central nervous system, sexual behaviour, pituitary and gonadal hormones and their receptors, gonadal functions (including ovarian follicullogenesis and spermatogenesis), improvement of the quality and quantity of gametes (at least of sperm) and fecundity. This ability of puncture vine is applicable for the improvement of man's sexual desire and sperm quality in vivo and in vitro, as well as of women's libido, activation of women's reproductive organs, fecundity, and treatment of infertility, especially that related to the polycystic ovarian syndrome.

Puncture vine (Tribulus Terrestris L.) in control of health and reproduction

Tribulus terrestris, L. (puncture vine) have been used as a folk medicine for five thousands of years, but its targets, effects, their mechanisms and application requires further studies. This paper reviews the provenance, constituents and properties of Tribulus terrestris, L., its general physiological and health effects, as well as the currently available knowledge concerning its influence on male and female reproductive processes and their dysfunctions. Analysis of the available publications demonstrated the influence of Tribulus terrestris on a wide spectrum of targets and physiological processe and disorders. In particular, Tribulus terrestris can be a stimulator of male and female reproductive processes at the level of central nervous system, sexual behaviour, pituitary and gonadal hormones and their receptors, gonadal functions (including ovarian follicullogenesis and spermatogenesis), improvement of the quality and quantity of gametes (at least of sperm) and fecundity. This ability of puncture vine is applicable for the improvement of man’s sexual desire and sperm quality in vivo and in vitro, as well as of women’s libido, activation of women’s reproductive organs, fecundity, and treatment of infertility, especially that related to the polycystic ovarian syndrome.

From gut feeling to visceral pain : Effects of negative expectations in the context of the gut-brain axis

Störungen der Darm-Gehirn-Achse sind durch komplexe Dysfunktionen auf peripherer und zentralnervöser Ebene gekennzeichnet, die zu viszeraler Hypervigilanz und Hyperalgesie beitragen können und viszeralen Schmerz prägen. An der viszeralen Schmerzmodulation sind zahlreiche kognitive, emotionale und psychoneurobiologische Faktoren beteiligt, die im psychosozialen Therapiekontext das viszerale Schmerzerleben sowohl positiv als auch negativ beeinflussen können. Durch negative Erwartungen vermittelte Noceboeffekte sind bei akuten, aber insbesondere auch bei chronischen viszeralen Schmerzen von hoher klinischer Relevanz; die ihnen zugrunde liegenden Mechanismen sind jedoch bislang unzureichend verstanden. Zur Entstehung und Aufrechterhaltung negativer Erwartungseffekte tragen insbesondere verbale Instruktionen, Vorerfahrungen und Lernprozesse sowie emotionale Faktoren wie Angst und Stress bei. Gezielte Kommunikationsstrategien, ein sensibler Umgang in der Aufklärung und positive Umgebungsbedingungen können in der klinischen Praxis dazu beitragen, ein adäquates Erwartungsmanagement zu etablieren und negative Erwartungseffekte zu minimieren. Zugleich sind translationale Forschungsansätze erforderlich, um tiefere Erkenntnisse bezüglich der Mediatoren und Moderatoren negativer Erwartungseffekte zu erlangen und diese in die Klinik zu übertragen. So kann die Versorgung von Patienten mit Störungen der Darm-Gehirn-Kommunikation verbessert werden.

Amyloid Beta Dynamics in Biological Fluids-Therapeutic Impact.

