RESUMEN
PURPOSE: To assess structural (optical coherence tomography, fundus autofluorescence) and functional (contrast sensitivity and visual field) test results which were used for detecting early retinal changes in patients using oral hydroxychloroquine. METHODS: Patients using oral hydroxychloroquine for at least one year were divided into two groups according to the duration of drug use. Groups 1 and 2 consisted of patients with drug use for more than 5 years and 1-5 years, respectively. The drug-using groups were compared with the control group. The mean retinal nerve fiber layer (RNFL), central macular thickness (CMT), ganglion cell-inner plexiform layer (GC-IPL), static 10-2 visual field, fundus autofluorescence (FAF) imaging, and contrast sensitivity tests were performed and statistically compared between groups. RESULTS: Median and temporal quadrant RNFL thicknesses were found to be statistically significantly lower in the drug groups. In the drug groups, the GC-IPL sectoral and mean thicknesses were found to be statistically lower in all quadrants. Central macular thickness was also found to be similar in all three groups. There was no significant difference between the groups in visual field parameters. Macular FAF images were significantly higher in the drug users, but there was no significant difference between the three groups in foveal FAF images. Contrast sensitivity measurements were significantly lower in the drug groups than in the control group at all spatial frequencies except 6 and 18 cycles/degree. CONCLUSIONS: The combined use of structural and functional tests in patients using hydroxychloroquine provides useful information in detecting early retinal changes.
Asunto(s)
Antirreumáticos , Sensibilidad de Contraste , Diagnóstico Precoz , Angiografía con Fluoresceína , Hidroxicloroquina , Mácula Lútea , Enfermedades de la Retina , Células Ganglionares de la Retina , Tomografía de Coherencia Óptica , Campos Visuales , Humanos , Hidroxicloroquina/efectos adversos , Tomografía de Coherencia Óptica/métodos , Femenino , Masculino , Campos Visuales/fisiología , Campos Visuales/efectos de los fármacos , Persona de Mediana Edad , Antirreumáticos/efectos adversos , Enfermedades de la Retina/inducido químicamente , Enfermedades de la Retina/diagnóstico , Mácula Lútea/efectos de los fármacos , Mácula Lútea/patología , Mácula Lútea/diagnóstico por imagen , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/efectos de los fármacos , Sensibilidad de Contraste/fisiología , Sensibilidad de Contraste/efectos de los fármacos , Angiografía con Fluoresceína/métodos , Adulto , Fibras Nerviosas/patología , Fibras Nerviosas/efectos de los fármacos , Agudeza Visual , Pruebas del Campo Visual/métodos , AncianoRESUMEN
Glaucoma is a blinding disease where the retinal ganglion cells and their axons degenerate. Degradation of axonal microtubules is thought to play a critical role in the pathogenesis, but the mechanism is unknown. Here we investigate whether microtubule disruption in glaucoma can be alleviated by metabolic rescue. The integrity of axonal microtubules and the morphology of the retinal nerve fibers were evaluated by second-harmonic generation microscopy in a mouse model of glaucoma, DBA/2J, which received a dietary supplement of nicotinamide (NAM) for reducing metabolic stress. It was compared with control DBA/2J, which did not receive NAM, and non-glaucomatous DBA/2J-Gpnmb+. We found that the morphology of the retinal nerve fibers, but not axonal microtubules, are significantly protected by NAM. The decoupling is analogous to microtubule deficit, a glaucoma pathology in which axonal microtubules exhibit rapid degradation compared to the morphology of the retinal nerve fibers. Understanding microtubule deficit could provide insights into the divergent responses to NAM. From co-registered images of second-harmonic generation and immunofluorescence, it was determined that microtubule deficit was not due to a shortage of tubulins. Furthermore, microtubule deficit colocalized with the sectors in which the retinal ganglion cells were disconnected from the brain, suggesting that microtubule disruption is associated with axonal transport deficit in glaucoma. Together, our data suggests significant role axonal microtubules play in glaucomatous degeneration, offering a new opportunity for neuroprotection.
