Increased levels of advanced oxidation protein products (AOPPs) were associated with nociceptive behavior and clinical scores in an experimental progressive autoimmune encephalomyelitis model (PMS-EAE).

Multiple sclerosis (MS) is a neurodegenerative disease that affects the central nervous system (CNS) generating neuropathic pain and anxiety. Primary progressive MS (PPMS) is the most disabling clinical form, and the patients present an intense neurodegenerative process. In this context, the advanced oxidation protein products (AOPPs) are oxidized compounds and their accumulation in plasma has been related to clinical disability in MS patients. However, the involvement of AOPPs in neuropathic pain- and anxiety-like symptoms was not previously evaluated. To assess this, female mice C57BL/6J were used to induce progressive experimental autoimmune encephalomyelitis (PMS-EAE). Clinical score, weight, strength of plantar pressure, rotarod test, mechanical allodynia, and cold hypersensitivity were evaluated before induction (baseline) and on days 7th, 10th, and 14th post-immunization. We assessed nest building, open field, and elevated plus-maze tests 13 days post-immunization. Animals were killed at 14 days post-immunization; then, AOPPs levels, NADPH oxidase, and myeloperoxidase (MPO) activity were measured in the prefrontal cortex, hippocampus, and spinal cord samples. The clinical score increased 14th post-immunization without changes in weight and mobility. Reduced paw strength, mechanical allodynia, and cold allodynia increased in the PMS-EAE animals. PMS-EAE mice showed spontaneous nociception and anxiety-like behavior. AOPPs concentration, NADPH oxidase, and MPO activity increase in CNS structures. Multivariate analyses indicated that the rise of AOPPs levels, NADPH oxidase, and MPO activity influenced the clinical score and cold allodynia. Thus, we indicated the association between non-stimuli painful perception, anxiety-like, and CNS oxidative damage in the PMS-EAE model.

Changes in markers of inflammation and their correlation with death in patients with COVID-19 in the intensive care unit.

This study aimed to characterize the changes in serum inflammatory mediators in hospitalized patients with COVID-19 correlating with death. The study includes 58 participants: i) inpatients (n = 37): patients suffering from severe acute respiratory syndrome due to COVID-19, who were admitted at Intensive Care Unit (ICU) recovered and who died and ii) control group (n = 21): community volunteers. Inflammatory mediators evaluated interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-17 (IL-17), interferon-gamma (IFN-γ) and interferon-gamma protein levels (IFN-γ), as well as, Urea, LDH, D-dimer, TAP/INR, AST, ALT and lymphocytes. Our results suggest that high levels of inflammatory markers, such as pro-inflammatory cytokines, and laboratory parameters, such as low levels of lymphocytes and high levels of IL-6, are associated with disease severity, especially in individuals who died. Constant measurement and monitoring of these inflammatory parameters is an effective tool in clinical practice, and it can help choosing appropriate therapies during the course of the disease.

Nitric oxide involvement in the disability and active disease of multiple sclerosis: Systematic review and meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic and immune-mediated disease of unknown etiology and leading to a physical and cognitive disability. Different studies suggest that nitrosative stress may play a pivotal role in the pathogenesis and disability in MS. Besides, reports evaluated NO and their metabolites, expressed by nitrite and nitrate (NOx) levels of MS patients compared with other pathologies, but did not evaluate disability and relapse/remission phases. OBJECTIVE: Thus, this study aimed to conduct a systematic review and meta-analysis of NOx levels in MS patients in relapse/remission phases and its involvement in patient disability. METHODS: The protocol was registered in PROSPERO (CRD42022327161). We used GRADE to estimate the articles' quality and evaluated the publication bias using Egger's and Begg's tests. RESULTS: Here, through a search in the Pubmed, Scopus, and EMBASE databases, 5.276 studies were found, and after the selection process, 20 studies were included in this systematic review and meta-analysis. The studies included data from 1.474 MS patients and 1.717 healthy controls, 1.010 RRMS and 221 primary progressive MS (PPMS). CONCLUSION: NOx levels are increased in relapsing-remitting MS (RRMS) patients in the relapse phase. Also, NOx levels were increased in MS patients with higher disability. However, further studies are still needed to control lifestyle habits, pain, and MS treatment effects in biased NOx levels.