Despite the significant impact of Alzheimer’s disease (AD) at individual and socioeconomic levels and the numerous research studies carried out on this topic over the last decades, the treatments available in daily clinical practice remain less than satisfactory. Among the accepted etiopathogenic hypotheses, the amyloidogenic pathway theory, although intensively studied and even sometimes controversial, is still providing relevant theoretical elements for understanding the etiology of AD and for the further development of possible therapeutic tools. In this sense, this review aims to offer new insights related to beta amyloid (Aβ), an essential biomarker in AD. First the structure and function of Aβ in normal and pathological conditions are presented in detail, followed by a discussion on the dynamics of Aβ at the level of different biological compartments. There is focus on Aβ elimination modalities at central nervous system (CNS) level, and clearance via the blood–brain barrier seems to play a crucial/dominant role. Finally, different theoretical and already-applied therapeutic approaches for CNS Aβ elimination are presented, including the recent “peripheral sink therapeutic strategy” and “cerebrospinal fluid sinks therapeutic strategy”. These data outline the need for a multidisciplinary approach designed to deliver a solution to stimulate Aβ clearance in more direct ways, including from the cerebrospinal fluid level.

Efficacy of a vectorized anti‐tau antibody using systemic dosing of a blood brain barrier penetrant AAV capsid in mouse models of tauopathies

AbstractBackgroundAnti‐tau immunotherapy is a promising therapy for tauopathies, including Alzheimer's disease (AD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). While passive immunization with anti‐tau monoclonal antibodies has been shown by several laboratories to reduce age‐dependent tau pathology and neurodegeneration in mouse tauopathy models, these studies have typically used repeated high weekly doses of antibody and reported only moderate reduction of tau pathology. To circumvent these limitations, using an adeno‐associated virus (AAV) vector to deliver a tau monoclonal antibody into hippocampus by direct injection to the location have been described. High levels of antibody and marked reduction of tau pathology is achieved by this approach. To further optimize this approach with a lesser invasive administration route, we have previously demonstrated broad distribution and expression of a vectorized anti‐tau antibody in the mouse brain using a blood‐brain barrier (BBB) penetrant AAV capsid administered intravenously (IV). This gene therapy‐based approach has potential advantages, including continuous expression of antibody in the central nervous system (CNS) after a single administration of vector, increased CNS levels of tau antibody relative to passive immunotherapy, and the potential to target intracellular tau aggregates. Here we describe studies characterizing the onset of transduction following dosing with a vectorized tau antibody and its efficacy in mouse models of tauopathy.MethodAAV vectors comprising the BBB‐penetrant AAV capsid and a transgene encoding an anti‐tau monoclonal antibody were administered by IV bolus to mouse models of tauopathy. Biodistribution and cellular tropism in the CNS were evaluated by ELISA and (or) immunostaining. Tau pathology was measured by AT100 immunohistochemistry and AT8 ELISA.ResultWe then investigated efficacy in reduction of tau pathology in mouse tauopathy models. Treatment with our vectorized antibody resulted in durable antibody expression in the CNS and a corresponding reduction in CNS insoluble pathological tau and neurofibrillary tangles.ConclusionOur results indicate that systemic dosing of a vectorized anti‐tau antibody using a BBB‐penetrant AAV capsid results in reduced tau pathology and may represent a new single‐dose therapeutic strategy for treating various tauopathies.

Atopic dermatitis in psychodermatology: a concise review for dermatologists.

Atopic dermatitis (AD) is a chronic disease of the skin with significant pruritus and phases of exacerbation and remission. The hallmarks of AD are changes in the epithelial barrier and chronic inflammation. This condition is associated with an increased risk of developing mental disorders such as depression, anxiety, and suicidal ideation. It has been proposed that psychological stress may impact on immunological factors with an up-regulation of mediating neuropeptides at the level of central nervous system and secondary involvement of endocrine glands, peripheral nervous system, and immune resident skin cells. This article provides a concise review for dermatologists on the psychodermatology of AD, in order to highlight the putative common pathways between the dermatologic and mental health issues in this illness.

CB2 Receptor Involvement in the Treatment of Substance Use Disorders.