Asunto(s)
Modelos Animales de Enfermedad , Glaucoma , Ratones Endogámicos DBA , Microtúbulos , Niacinamida , Células Ganglionares de la Retina , Animales , Glaucoma/patología , Glaucoma/metabolismo , Glaucoma/tratamiento farmacológico , Niacinamida/farmacología , Niacinamida/uso terapéutico , Ratones , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/metabolismo , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Axones/efectos de los fármacos , Axones/metabolismo , Axones/patología , Microscopía/métodos , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/patología , Fibras Nerviosas/metabolismoRESUMEN
PURPOSE: To study the effect of brimonidine on vascular density and flow index of optic nerve head (ONH) and macula in primary open angle glaucoma (POAG) using optical coherence tomography angiography (OCTA). METHODS: Twenty-three brimonidine-naïve POAG patients were started on brimonidine. They underwent OCTA ONH and macula before commencing brimonidine and one month thereafter. Systemic arterial blood pressure (SABP) and intraocular pressure (IOP) were measured at each visit to calculate mean ocular perfusion pressure (MOPP). The OCT angiograms were analyzed using ImageJ software to calculate ONH and macular flow indices. RESULTS: Thirty-seven eyes (23 patients) with a mean age of 56.7 ± 12.49 years were included of whom 60.8% were males. Brimonidine was associated with an increase in the superficial flow index (SFI) (P-value = 0.02) and optic nerve head flow index (ONHFI) (P-value = 0.01). Also, superficial vascular density (SVD) for whole image, superior-hemi and fovea increased (P-value = 0.03, 0.02, 0.03 respectively). ONH inferior-hemi vascular density decreased (P-value = 0.01) despite an increase in inferior quadrant retinal nerve fiber layer thickness (RNFLT) (P-value = 0.03). There was no statistically significant correlation between flow indices and MOPP at baseline and follow-up. A moderate negative correlation was found between SVD and DVD at the fovea and MOPP at baseline and follow-up (P-value = 0.03, 0.05) (P-value = 0.02, 0.01) respectively. CONCLUSIONS: Brimonidine was associated with an increase in SFI, ONHFI and SVD indicating improved GCC and RNFL perfusion in POAG. Despite the increase in inferior quadrant RNFLT, the concomitant decrease in inferior-hemi ONHVD precluded a conclusion of hemodynamically-mediated improvement of RNFLT.
Asunto(s)
Tartrato de Brimonidina , Angiografía con Fluoresceína , Glaucoma de Ángulo Abierto , Presión Intraocular , Mácula Lútea , Disco Óptico , Vasos Retinianos , Tomografía de Coherencia Óptica , Humanos , Glaucoma de Ángulo Abierto/fisiopatología , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Glaucoma de Ángulo Abierto/diagnóstico , Masculino , Disco Óptico/irrigación sanguínea , Tartrato de Brimonidina/administración & dosificación , Tartrato de Brimonidina/farmacología , Tartrato de Brimonidina/uso terapéutico , Persona de Mediana Edad , Femenino , Tomografía de Coherencia Óptica/métodos , Mácula Lútea/irrigación sanguínea , Mácula Lútea/diagnóstico por imagen , Presión Intraocular/fisiología , Presión Intraocular/efectos de los fármacos , Vasos Retinianos/diagnóstico por imagen , Vasos Retinianos/fisiopatología , Vasos Retinianos/efectos de los fármacos , Angiografía con Fluoresceína/métodos , Flujo Sanguíneo Regional/fisiología , Flujo Sanguíneo Regional/efectos de los fármacos , Anciano , Fondo de Ojo , Estudios Prospectivos , Campos Visuales/fisiología , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/efectos de los fármacos , Antihipertensivos/uso terapéutico , Fibras Nerviosas/patología , Fibras Nerviosas/efectos de los fármacos , Adulto , Estudios de SeguimientoRESUMEN
Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9-month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50-mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double-blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4-week loading dose of 200 mg QD or placebo for 9 months (placebo-controlled phase); they then entered the active-therapy extension and received ritlecitinib 50 mg QD (with a 4-week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I-V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans.
Asunto(s)
Alopecia Areata , Potenciales Evocados Auditivos del Tronco Encefálico , Fibras Nerviosas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Alopecia Areata/tratamiento farmacológico , Alopecia Areata/patología , Método Doble Ciego , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/patología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , PerrosRESUMEN
Melanocortin 4 receptor (MC4R) mutations are the commonest cause of monogenic obesity through dysregulation of neuronal pathways in the hypothalamus and prefrontal cortex that regulate hunger and satiety. MC4R also regulates neuropathic pain pathways via JNK signaling after nerve injury. We show evidence of corneal small fiber degeneration in 2 siblings carrying a heterozygous missense variant c.508A>G, p.Ille170Val in the MC4R gene. Both children were treated with once weekly semaglutide for 6 months with no change in weight, and only a minor improvement in HbA1c and lipid profile. However, there was evidence of nerve regeneration with an increase in corneal nerve fiber density (CNFD) [child A (13.9%), child B (14.7%)], corneal nerve branch density (CNBD) [child A (110.2%), child B (58.7%)] and corneal nerve fiber length (CNFL) [child A (21.5%), child B (44.0%)].
Asunto(s)
Regeneración Nerviosa , Receptor de Melanocortina Tipo 4 , Humanos , Receptor de Melanocortina Tipo 4/genética , Masculino , Femenino , Niño , Regeneración Nerviosa/efectos de los fármacos , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/farmacología , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/patología , Mutación , Obesidad/tratamiento farmacológico , Obesidad/genética , Córnea/efectos de los fármacos , Córnea/inervación , Córnea/patología , Obesidad Infantil/tratamiento farmacológico , AdolescenteRESUMEN
Background and purpose:
The aim of this study is to comprehensively determine the types of affected fibers in Parkinson’s disease (PD) patients by employing nerve conduction studies (NCS), sympathetic skin response (SSR) examinations, and current perception threshold (CPT) testing and to analyze the correlation between levodopa use and nerve involvement.