Involvement of the Transient Receptor Channels in Preclinical Models of Musculoskeletal Pain.

BACKGROUND: Musculoskeletal pain is a condition that affects bones, muscles, and tendons and is present in various diseases and/or clinical conditions. This type of pain represents a growing problem with enormous socioeconomic impacts, highlighting the importance of developing treatments tailored to the patient's needs. TRP is a large family of non-selective cation channels involved in pain perception. Vanilloid (TRPV1 and TRPV4), ankyrin (TRPA1), and melastatin (TRPM8) are involved in physiological functions, including nociception, mediation of neuropeptide release, heat/cold sensing, and mechanical sensation. OBJECTIVE: In this context, we provide an updated view of the most studied preclinical models of muscle hyperalgesia and the role of transient receptor potential (TRP) in these models. METHODS: This review describes preclinical models of muscle hyperalgesia induced by intramuscular administration of algogenic substances and/or induction of muscle damage by physical exercise in the masseter, gastrocnemius, and tibial muscles. RESULTS: The participation of TRPV1, TRPA1, and TRPV4 in different models of musculoskeletal pain was evaluated using pharmacological and genetic tools. All the studies detected the antinociceptive effect of respective antagonists or reduced nociception in knockout mice. CONCLUSION: Hence, TRPV1, TRPV4, and TRPA1 blockers could potentially be utilized in the future for inducing analgesia in muscle hypersensitivity pathologies.

Targeting TRPV4 Channels for Cancer Pain Relief.

Despite the unique and complex nature of cancer pain, the activation of different ion channels can be related to the initiation and maintenance of pain. The transient receptor potential vanilloid 4 (TRPV4) is a cation channel broadly expressed in sensory afferent neurons. This channel is activated by multiple stimuli to mediate pain perception associated with inflammatory and neuropathic pain. Here, we focused on summarizing the role of TRPV4 in cancer etiology and cancer-induced pain mechanisms. Many studies revealed that the administration of a TRPV4 antagonist and TRPV4 knockdown diminishes nociception in chemotherapy-induced peripheral neuropathy (CIPN). Although the evidence on TRPV4 channels' involvement in cancer pain is scarce, the expression of these receptors was reportedly enhanced in cancer-induced bone pain (CIBP), perineural, and orofacial cancer models following the inoculation of tumor cells to the bone marrow cavity, sciatic nerve, and tongue, respectively. Effective pain management is a continuous problem for patients diagnosed with cancer, and current guidelines fail to address a mechanism-based treatment. Therefore, examining new molecules with potential antinociceptive properties targeting TRPV4 modulation would be interesting. Identifying such agents could lead to the development of treatment strategies with improved pain-relieving effects and fewer adverse effects than the currently available analgesics.

Prevalence of radicular neuropathic pain in idiopathic Parkinson's disease: A systematic review and meta-analysis.

Parkinson's disease (PD) is estimated to impact up to 1 % of the global population aged 60 years and older. Among the non-motor manifestations of idiopathic PD, radicular neuropathic pain emerges as a noteworthy concern due to its potential for debility in affected individuals. In, this systematic review and meta-analysis we aimed to evaluate the prevalence of radicular neuropathic pain and thus provide evidence of how this painful symptom affects the lives of patients with idiopathic PD. We registered the research protocol for this study in PROSPERO (CRD42022327220). We searched the Embase, Scopus, and PubMed platforms for studies on PD and neuropathic pain until April 2023. The search yielded 36 articles considered to have a low risk of bias. The prevalence of radicular neuropathic pain in patients with PD was 12.7 %, without a difference when we consider the duration of diagnosis (cut-off < 7 years) or levodopa dosage (cut-off <600 mg/dL). Moreover, there was no variation in the prevalence of radicular neuropathic pain regarding a Hoehn and Yahr stage cut-off of <2.5 or >2.5. Of note, a limited number of patients received pain treatment (21.5 %). We also found that the source of publication bias is the use of the Ford criteria (FC), suggesting that this type of diagnostic criteria may contribute to an underdiagnosis of radicular neuropathic pain in patients with PD. This study underlines the necessity for a more discerning and comprehensive approach to the diagnosis and management of radicular neuropathic pain in patients with idiopathic PD.

