Tonantzitlolone B Modulates the Endogenous Opioid System to Promote Antinociception in Mice.

Tonantzitlolone B (TZL-B) is a diterpene isolated from the roots of Stillingia loranthacea. Its antinociceptive effects were investigated in male Swiss mice using the following models of pain: formalin test, inflammation induced by Complete Freund's Adjuvant (CFA), tail flick test, and cold plate test. The influence of TZL-B on the opioid system was assessed in vivo, using opioid antagonists; in silico, investigating the chemical similarity among TZL-B and opioid agonists; and ex vivo, measuring preproenkephalin (PENK) gene expression in the spinal cord by RT-qPCR. TZL-B (10-1000 µg/kg) promoted antinociception in the four experimental models without impairing mice's motor function. TZL-B did not alter paw edema during CFA-induced inflammation. The antinociceptive effects of TZL-B in the tail flick and cold plate tests were diminished by the opioid antagonists naloxone (5 mg/kg), NOR-BNI (0.5 mg/kg), naltrindole (3 mg/kg), and CTOP (1 mg/kg), indicating the involvement of κ-, δ-, and µ-opioid receptors. TZL-B showed no significant chemical similarity to opioid agonists, but the treatment with TZL-B (1000 µg/kg) increased PENK gene expression in the spinal cord of mice. These data suggest that TZL-B promotes antinociception by enhancing the transcription of PENK, hence modulating the endogenous opioid system.

Auditory Pathway Maturation in Full-term Small for Gestational Age Children: A Systematic Review with Meta-analysis.

Introduction Factors of intrauterine growth restriction have been responsible for the births of full-term babies small for their gestational age (SGA). Scientific evidence points that this restriction can cause changes in the neural maturation process. Objectives To analyze the absolute latencies and interpeak intervals of brainstem auditory evoked potential waves in full-term and SGA children to investigate whether there are changes of neural maturation in this population. Data Synthesis The search for articles that reported the assessment of brainstem auditory evoked potential in SGA newborns compared with a control, appropriate for their gestational age, both born full-term, for the entire period available in the database research until October 31, 2021 was performed based on the MEDLINE/PubMed Central and on the Latin America and the Caribbean Health Sciences Literature and Virtual Health Library electronic databases. A total of 311 studies were found in the database research. Out of this total, 10 studies were included in the review, 5 of which were eligible for the meta-analysis, involving a total of 473 participants of both genders, with 193 participants belonging to the study group and 280 to the control group. Differences between the groups were only observed in the absolute latency of wave V (95% confidence interval [CI]: 0.02-0.15; p < 0.01). Conclusion The SGA condition is responsible for the appearance of brainstem neural conduction dysfunction measured by the brainstem auditory evoked potentials, probably by the maturation process of the auditory pathway of this population.

Auditory Pathway Maturation in Full-term Small for Gestational Age Children: A Systematic Review with Meta-analysis

Abstract Introduction Factors of intrauterine growth restriction have been responsible for the births of full-term babies small for their gestational age (SCA). Scientific evidence points that this restriction can cause changes in the neural maturation process. Objectives To analyze the absolute latencies and interpeak intervals of brainstem auditory evoked potential waves in full-term and SCA children to investigate whether there are changes of neural maturation in this population. Data Synthesis The search for articles that reported the assessment of brainstem auditory evoked potential in SCA newborns compared with a control, appropriate for their gestational age, both born full-term, for the entire period available in the database research until October31, 2021 was performed based on the MEDLINE/PubMed Central and on the Latin America and the Caribbean Health Sciences Literature and Virtual Health Library electronic databases. A total of 311 studies were found in the database research. Out of this total, 10 studies were included in the review, 5 of which were eligible for the meta-analysis, involving a total of 473 participants of both genders, with 193 participants belonging to the study group and 280 to the control group. Differences between the groups were only observed in the absolute latency of wave V (95% confidence interval [CI]: 0.02-0.15; p<0.01). Conclusion The SCA condition is responsible for the appearance of brainstem neural conduction dysfunction measured by the brainstem auditory evoked potentials, probably by the maturation process of the auditory pathway of this population.

Mesenchymal stem cells reduce the oxaliplatin-induced sensory neuropathy through the reestablishment of redox homeostasis in the spinal cord.