. Methods:This retrospective study included 36 clinically diagnosed PD patients who were recruited between January 2018 and April 2019. All patients underwent NCS, SSR testing, and CPT sensory examinations. Additionally, the PD patients were assessed for disease staging using the Hoehn and Yahr (H-Y) scale.
. Results:Fifteen patients were included in the tremor-dominant subtype, ten patients in the rigid-dominant subtype, and eleven patients in the mixed subtype. Eleven patients were using levodopa, while twenty-five patients had never used any anti-Parkinson’s medication. Ten patients (28%) showed abnormal sympathetic skin responses (SSR). The CPT examination revealed sensory abnormalities in twenty-four patients (67%), with eighteen patients (75%) experiencing sensory hypersensitivity and six patients (25%) experiencing sensory hypoesthesia. Twelve patients (33%) had normal CPT results. Among the patients with abnormal CPT findings, seven cases (29%) involved large myelinated fiber damage, twenty-two cases (92%) involved small myelinated fiber damage, and nineteen cases (79%) involved unmyelinated fiber damage. The rate of sensory abnormalities was 64% (7/11) in the levodopa group and 68% (17/25) in the non-levodopa group, with no statistically significant difference between the two groups.
. Conclusion:The incidence of abnormal CPT findings in PD patients was higher than that of abnormal SSR responses, suggesting that nerve fiber damage primarily affects small fiber nerves (SFN).
.Asunto(s)
Levodopa , Conducción Nerviosa , Enfermedad de Parkinson , Humanos , Levodopa/administración & dosificación , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/complicaciones , Persona de Mediana Edad , Femenino , Anciano , Estudios Retrospectivos , Masculino , Conducción Nerviosa/efectos de los fármacos , Fibras Nerviosas/patología , Fibras Nerviosas/efectos de los fármacos , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/efectos adversos , Nervios Periféricos/patologíaRESUMEN
BACKGROUND: Alzheimer's disease is characterized by extracellular beta-amyloid plaques, intraneuronal tau neurofibrillary tangles and excessive neurodegeneration. The mechanisms of neuron degeneration and the potential of these neurons to form new nerve fibers for compensation remain elusive. The present study aimed to evaluate the impact of beta-amyloid and tau on new formations of nerve fibers from mouse organotypic brain slices connected to collagen-based microcontact prints. METHODS: Organotypic brain slices of postnatal day 8-10 wild-type mice were connected to established collagen-based microcontact prints loaded with polyornithine to enhance nerve fiber outgrowth. Human beta-amyloid(42) or P301S mutated aggregated tau was co-loaded to the prints. Nerve fibers were immunohistochemically stained with neurofilament antibodies. The physiological activity of outgrown neurites was tested with neurotracer MiniRuby, voltage-sensitive dye FluoVolt, and calcium-sensitive dye Rhod-4. RESULTS: Immunohistochemical staining revealed newly formed nerve fibers extending along the prints derived from the brain slices. While collagen-only microcontact prints stimulated nerve fiber growth, those loaded with polyornithine significantly enhanced nerve fiber outgrowth. Beta-amyloid(42) significantly increased the neurofilament-positive nerve fibers, while tau had only a weak effect. MiniRuby crystals, retrogradely transported along these newly formed nerve fibers, reached the hippocampus, while FluoVolt and Rhod-4 monitored electrical activity in newly formed nerve fibers. CONCLUSIONS: Our data provide evidence that intact nerve fibers can form along collagen-based microcontact prints from mouse brain slices. The Alzheimer's peptide beta-amyloid(42) stimulates this growth, hinting at a neuroprotective function when physiologically active. This "brain-on-chip" model may offer a platform for screening bioactive factors or testing drug effects on nerve fiber growth.