Alpha-lipoic acid reduces nociception by reducing oxidative stress and neuroinflammation in a model of complex regional pain syndrome type I in mice.

Complex regional pain syndrome type I (CRPS-I) is a disabling pain condition without adequate treatment. Chronic post-ischemia pain injury (CPIP) is a model of CRPS-I that causes allodynia, spontaneous pain, inflammation, vascular injury, and oxidative stress formation. Antioxidants, such as alpha lipoic acid (ALA), have shown a therapeutic potential for CRPS-I pain control. Thus, we aim to evaluate if ALA repeated treatment modulates neuroinflammation in a model of CRPS-I in mice. We used male C57BL/6 mice to induce the CPIP model (O-ring torniquet for 2 h in the hindlimb). For the treatment with ALA or vehicle (Veh) mice were randomly separated in four groups and received 100 mg/kg orally once daily for 15 days (CPIP-ALA, CPIP-Veh, Control-ALA, and Control-Veh). We evaluated different behavioral tests including von Frey (mechanical stimulus), acetone (cold thermal stimulus), rotarod, open field, hind paw edema determination, and nest-building (spontaneous pain behavior). Also, hydrogen peroxide (H2O2) levels, NADPH oxidase and superoxide dismutase (SOD) activity in the sciatic nerve and spinal cord, and Iba1, Nrf2, and Gfap in spinal cord were evaluated at 16 days after CPIP or sham induction. Repeated ALA treatment reduced CPIP-induced mechanical and cold allodynia and restored nest-building capacity without causing locomotor or body weight alteration. ALA treatment reduced SOD and NADPH oxidase activity, and H2O2 production in the spinal cord and sciatic nerve. CPIP-induced neuroinflammation in the spinal cord was associated with astrocyte activation and elevated Nfr2, which were reduced by ALA. ALA repeated treatment prevents nociception by reducing oxidative stress and neuroinflammation in a model of CRPS-I in mice.

Oxidative profile, inflammatory responses and δ-aminolevulinate dehydratase enzyme activity in influenza B virus infection.

The aim of the current study was to determine the activity of the delta-aminolevulinate dehydratase (δ-ALA-D) enzyme, oxidative stress biomarkers and the expression of cytokines in those infected with influenza B virus (IBV). To evaluate the activity of the δ-ALA-D enzyme, lipid peroxidation was estimated as levels of thiobarbituric acid reactive substances, protein and non-protein thiol groups, ferric-reducing antioxidant power (FRAP), vitamin C concentration and cytokine levels in IBV-infected individuals (n = 50) and a control group (n = 30). δ-ALA-D activity was significantly lower in IBV-infected individuals compared with controls, as well as levels of thiols, vitamin C and FRAP. Lipid peroxidation and cytokine levels of IL-6, IL-10, IL-17A and IFN-y were statistically higher in the IBV group. In conclusion, we found evidence of the generation of oxidants, the depletion of the antioxidant system, decrease in the activity of the δ-ALA-D enzyme and an increase in the synthesis of cytokines, thus contributing to a better understanding of oxidative and inflammatory pathways during IBV infection.

Characterization of Depression- and Anxiety-Like Behaviours in a Mouse Model of Relapsing-Remitting Multiple Sclerosis.