AIMS: The present study was designed to investigate whether the antinociceptive effect of bone marrow-derived mesenchymal stem/stromal cells (MSC) during oxaliplatin (OXL)-induced sensory neuropathy is related to antioxidant properties. MAIN METHODS: Male mice C57BL/6 were submitted to repeated intravenous administration of OXL (1 mg/kg, 9 administrations). After the establishment of sensory neuropathy, mice were treated with a single intravenous administration of MSC (1 × 106), vehicle or gabapentin. Paw mechanical and thermal nociceptive thresholds were evaluated through von Frey filaments and cold plate test, respectively. Motor performance was evaluated in the rota-rod test. Gene expression profile, cytokine levels, and oxidative stress markers in the spinal cord were evaluated by real-time PCR, ELISA and biochemical assays, respectively. KEY FINDINGS: OXL-treated mice presented behavioral signs of sensory neuropathy, such as mechanical allodynia and thermal hyperalgesia, which were completely reverted by a single administration of MSC. Repeated oral treatment with gabapentin (70 mg/kg) induced only transient antinociception. The IL-1ß and TNF-α spinal levels did not differ between mice with or without sensory neuropathy. MSC increased the levels of anti-inflammatory cytokines, IL-10 and TGF-ß, in the spinal cord of neuropathic mice, in addition to increasing the gene expression of antioxidant factors SOD and Nrf-2. Additionally, nitrite and MDA spinal levels were reduced by the MSC treatment. SIGNIFICANCE: MSC induce reversion of sensory neuropathy induced by OXL possibly by activation of anti-inflammatory and antioxidant pathways, leading to reestablishment of redox homeostasis in the spinal cord.

Perda auditiva na hemoglobinopatia SC (HbSC): relato de caso / Hearing loss in SC hemoglobinopathy (HbSC): case report

Introdução: Doença falciforme (DF) engloba um conjunto de hemoglobinopatias marcadas pela hemoglobina (Hb) anormal S (HbS). A HbS possui um formato de foice e aumento de rigidez, culminando em hemólise. Além disso, dificulta a passagem pela microcirculação sanguínea, causando vaso-oclusão e lesão isquêmica em diversos órgãos e tecidos. Na orelha interna, tem sido descrita como os responsável por danos auditivos. Objetivo: apresentar um relato de caso de paciente do sexo feminino com doença falciforme, acometida de perda auditiva sensorioneural (PASN) bilateral assimétrica. Relato do caso: paciente do sexo feminino, destra, 45 anos, compareceu para avaliação, queixando se de diminuição da audição e zumbido na orelha esquerda. Foi submetida à avaliação audiológica, constituída por audiometria tonal limiar, logoaudiometria, imitanciometria, emissões otoacústicas por produto de distorção (EOAPD) e potencial evocado auditivo do tronco encefálico (PEATE). Resultados: constatou-se: perda auditiva sensorioneural bilateral de grau leve na orelha direita e severo na orelha esquerda; presença dos reflexos estapedianos contralaterais na orelha direita e ausência na orelha esquerda; curvas timpanométricas tipo A; ausência de emissões otoacústicas bilateralmente; e os potenciais auditivos evocados do tronco encefálico dentro dos padrões de normalidade. Discussão: diversos mecanismos estão envolvidos na relação DF e PASN, como a falta de oxigenação e infarto do órgão de Corti, hemorragia labiríntica e labirintite ossificante, bem como uma associação entre o nível de viscosidade sanguínea, disfunção endotelial e hipertensão sistêmica. E ainda deve ser considerada a questão de dominância hemisférica na assimetria da perda. Conclusão: os conhecimentos sobre as características dos danos auditivos na HbSC ainda não são conclusivos e merecem mais investigações. A implementação de avaliações periódicas da função auditiva tem contribuído para prevenir a progressão dos danos e auxiliado no tratamento precoce.