Asunto(s)
Péptidos beta-Amiloides , Encéfalo , Fibras Nerviosas , Animales , Péptidos beta-Amiloides/metabolismo , Ratones , Fibras Nerviosas/metabolismo , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Proteínas tau/metabolismo , Humanos , Inmunohistoquímica , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/patología , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: ATTR (ATTRv) amyloidosis neuropathy is characterized by progressive sensorimotor and autonomic nerve degeneration secondary to amyloid deposition caused by a misfolded transthyretin protein (TTR). Small nerve fiber neuropathy is an early clinical manifestation of this disease resulting from the dysfunction of the Aδ and C small nerve fibers. Tafamidis, a selective TTR stabilizer, has proven its efficacy in the earlier stages of hATTR. OBJECTIVES: To evaluate the clinical course and utility of cutaneous pathological biomarkers in patients with ATTR amyloidosis treated with tafamidis compared to control patients. METHODS: Forty patients diagnosed with early stages of ATTRv amyloidosis (polyneuropathy disability [PND] scores 0-II) underwent small and large nerve fiber neurological evaluations, and annual skin biopsies for intraepidermal nerve fiber density (IENFD) and amyloid deposition index (ADI) estimation. Thirty patients were allocated to receive tafamidis, and 10 patients served as controls. Tafamidis pharmacokinetics analysis was performed in patients who received the treatment. RESULTS: At baseline, 12% of patients in stage PND 0 and 28% in PND I displayed small nerve fiber denervation in the distal thigh, whereas 23% and 38%, respectively, in the distal leg. Similarly, 72% and 84% had amyloid deposition in the distal thigh and 56% and 69% in the distal leg. Following 1 year of treatment, the tafamidis group showed significant clinical improvement compared to the control group, revealed by the following mean differences (1) -9.3 versus -4 points (p = <.00) in the patient's neuropathy total symptom score 6 (NTSS-6) questionnaire, (2) -2.5 versus +2.8 points (p = <.00) in the Utah Early Neuropathy Score (UENS), and (3) +1.2°C versus -0.6 (p = .01) in cold detection thresholds. Among the patients who received tafamidis, 65% had stable or increased IENFD in their distal thigh and 27% in the distal leg. In contrast, all patients in the control group underwent denervation. The ADI either decreased or remained constant in 31% of the biopsies in the distal thigh and in 24% of the biopsies in the distal leg of the tafamidis-treated patients, whereas it rose across all the biopsies in the control group. At the 4-year follow-up, the tafamidis group continued to display less denervation in the distal thigh (mean difference [MD] of -3.0 vs. -9.3 fibers/mm) and the distal leg (mean difference [MD] -4.9 vs. -8.6 fibers/mm). ADI in tafamidis-treated patients was also lower in the distal thigh (10 vs. 30 amyloid/mm2) and the distal leg (23 vs. 40 amyloid/mm2) compared to control patients. Plasma tafamidis concentrations were higher in patients with IENFD improvement and in patients with reduced amyloid deposition. Patients without amyloid deposition in the distal leg at baseline displayed delayed disease progression at 4 years. CONCLUSIONS: Cutaneous IENFD and amyloid deposition assessments in the skin of the distal thigh and distal leg are valuable biomarkers for early diagnosis of ATTR amyloidosis and for measuring the progression of small nerve fiber neuropathy. Early treatment with tafamidis slows the clinical progression of the disease, skin denervation, and amyloid deposition in the skin. Higher plasma concentrations of tafamidis are associated with better disease outcomes, suggesting that increasing the drug dose could achieve better plasma concentrations and response rates. This study describes the longest small nerve fiber neuropathy therapeutic trial with tafamidis and is the first to report small fiber symptoms, function, and structural assessments as outcomes.
Asunto(s)
Neuropatías Amiloides Familiares , Benzoxazoles , Piel , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neuropatías Amiloides Familiares/tratamiento farmacológico , Benzoxazoles/farmacología , Benzoxazoles/administración & dosificación , Anciano , Piel/patología , Piel/inervación , Piel/efectos de los fármacos , Biomarcadores/metabolismo , Prealbúmina , Adulto , Resultado del Tratamiento , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/patologíaRESUMEN
SUMMARY: The preserved form of all components of the nerve fiber is a prerequisite for the proper conduction of the nerve impulse. various factors can change the shape of nerve fibers. In everyday practice, qualitative histological analysis is the gold standard for detecting changes in shape. Geometric morphometry is an innovative method that objectively enables the assessment of changes in nerve fibers' shape after local anesthetics action. A total of sixty sciatic nerves were used as material, which was intraneural injected with saline solution in the control group (n=30), and a solution of 1.33 % liposomal bupivacaine (n=30) in the test group. After the animals were sacrificed, nerve samples were taken and histological preparations were made. The preparations were first described and examined using a qualitative histological method, after which digital images were made. The images were entered into the MorphoJ program and processed using the method of geometric morphometry. Qualitative histological examination revealed no differences in nerve fibers after intraneurally applied physiological solution and liposomal bupivacaine. Using the method of geometric morphometry, a statistically significant change in the shape of axons was found after intraneurally applied saline solution and liposomal bupivacaine (p=0.0059). No significant differences in histological changes were found after the qualitative histological analysis of nerve fiber cross-section preparations. A statistically significant change in the shape of nerve fiber axons was observed after geometric morphometric analysis of digital images after intraneural application of saline and liposomal bupivacaine.