Relapsing-remitting multiple sclerosis (RRMS) is an autoimmune neurological disease and is the most common subtype of MS. In addition, it is associated with the development of depression and anxiety. To date, depressive- and anxiety-like behaviours were only studied using models of progressive MS, which causes severe motor alterations. Thus, we sought to standardise the depressive and anxiety-like behaviours in an RRMS model induced by experimental autoimmune encephalomyelitis (RR-EAE) in mice. The RR-EAE model was induced in C57BL/6 female mice using myelin oligodendrocyte glycoprotein (MOG35-55) antigen and Quillaja saponin (Quil A) as an adjuvant. The immunisation of RR-EAE did not induce locomotor alteration but caused relapsing-remitting induction of clinical scores in mice until 35 post-immunization (p.i.). Also, increased levels of tumour necrosis factor alpha (TNF-α), astrocyte marker (GFAP), and microglial markers (IBA-1) were detected in the prefrontal cortex at 35 p.i. of RR-EAE. In the open field test, RR-EAE mice showed decreased time spent at the centre and sniffing behaviour (at days 21 and 34 p.i.). Also, on day 35 p.i. the RR-EAE group spent less time in the open arms and had decreased open-arm entries compared to control mice in the elevated plus maze (EPM) test, confirming the anxiety-like behaviour. At day 36° p.i. in the tail suspension test, mice showed depression-like behaviour with decreased latency time and increased immobility time. Thus, the RR-EAE model mimics the neuroinflammatory and behavioural features of the RRMS, including depression- and anxiety-like symptoms.

Cognitive or daily stress association with headache and pain induction in migraine and tension-type headache patients: a systematic review.

INTRODUCTION: Primary headache disorders, such as migraine and tension-type headache (TTH), represent a significant public health concern. Besides, cognitive/mental stress was suggested to contribute to TTH and migraine physiopathology. Thus, this study aimed to evaluate the existence of a causal relationship between stress (mental/cognitive or daily stress) and headache or pain improvement in migraine and TTH patients. AREAS COVERED: We developed a systematic review of the literature, including studies that utilized mental/cognitive stress tasks or daily stress by lifestyle questionnaire in migraine and TTH patients. Necessarily, these studies should have healthy patients and a pain measure (quantitative sensory tests or headache/migraine detection). PubMed, EMBASE, and SCOPUS were searched, using terms about stress and primary headaches. EXPERT OPINION: Both mental/cognitive stress and daily stress (perceived) were related to an increase in pain perception and related to the development of headache or enhanced transient pain intensity in migraine and TTH patients. Different factors could enrich the comprehension of the influence of stress on pain/headache induction in migraine and TTH patients, including methodological standardization, consistency of assessing, and isolating the many headache triggers in randomized controlled trial studies.

Interferon-Beta Injection in Multiple Sclerosis Patients Related to the Induction of Headache and Flu-Like Pain Symptoms: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Multiple sclerosis (MS) is a chronic neurodegenerative, inflammatory, and autoimmune disease characterised by the demyelination of the central nervous system. One of the main approaches for treating MS is the use of disease-modifying therapies (DMTs). Among the DMTs are interferons (IFNs), which are cytokines responsible for controlling the activity of the immune system while exerting immunomodulatory, antiviral, and antiproliferative activities. IFN-beta (IFN-ß) is the first-choice drug used to treat relapsing-remitting MS. However, the administration of IFN-ß causes numerous painful adverse effects, resulting in lower adherence to the treatment. Therefore, this study aimed to investigate the headache and flu-like pain symptoms observed after IFNß injection in MS patients using a systematic review and meta-analysis of randomised controlled trials. A total of 2370 articles were identified through research databases. Nine articles were included (three involving IFNß-1b and six involving IFNß-1a). All studies included in the meta-analysis had a low risk of bias. The odds ratio of headache and flu-like pain symptoms increased in MS patients treated with IFN-ß. Thus, the adverse effects of headache and flu-like pain symptoms appear to be linked to IFN-ß treatment in MS. The protocol of the study was registered in the Prospective International Registry of Systematic Reviews (registration number CRD42021227593).

Prevalence of depression and anxiety in the different clinical forms of multiple sclerosis and associations with disability: A systematic review and meta-analysis.