Introduction: Sickle cell disease (SCD) comprises a set of hemoglobinopathies marked by abnormal hemoglobin (Hb) S (HbS). HbS has a sickle shape and increased stiffness culminating in hemolysis, in addition to making it difficult to pass through the blood microcirculation, causing vessel-occlusion and ischemic damage in various organs and tissues. In the inner ear, they have been described as responsible for hearing damage. Objective: describing a case report of a female patient with sickle cell disease affected by asymmetric bilateral sensorineural hearing loss (SNHL). Case report: a 45-year-old female patient, right-handed, came for evaluation, complaining of decreased hearing and tinnitus in her left ear. She underwent audiological evaluation consisting of pure tone audiometry, logoaudiometry, immittance testing, distortion product otoacoustic emissions (DPOAE) and brainstem auditory evoked potential (BAEP). Results: bilateral mild sensorineural hearing loss in the right ear and severe in the left ear, presence of contralateral stapedial reflexes in the right ear and absence in the left ear, type A tympanometric curves, absence of bilateral otoacoustic emissions and the brainstem auditory evoked potentials within the normality patterns. Discussion: Several mechanisms are involved in the SCD and SNHL relationship, such as the lack of oxygen and infarction of the Organ of Corti, labyrinthine hemorrhage and ossifying labyrinthitis, as well as an association between the level of blood viscosity, endothelial dysfunction and systemic hypertension. And the question of hemispheric dominance in the loss asymmetry must still be considered. Conclusion: knowledge about the characteristics of hearing damage in HbSC is not yet conclusive and deserves further investigation. Implementation of periodic auditory function assessments has helped to prevent the progression of damage and has helped in early treatment.

Conditioned Medium of Bone Marrow-Derived Mesenchymal Stromal Cells as a Therapeutic Approach to Neuropathic Pain: A Preclinical Evaluation.

Neuropathic pain is a type of chronic pain caused by injury or dysfunction of the nervous system, without effective therapeutic approaches. Mesenchymal stromal cells (MSCs), through their paracrine action, have great potential in the treatment of this syndrome. In the present study, the therapeutic potential of MSC-derived conditioned medium (CM) was investigated in a mouse model of neuropathic pain induced by partial sciatic nerve ligation (PSL). PSL mice were treated by endovenous route with bone marrow-derived MSCs (1 × 106), CM, or vehicle. Gabapentin was the reference drug. Twelve hours after administration, neuropathic mice treated with CM exhibited an antinociceptive effect that was maintained throughout the evaluation period. MSCs also induced nonreversed antinociception, while gabapentin induced short-lasting antinociception. The levels of IL-1ß, TNF-α, and IL-6 were reduced, while IL-10 was enhanced on sciatic nerve and spinal cord by treatment with CM and MSCs. Preliminary analysis of the CM secretome revealed the presence of growth factors and cytokines likely involved in the antinociception. In conclusion, the CM, similar to injection of live cells, produces a powerful and long-lasting antinociceptive effect on neuropathic pain, which is related with modulatory properties on peripheral and central levels of cytokines involved with the maintenance of this syndrome.

Structural improvement of new thiazolidinones compounds with antinociceptive activity in experimental chemotherapy-induced painful neuropathy.

Chemotherapy-induced neuropathy is a disabling pain condition resulting from chemotherapy for cancers. Up to now, no drug is available to cure chemotherapy-induced neuropathy. In the present study, we describe the structural design, synthesis, chemical and pharmacological characterization of 15 thiazolidinones, a class of potential analgesic compounds. The synthesis of new thiazolidinones was achieved by using the thiazolidinone heterocyclic as main structural pharmacophoric group and varying the substituents attached to the phenyl near to the iminic bond. The analgesic potential of the compounds was investigated in a mice model of oxaliplatin-induced neuropathic pain, using von Frey, rota-rod and open-field tests. Except for compound 14, these thiazolidinones exhibited antinociceptive property without causing motor impairment. Thiazolidinones 12, 15 and 16 displayed a dose-dependent antinociceptive effect, with similar efficacy and enhanced potency than gabapentin, the gold standard drug used for neuropathic pain. In addition, the antinociceptive activity of 16 lasted longer than gabapentin. The antinociceptive effect of thiazolidinones was prevented by GW9662, a PPARγ antagonist. The main antinociceptive compounds exhibited positive Lipinski's index, predicting their oral bioavailability. In conclusion, the structural design performed here led to the identification of new compounds endowed with potent antinociceptive activity, potentially useful to treat chemotherapy-induced neuropathic pain.