La forma conservada de todos los componentes de la fibra nerviosa es un requisito previo para la conducción correcta del impulso nervioso. Varios factores pueden cambiar la forma de las fibras nerviosas. En la práctica diaria, el análisis histológico cualitativo es el estándar de oro para detectar cambios de forma. La morfometría geométrica es un método innovador que permite evaluar objetivamente los cambios en la forma de las fibras nerviosas después de la acción de los anestésicos locales. Se utilizó como material un total de sesenta nervios ciáticos, que se inyectaron intraneuralmente con solución salina en el grupo control (n=30), y una solución de bupivacaína liposomal al 1,33 % (n=30) en el grupo de prueba. Después de sacrificados los animales, se tomaron muestras de nervios y se realizaron preparaciones histológicas. Primero se describieron y examinaron las preparaciones utilizando un método histológico cualitativo, después de lo cual se tomaron imágenes digitales. Las imágenes fueron ingresadas al programa MorphoJ y procesadas mediante el método de morfometría geométrica. El examen histológico cualitativo no reveló diferencias en las fibras nerviosas después de la aplicación intraneural de solución fisiológica y bupivacaína liposomal. Usando el método de morfometría geométrica, se encontró un cambio estadísticamente significativo en la forma de los axones después de la aplicación intraneural de solución salina y bupivacaína liposomal (p = 0,0059). No se encontraron diferencias significativas en los cambios histológicos después del análisis histológico cualitativo de las preparaciones de secciones transversales de fibras nerviosas. Se observó un cambio estadísticamente significativo en la forma de los axones de las fibras nerviosas después del análisis de morfometría geométrica de imágenes digitales después de la aplicación intraneural de solución salina y bupivacaína liposomal.
Asunto(s)
Animales , Ratas , Bupivacaína/administración & dosificación , Técnicas Histológicas/métodos , Anestésicos Locales/administración & dosificación , Fibras Nerviosas/efectos de los fármacos , Análisis Discriminante , Ratas Wistar , Análisis de Componente Principal , Solución Salina/administración & dosificación , Inyecciones , Liposomas/administración & dosificaciónRESUMEN
BACKGROUND: Inactivation of sensory neurons expressing transient receptor potential vanilloid 1 (TRPV1) enhances breast cancer metastasis. Sensory neurons have profound effects on immune response to a wide range of diseases including cancer. Hence, activation of sensory nerves using feasible approaches such as specific TRPV1 agonists may inhibit breast cancer metastasis through neuroimmune pathways. TRPV1 agonists are considered for the treatment of pain and inflammatory diseases. METHODS: We here first determined the effects of four different TRPV1 agonists on proliferation of three different metastatic breast carcinoma cells since TRPV1 is also expressed in cancer cells. Based on the results obtained under in-vitro conditions, brain metastatic breast carcinoma cells (4TBM) implanted orthotopically into the mammary-pad of Balb-c mice followed by olvanil treatment (i.p.). Changes in tumor growth, metastasis and immune response to cancer cells were determined. RESULTS: Olvanil dose-dependently activated sensory nerve fibers and markedly suppressed lung and liver metastasis without altering the growth of primary tumors. Olvanil (5 mg/kg) systemically increased T cell count, enhanced intra-tumoral recruitment of CD8+ T cells and increased IFN-γ response to irradiated cancer cells and Con-A. Anti-inflammatory changes such as increased IL-10 and decrease IL-6 as well as S100A8+ cells were observed following olvanil treatment. CONCLUSIONS: Our results show that anti-metastatic effects of olvanil is mainly due to activation of neuro-immune pathways since olvanil dose used here is not high enough to directly activate immune cells. Furthermore, olvanil effectively depletes sensory neuropeptides; hence, olvanil is a good non-pungent alternative to capsaicin.
Asunto(s)
Neoplasias de la Mama/metabolismo , Capsaicina/análogos & derivados , Células Receptoras Sensoriales/efectos de los fármacos , Animales , Neoplasias de la Mama/tratamiento farmacológico , Capsaicina/metabolismo , Capsaicina/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Ratones , Ratones Endogámicos BALB C , Metástasis de la Neoplasia/tratamiento farmacológico , Fibras Nerviosas/efectos de los fármacos , Dolor , Células Receptoras Sensoriales/metabolismo , Canales Catiónicos TRPVRESUMEN
Purpose: Liraglutide treatment has shown promising anti-inflammatory and nerve regenerative results in preclinical and clinical trials. We sought to assess if liraglutide treatment would induce nerve regeneration through its anti-inflammatory and neurotrophic mechanisms by increasing peripapillary retinal nerve fiber layer (RNFL) thickness in individuals with long-term type 1 diabetes. Methods: Secondary analyses were performed on a prospective, double-blinded, randomized, placebo-controlled trial on adults with type 1 diabetes, distal symmetric polyneuropathy (DSPN), and confirmed diabetic retinopathy, who were randomized 1:1 to either 26 weeks placebo or liraglutide treatment. The primary endpoint was a change in peripapillary RNFL thickness between treatments, assessed by optical coherence tomography. Results: Thirty-seven participants were included in the secondary analysis. No differences in mean peripapillary RNFL thickness (overall ΔMean RNFL thickness; liraglutide -1 (±8) µm (-1%) vs. placebo -1 (±5) µm (-1%), P = 0.78, n = 37) or any of the quadrants. Peripapillary RNFL thicknesses were shown between treatments in either nonproliferative (ΔMean RNFL thickness; liraglutide -1 (±5) µm (-1%) vs. placebo 0 (±4) µm (0%), P = 0.80, N = 26) or proliferative diabetic retinopathy subgroup (ΔMean RNFL thickness; liraglutide -2 (±14) µm (-3%) vs. placebo -1 (±6) µm (-2%), P = 0.88, N = 11). Conclusions: In this study, 26 weeks of liraglutide treatment did not induce measurable changes in the assessed optic nerve thickness. Thus, this methodology does not support the induction of substantial nerve regeneration in this cohort with established retinopathy and DSPN. The trial was approved by the Danish Health and Medicines Authority. Informed consent was obtained from all participants. TODINELI study: EUDRA CT: 2013-004375-12, Ethics Ref: N-20130077 Clinical trial registration number: clinicaltrials.gov NCT02138045.
