Patrícia Rodrigues

Relapsing–remitting multiple sclerosis (RRMS) is a chronic autoimmune and neurodegenerative disease characterized by neuroinflammation and demyelination. Neuropathic pain is a frequent and poorly managed symptom associated with oxidative stress. Transient receptor potential ankyrin 1 (TRPA1), which is activated by oxidative mediators, contributes to nociceptive signaling and neuroinflammatory processes in the relapsing–remitting experimental autoimmune encephalomyelitis (RR-EAE) model. This study investigated the effects of repeated pharmacological blockade of TRPA1 on nociceptive behaviors and disease-associated pathological mechanisms using an RR-EAE mouse model. Female C57BL/6 mice received the TRPA1 antagonist A-967079 (30 mg/kg, intragastric) from day 16 to day 36 post-induction. Behavioral, molecular, and biochemical analyses were performed. Repeated administration of A-967079 attenuated mechanical and cold allodynia without impairing locomotor function or altering body weight. TRPA1 antagonism modulated glial marker expression and plasma pro-inflammatory cytokine levels. A-967079 attenuated oxidative stress, reducing hydrogen peroxide, 4-hydroxynonenal, advanced oxidation protein product levels (TRPA1 endogenous agonists), and NADPH–cytochrome c reductase activity. These findings demonstrate that repeated TRPA1 antagonism effectively modulates neuropathic pain-like behaviors and targets key pathological mechanisms associated with RRMS. This approach closely reflects clinical management, as treatment was initiated after disease onset, when symptoms were already present. Our results support TRPA1 antagonism as a promising therapeutic strategy for pain management in RRMS.

Background: Multiple sclerosis (MS) is a chronic inflammatory disease characterized by demyelination in the central nervous system (CNS). Despite the availability of interventions for disease exacerbations and symptomatic management, EM remained without a cure. Oxidative stress has been implicated in the MS demyelination mechanism. Adjuvant therapies like α-lipoic acid (ALA) have garnered interest for their potential to mitigate oxidative damage and control MS symptoms. ALA is found naturally in vegetables and red meat and can also be synthesized in mitochondria through enzymatic reactions involving octanoic acid and cysteine. However, its bioavailability from dietary sources is limited, prompting an investigation into supplemental forms. We conducted a systematic review and meta-analysis to assess the effect of ALA on disability in randomized clinical trials (RCTs) for MS. Methods: Records were searched until June 2023 (CRD42023397760). Five RCTs evaluated ALA’s effect on MS progression using the Expanded Disability Status Scale (EDSS). The quality of evidence was assessed using GRADE, and publication bias was evaluated using Egger’s and Begg’s tests. Results: Following the selection process, five studies were included involving 179 patients (87 placebo and 92 ALA). Oral administration of racemic ALA (R/S-ALA) at 600 mg twice daily reduced EDSS, indicating a potential for ALA supplementation to mitigate MS disability. The North American trials (SPMS patients) did not show heterogeneity, while Asian studies (RRMS patients) were moderated. The quality of evidence was high without publication bias. Conclusions: ALA treatment reduce EDSS scores. However, further studies are warranted to establish the role of ALA as an adjuvant in clinical practice in long-term follow-up (>2 years) RCTs.

The aim of this study was to determine the season that provides the highest production and best quality of peppermint (Mentha x piperita L.) essential oil in summer and winter transplantations. Two experiments were performed in a protected cultivation, the first with transplantation in summer and the second with transplantation in winter, with a completely randomized design with four treatments, being the seasons of the year. Content, yield and chemical composition of the essential oil were determined. The essential oil was extracted by hydrodistillation and analyzed by gas chromatography. Essential oil content in summer and winter transplantations was higher in summer and essential oil yield was higher in spring. In the summer transplanting the major components were menthone, isomenthone and pulegone. In the winter transplanting menthone, menthofuran, isopulegone, pulegone and menthol were detected as major components. Menthofuran, a compound which reduces the essential oil quality, were found in high amounts in winter transplanted plants. The higher production of peppermint essential oil is obtained in summer and spring harvests and the main compound is menthone in all seasons. The best quality of essential oil is obtained in the summer transplanting.

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.

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 7^th, 10^th, and 14^th 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 14^th 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. image

Neuropathic pain is a chronic pain caused by a disease or damage to the somatosensory nervous system. The knowledge about the complete mechanisms is incomplete, but the role of oxidative compounds has been evaluated. In this context, we highlight the transient potential receptor vanilloid 4 (TRPV4), a non-selective cation channel, that can be activated by oxidated compounds. In clinical trials, the TRPV4 antagonist (GSK2798745) has been well-tolerated in healthy volunteers. The TRPV4 activation by oxidative compounds, such as hydrogen peroxide (H₂O₂) and nitric oxide (NO), has been researched in neuropathic pain models. Thus, the modulation of TRPV4 activation by decreasing oxidated compounds could represent a new pharmacological approach for neuropathic pain treatment. Most models evaluated the TRPV4 using knockout mice, antagonist or antisense treatments and detected mechanical allodynia, hyposmotic solution-induced nociception and heat hyperalgesia, but this channel is not involved in cold allodynia. Only H₂O₂ and NO were evaluated as TRPV4 agonists, so one possible target to reduce neuropathic pain should focus on reducing these compounds. Therefore, this review outlines how the TRPV4 channel represents an innovative target to tackle neuropathic pain signaling in models induced by trauma, surgery, chemotherapy, cancer, diabetes and alcohol intake.