Multiple sclerosis (MS) is a chronic neurodegenerative and autoimmune disease. Motor, sensory and cognitive deficits in MS are commonly accompanied by psychiatric disorders. Depression and anxiety affect the quality of life of MS patients, and the treatment is still not well-established. Prevalence rates in MS patients for depression and anxiety vary widely between studies. However, the prevalence of these psychiatric disorders in the subgroups of MS patients and their association with a disability has not been studied yet. Therefore, this systematic review and meta-analysis proposes to estimate the prevalence of depression and anxiety in MS and to perform subgroup analyses (study type, Extended Disability Status Scale/EDSS, duration of MS, region, type of MS) on observational studies. The protocol was registered in PROSPERO (4202125033). A computerized search on PubMed, EMBASE and Scopus for studies on depression and anxiety in MS was performed from 2015 to 2021, and 12 articles were included. Most of the studies in the meta-analysis had a low risk of bias. The prevalence of depression was 27.01% (MS), 15.78% (relapsing-remitting multiple sclerosis/RRMS), and 19.13% (progressive multiple sclerosis/PMS). For anxiety the prevalence was 35.19% (MS), 21.40% (RRMS), and 24.07% (PMS). The prevalence of depression/anxiety for patients with EDSS <3 was 26.69/45.56% and for EDSS >3 was 22.96/26.70%. Using HADS-A (8) the prevalence was 38.5% and for depression was 22.4%. Then, our study brought together current data regarding psychiatric disorders in MS patients, which are comorbidities that affect the quality of life of these patients.

Unpredictable Sound Stress Model Causes Migraine-Like Behaviors in Mice With Sexual Dimorphism.

Migraine represents one of the major causes of disability worldwide and is more prevalent in women; it is also related to anxiety symptoms. Stress, such as sound stress, is a frequently reported trigger in migraine patients, but the underlying mechanisms are not fully understood. However, it is known that patients with migraine have higher levels of plasma inflammatory cytokines and calcitonin gene-related peptide (CGRP). Stress mediated by unpredictable sound is already used as a model of painful sensitization, but migraine-like behaviors and sexual dimorphism have not yet been evaluated. This study characterized nociception and anxiety-related symptoms after the induction of sound stress in mice. C57BL/6 mice (20-30 g) were exposed to unpredictable sound stress for 3 days, nonconsecutive days. We observed enhanced plasma corticosterone levels on day 1 after stress induction. First, 7 days after the last stress session, mice developed hind paw and periorbital mechanical allodynia, grimacing pain behavior, anxiety-like symptoms, and reduced exploratory behavior. The nociceptive and behavioral alterations detected in this model were mostly shown in female stressed mice at day 7 post-stress. In addition, on day 7 post-stress nociception, these behaviors were consistently abolished by the CGRP receptor antagonist olcegepant (BIBN4096BS, 100 mg/kg by intraperitoneal route) in female and male stressed mice. We also demonstrated an increase in interleukine-6 (IL-6), tumor necrosis factor (TNF-α), and CGRP levels in stressed mice plasma, with female mice showing higher levels compared to male mice. This stress paradigm allows further preclinical investigation of mechanisms contributing to migraine-inducing pain.

Spermidine-induced improvement of memory consolidation involves PI3K/Akt signaling pathway.

Spermidine (SPD) is an endogenous polyamine that plays a facilitatory role in memory acquisition and consolidation. Memory consolidation occurs immediately after learning and again around 3-6 hours later. Current evidence indicates that the polyamine binding site at the NMDA receptor (NMDAr) mediates the effects of SPD on memory. While NMDAr activation increases brain-derived neurotrophic factor (BDNF) release, no study has investigated whether BDNF-activated signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/Akt pathway play a role in SPD-induced improvement of memory consolidation. Therefore, the aim of the current study was to evaluate whether the TrkB receptor and the PI3K/Akt pathway are involved in the facilitatory effect of SPD on memory consolidation. Male Wistar rats were trained in the contextual conditioned fear task. SPD, ANA-12 (TrkB antagonist), and LY294002 (PI3K inhibitor) were administered immediately after training. The animals were tested 24 h after training. We found that SPD improved fear memory consolidation and that both ANA-12 and LY294002 prevented the facilitatory effect of SPD on memory. These results suggest that SPD-induced improvement of memory consolidation involves the activation of the TrkB receptor and PI3K/Akt pathway.