Asunto(s)
Retinopatía Diabética/patología , Liraglutida/farmacología , Fibras Nerviosas/efectos de los fármacos , Retina/efectos de los fármacos , Adulto , Diabetes Mellitus Tipo 1/patología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tomografía de Coherencia ÓpticaRESUMEN
Immune cell infiltration has been implicated in neurotoxic chemotherapy for cancer treatment. However, our understanding of immune processes is still incomplete and current methods of observing immune cells are time consuming or invasive. Corneal dendritic cells are potent antigen-presenting cells and can be imaged with in-vivo corneal confocal microscopy. Corneal dendritic cell densities and nerve parameters in patients treated with neurotoxic chemotherapy were investigated. Patients treated for cancer with oxaliplatin (n = 39) or paclitaxel (n = 48), 3 to 24 months prior to assessment were recruited along with 40 healthy controls. Immature (ImDC), mature (MDC) and total dendritic cell densities (TotalDC), and corneal nerve parameters were analyzed from in-vivo corneal confocal microscopy images. ImDC was increased in the oxaliplatin group (Median, Md = 22.7 cells/mm2) compared to healthy controls (Md = 10.1 cells/mm2, p = 0.001), but not in the paclitaxel group (Md = 10.6 cells/mm2). ImDC was also associated with higher oxaliplatin cumulative dose (r = 0.33, p = 0.04) and treatment cycles (r = 0.40, p = 0.01). There was no significant difference in MDC between the three groups (p > 0.05). Corneal nerve parameters were reduced in both oxaliplatin and paclitaxel groups compared to healthy controls (p < 0.05). There is evidence of elevation of corneal ImDC in oxaliplatin-treated patients. Further investigation is required to explore this potential link through longitudinal studies and animal or laboratory-based immunohistochemical research.
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Antineoplásicos/efectos adversos , Córnea/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Fibras Nerviosas/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Oxaliplatino/efectos adversos , Paclitaxel/efectos adversos , Anciano , Estudios de Casos y Controles , Córnea/inmunología , Córnea/inervación , Córnea/patología , Estudios Transversales , Células Dendríticas/inmunología , Células Dendríticas/patología , Femenino , Humanos , Masculino , Microscopía Confocal , Persona de Mediana Edad , Fibras Nerviosas/patología , Síndromes de Neurotoxicidad/inmunología , Síndromes de Neurotoxicidad/patología , Factores de Tiempo , Resultado del TratamientoRESUMEN
ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.
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Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/metabolismo , Antagonistas del Receptor Purinérgico P2X/farmacología , Receptores Purinérgicos P2X3/metabolismo , Trastornos Somatosensoriales/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Línea Celular , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Humanos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Potenciales de la Membrana/efectos de los fármacos , Ratones , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Ratas , Receptores Purinérgicos P2X3/genética , Trastornos Somatosensoriales/tratamiento farmacológico , Trastornos Somatosensoriales/etiologíaRESUMEN
Lidocaine has been shown to inhibit the invasion and metastasis of breast cancer, but the mechanism still remains unclear. This study explored the relationship between lidocaine and circulating seeding of breast cancer cells from the perspective of nerve fiber formation. The cell lines MDA-MB-231 and 4T1 were subcutaneously inoculated in mice to simulate the tumor self-seeding by circulating cancer cells. Lidocaine was used to treat these mice and tumor growth was observed. Silver staining was performed to observe the distribution of nerve fibers in tumor-bearing tissues, and immunohistochemical analysis was performed to observe the expression levels of nerve-related proteins. The results showed that lidocaine treatment effectively inhibited tumor growth and nerve fiber formation, and down-regulated the expression levels of protein gene product 9.5, neurofilament, nerve growth factor (NGF), and neuronatin (Nnat). Overexpression NGF and Nnat both could reverse the therapeutic effects of lidocaine. These results suggest that the effect of lidocaine on inhibiting breast cancer invasion and metastasis may be achieved by targeting Nnat, regulating the production of NGFs in cancer cells, and subsequently inhibiting the formation of nerve fibers.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/fisiopatología , Lidocaína/farmacocinética , Lidocaína/uso terapéutico , Metástasis de la Neoplasia/prevención & control , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Animales , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Metástasis de la Neoplasia/tratamiento farmacológico , Proteínas del Tejido Nervioso/efectos de los fármacosRESUMEN
The neurophysiological mechanisms underlying NGF-induced masseter muscle sensitization and sex-related differences in its effect are not well understood in humans. Therefore, this longitudinal cohort study aimed to investigate the effect of NGF injection on the density and expression of substance P, NMDA-receptors and NGF by the nerve fibers in the human masseter muscle, to correlate expression with pain characteristics, and to determine any possible sex-related differences in these effects of NGF. The magnitude of NGF-induced mechanical sensitization and pain during oral function was significantly greater in women than in men (P < 0.050). Significant positive correlations were found between nerve fiber expression of NMDA-receptors and peak pain intensity (rs = 0.620, P = 0.048), and expression of NMDA-receptors by putative nociceptors and change in temporal summation pain after glutamate injection (rs = 0.561, P = 0.003). In women, there was a significant inverse relationship between the degree of NGF-induced mechanical sensitization and the change in nerve fiber expression of NMDA-receptors alone (rs = - 0.659, P = 0.013), and in combination with NGF (rs = - 0.764, P = 0.001). In conclusion, women displayed a greater magnitude of NGF-induced mechanical sensitization that also was associated with nerve fibers expression of NMDA-receptors, when compared to men. The present findings suggest that, in women, increased peripheral NMDA-receptor expression could be associated with masseter muscle pain sensitivity.