The pharmacological modulation of the cannabinoid receptor 2 (CB2r) has emerged as a promising potential therapeutic option in addiction. The purpose of this review was to determine the functional involvement of CB2r in the effects produced by drugs of abuse at the central nervous system (CNS) level by assessing evidence from preclinical and clinical studies. In rodents, several reports suggest the functional involvement of CB2r in the effects produced by drugs of abuse such as alcohol, cocaine, or nicotine. In addition, the discovery of CB2r in brain areas that are part of the reward system supports the relevance of CB2r in the field of addiction. Interestingly, animal studies support that the CB2r regulates anxiety and depression behavioral traits. Due to its frequent comorbidity with neuropsychiatric disorders, these pharmacological actions may be of great interest in managing SUD. Preliminary clinical trials are focused on exploring the therapeutic potential of modulating CB2r in treating addictive disorders. These promising results support the development of new pharmacological tools regulating the CB2r that may help to increase the therapeutic success in the management of SUD.

SARS-CoV-2-specific neuropathology: fact or fiction?

Neurological symptoms and varying levels of central nervous system (CNS) immunopathology have been described in COVID-19. Recent reports have suggested an increased level of innate immune activation associated with CNS border areas, as well as with a compartmentalized cytokine response and a dysregulated, autoreactive cerebrospinal fluid (CSF) immune profile. However, it remains contested whether these changes reflect bystander effects of systemic inflammation or relate to CNS-specific viral infection. We summarize some of the key findings pertaining to this ongoing debate and highlight directions for future investigation.

VEGF-A/VEGFR-1 signalling and chemotherapy-induced neuropathic pain: therapeutic potential of a novel anti-VEGFR-1 monoclonal antibody

BackgroundNeuropathic pain is a clinically relevant adverse effect of several anticancer drugs that markedly impairs patients’ quality of life and frequently leads to dose reduction or therapy discontinuation. The poor knowledge about the mechanisms involved in neuropathy development and pain chronicization, and the lack of effective therapies, make treatment of chemotherapy-induced neuropathic pain an unmet medical need. In this context, the vascular endothelial growth factor A (VEGF-A) has emerged as a candidate neuropathy hallmark and its decrease has been related to pain relief. In the present study, we have investigated the role of VEGF-A and its receptors, VEGFR-1 and VEGFR-2, in pain signalling and in chemotherapy-induced neuropathy establishment as well as the therapeutic potential of receptor blockade in the management of pain.MethodsBehavioural and electrophysiological analyses were performed in an in vivo murine model, by using selective receptor agonists, blocking monoclonal antibodies or siRNA-mediated silencing of VEGF-A and VEGFRs. Expression of VEGF-A and VEGFR-1 in astrocytes and neurons was detected by immunofluorescence staining and confocal microscopy analysis.ResultsIn mice, the intrathecal infusion of VEGF-A (VEGF165 isoforms) induced a dose-dependent noxious hypersensitivity and this effect was mediated by VEGFR-1. Consistently, electrophysiological studies indicated that VEGF-A strongly stimulated the spinal nociceptive neurons activity through VEGFR-1. In the dorsal horn of the spinal cord of animals affected by oxaliplatin-induced neuropathy, VEGF-A expression was increased in astrocytes while VEGFR-1 was mainly detected in neurons, suggesting a VEGF-A/VEGFR-1-mediated astrocyte-neuron cross-talk in neuropathic pain pathophysiology. Accordingly, the selective knockdown of astrocytic VEGF-A by intraspinal injection of shRNAmir blocked the development of oxaliplatin-induced neuropathic hyperalgesia and allodynia. Interestingly, both intrathecal and systemic administration of the novel anti-VEGFR-1 monoclonal antibody D16F7, endowed with anti-angiogenic and antitumor properties, reverted oxaliplatin-induced neuropathic pain. Besides, D16F7 effectively relieved hypersensitivity induced by other neurotoxic chemotherapeutic agents, such as paclitaxel and vincristine.ConclusionsThese data strongly support the role of the VEGF-A/VEGFR-1 system in mediating chemotherapy-induced neuropathic pain at the central nervous system level. Thus, treatment with the anti-VEGFR-1 mAb D16F7, besides exerting antitumor activity, might result in the additional advantage of attenuating neuropathic pain when combined with neurotoxic anticancer agents.