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Ácido Glutámico/farmacología , Voluntarios Sanos , Inyecciones , Músculo Masetero/efectos de los fármacos , Factor de Crecimiento Nervioso/farmacología , Caracteres Sexuales , Adulto , Biomarcadores/metabolismo , Tejido Conectivo/metabolismo , Femenino , Humanos , Masculino , Masticación , Células Musculares/efectos de los fármacos , Células Musculares/metabolismo , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/metabolismo , Dolor/patología , Umbral del Dolor/efectos de los fármacos , Presión , Receptores de N-Metil-D-Aspartato/metabolismo , Sustancia P/metabolismo , Factores de TiempoRESUMEN
This study was aimed at disclosing the influence of intravesically instilled guanethidine (GUA) on the distribution, relative frequency and chemical coding of both the urinary bladder intramural sympathetic nerve fibers and their parent cell bodies in the caudal mesenteric ganglion (CaMG) in juvenile female pigs. GUA instillation led to a profound decrease in the number of perivascular nerve terminals. Furthermore, the chemical profile of the perivascular innervation within the treated bladder also distinctly changed, as most of axons became somatostatin-immunoreactive (SOM-IR), while in the control animals they were found to be neuropeptide Y (NPY)-positive. Intravesical treatment with GUA led not only to a significant decrease in the number of bladder-projecting tyrosine hydroxylase (TH) CaMG somata (94.3 ± 1.8% vs. 73.3 ± 1.4%; control vs. GUA-treated pigs), but simultaneously resulted in the rearrangement of their co-transmitters repertoire, causing a distinct decrease in the number of TH+/NPY+ (89.6 ± 0.7% vs. 27.8 ± 0.9%) cell bodies and an increase in the number of SOM-(3.6 ± 0.4% vs. 68.7 ± 1.9%), calbindin-(CB; 2.06 ± 0.2% vs. 9.1 ± 1.2%) or galanin-containing (GAL; 1.6 ± 0.3% vs. 28.2 ± 1.3%) somata. The present study provides evidence that GUA significantly modifies the sympathetic innervation of the porcine urinary bladder wall, and thus may be considered a potential tool for studying the plasticity of this subdivision of the bladder innervation.
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Antagonistas Adrenérgicos/farmacología , Axones/fisiología , Ganglios Simpáticos/fisiología , Guanetidina/farmacología , Vejiga Urinaria/inervación , Animales , Axones/efectos de los fármacos , Dopamina beta-Hidroxilasa/metabolismo , Femenino , Ganglios Simpáticos/efectos de los fármacos , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/metabolismo , Neuropéptido Y/metabolismo , Porcinos , Vejiga Urinaria/efectos de los fármacosRESUMEN
Bisphenol A (BPA) is used in the production of plastics approved for contact with feed and food. Upon entering living organisms, BPA, as a potent endocrine disruptor, negatively affects various internal organs and regulatory systems, especially in young individuals. Although previous studies have described the neurotoxic effects of BPA on various tissues, it should be underlined that the putative influence of this substance on the chemical architecture of the urinary bladder intrinsic innervation has not yet been studied. One of the most important neuronal substances involved in the regulation of urinary bladder functions is vasoactive intestinal polypeptide (VIP), which primarily participates in the regulation of muscular activity and blood flow. Therefore, this study aimed to determine the influence of various doses of BPA on the distribution pattern of VIP-positive neural structures located in the wall of the porcine urinary bladder trigone using the double-immunofluorescence method. The obtained results show that BPA influence leads to an increase in the number of both neurons and nerve fibres containing VIP in the porcine urinary bladder trigone. This may indicate that VIP participates in adaptive processes of the urinary bladder evoked by BPA.