Autonomic and cardiac evaluation upon sub-therapeutic doxorubicin administration

Abstract Doxorubicin (DOX) is a chemotherapeutic agent that improves the survival and quality of life of patients with solid tumours. However, these improvements are counterbalanced by various dose-dependent side effects including cardiac dysfunction, which may occur in a subset of patients leading to treatment discontinuation. In addition, despite overall insufficiently studied, available data clearly show that women are more susceptible to drugs toxicity due to sex differences in drug metabolism or sensitivity. Regarding doxorubicin, apart its acute toxicity, women are also more vulnerable to late cardiotoxicity. Currently, there are no robust clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline and, despite treatment personalization, subclinical signs of toxicity are not yet well identified. Thus, in the present work, we sought to characterize the toxic effects of a sub-therapeutic dose of doxorubicin upon cardiovascular and autonomic function. For that, adult healthy female wistar rats (n=14), aged &amp;gt;3 months, were intraperitoneally treated with doxorubicin (2 mg/kg) at weekly intervals for up to 4 weeks. A control (Ctrl, n=7) group received saline solution 0,9% NaCl as a vehicle. Rats underwent an echocardiographic evaluation at 4 weeks. Blood pressure, heart rate and respiratory frequency were assessed in an acute experiment. Cardiovascular variability studies in the time-frequency domain (LF, HF and LF/HF calculation) and cardiorespiratory reflexes assessment were performed. T-Student test for paired observations was applied (level significance p&amp;lt;0.05) DOX-treated animals showed a severe bradypnea and hypotension, significant decrease in ejection fraction and fractional shortening, sympatho-inhibition and reduced baroreceptor reflex gain and chemoreflex sensitivity. Our functional results might be due to cellular respiratory dysfunction and vascular adaptations induced by doxorubicin via TNF alpha actions at central nervous system (CNS) and peripheral level. In fact, peripheral TNF alpha release elicits NO production, which through vasodilation will induce hypotension and baroreceptor reflex adjustments. Reinforcing these actions, and despite doxorubicin low ability to pass BBB, TNF alpha acting at CNS induces neuronal apoptosis and impairment of mitochondrial function which might also contribute to affect autonomic and respiratory function, expressed by a decreased chemoreflex sensitivity and sympathetic tone. In conclusion, sub-therapeutic doses of doxorubicin are able to produce per se the impairment of autonomic and cardiac functions. Thus, a tight monitoring of these functions in patients treated with therapeutic doses of doxorubicin is highly recommended. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fundação para a Ciência e a Tecnologia

The costs of coping: Different strategies to deal with social defeat stress might come with distinct immunologic, neuroplastic, and oxidative stress consequences in male Wistar rats.

The impact of stress on health and well-being is determined by the ability of an individual to cope with challenges imposed by the stressor. Animals exposed to social defeat stress show different patterns of response during confrontations, leading to distinct stress-induced consequences. Using an established resident-intruder paradigm, we explored the outcomes of adopting active or passive coping strategies during a social defeat protocol over peripheral and central nervous system (CNS) levels of inflammatory cytokines, growth factors, glucocorticoid, and oxidative stress markers in male Wistar rats. Animals that presented short latency to assume a defeated posture during confrontation-considered as susceptible to stress-exhibited increased levels of brain-derived neurotrophic factor (BDNF) in the amygdala (AMY) and in the bed nucleus of the stria terminalis (BNST), and decreased lipid peroxidation in the CNS, suggesting changes in antioxidative defenses as well as stress-induced neuroadaptations. On the other hand, animals with longer latencies to assume a submissive posture-considered to be resilient to stress-presented lower levels of CNS BDNF compared to short-latency animals and decreased enzymatic antioxidant defenses in the CNS in comparison to controls, which might indicate an increased risk of central oxidative damage. From the results, behavioral reactivity cannot be considered a predictor of success in responding to stress; however, the findings of this study reinforce the idea that exposure to stress has no predetermined negative effects. (PsycInfo Database Record (c) 2021 APA, all rights reserved).