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Compuestos de Bencidrilo/toxicidad , Sistema Nervioso Entérico/efectos de los fármacos , Fibras Nerviosas/efectos de los fármacos , Neuronas/efectos de los fármacos , Fenoles/toxicidad , Vejiga Urinaria/efectos de los fármacos , Péptido Intestinal Vasoactivo/metabolismo , Contaminantes Ocupacionales del Aire/toxicidad , Animales , Sistema Nervioso Entérico/metabolismo , Sistema Nervioso Entérico/patología , Femenino , Fibras Nerviosas/metabolismo , Fibras Nerviosas/patología , Neuronas/metabolismo , Neuronas/patología , Porcinos , Vejiga Urinaria/metabolismo , Vejiga Urinaria/patologíaRESUMEN
OBJECTIVE: In patients with chemotherapy-induced peripheral neuropathy (CIPN), demonstration of small fibre (SF) damage is important to understand chronic late effects. METHODS: Thirty patients having complaints compatible with possible CIPN following treatment with oxaliplatin or docetaxel were compared with 27 healthy subjects. All subjects were evaluated with quantitative sensory testing (QST) assessing SF function and laser evoked potentials (LEP). In addition, SF-damage was assessed using cutaneous silent periods evoked with electrical (El-CSP) and laser (Ls-CSP) stimuli. RESULTS: For LEP, N2P2 amplitudes were significantly smaller in patients than controls in both upper (P = 0.007) and lower extremities (P = 0.002), and the N1 amplitude in upper extremities of patients were significantly smaller than in controls (P = 0.001). SF-QST, LEP, Ls-CSP, and El-CSP were abnormal in 10 (33.3%), 16 (53.3%), 19 (63.3%), and 24 (80%) of CIPN patients, respectively. CONCLUSIONS: In patients with possible CIPN, El-CSP and Ls-CSP were more often abnormal than LEP and QST. This is probably because El-CSP and Ls-CSP inform mainly about peripheral nociceptive fibres, while LEP and QST inform about peripheral and central nociceptive pathways together. SIGNIFICANCE: LEP and QST are established methods to detect SF-damage. El- and Ls-CSP might help clinicians in diagnosing SF-damage.
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Antineoplásicos/efectos adversos , Potenciales Evocados por Láser/fisiología , Fibras Nerviosas/fisiología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Adulto , Anciano , Estudios Transversales , Docetaxel/efectos adversos , Electromiografía/efectos de los fármacos , Electromiografía/métodos , Femenino , Humanos , Potenciales Evocados por Láser/efectos de los fármacos , Masculino , Persona de Mediana Edad , Fibras Nerviosas/efectos de los fármacos , Oxaliplatino/efectos adversos , Enfermedades del Sistema Nervioso Periférico/diagnósticoRESUMEN
Autonomic nerve fibers in the liver are distributed along the portal tract, being involved in the regulation of blood flow, bile secretion and hepatic metabolism, thus contributing to systemic homeostasis. The present study investigated changes in hepatic nerve fibers in liver biopsy specimens from patients with normal liver, viral hepatitis and non-alcoholic steatohepatitis, in relation to clinical background. The areal ratio of nerve fibers to the total portal area was automatically calculated for each sample. The nerve fiber areal ratios (NFAR) for total nerve fibers and sympathetic nerve fibers were significantly lower in liver affected by chronic hepatitis, particularly viral hepatitis, and this was also the case for advanced liver fibrosis. However, the degree of inflammatory activity did not affect NFAR for either whole nerves or sympathetic nerves. Comparison of samples obtained before and after antiviral treatment for HCV demonstrated recovery of NFAR along with improvement of liver fibrosis.
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Antivirales/uso terapéutico , Hepatitis C/patología , Hepatitis Crónica/patología , Fibras Nerviosas/patología , Enfermedad del Hígado Graso no Alcohólico/patología , Adulto , Anciano , Antivirales/farmacología , Biopsia , Femenino , Hepatitis C/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Fibras Nerviosas/efectos de los fármacosRESUMEN
The synthetic progestin 17-α-hydroxyprogesterone caproate (17-OHPC) is commonly prescribed to pregnant women with a history of preterm delivery, despite little evidence of efficacy. The timing of 17-OHPC administration coincides with fetal mesocortical dopamine pathway development, yet the potential effects on cortical development and cognition are almost unknown. In rodent models, exposure to 17-OHPC significantly increased dopaminergic innervation of the medial prefrontal cortex (mPFC), an aberrant pattern of connectivity that may underlie deficits in cognitive flexibility observed in adulthood. In the present study, tyrosine hydroxylase (TH) immunoreactivity was used to determine whether 17-OHPC altered dopaminergic innervation of the mPFC during a neonatal period of synaptogenesis in males and females. Although there were no differences in the amount of TH-immunoreactive (-IR) fibres, there was a sex difference in TH-IR fibre distribution in deep layers of the prelimbic area (PL) mPFC; males had a narrower pattern of dopaminergic innervation than females. 17-OHPC exposure abolished these sex-specific patterns, such that 17-OHPC females had a narrower pattern in the PL than control females. In the infralimbic mPFC (IL), 17-OHPC males had a broader pattern of distribution of TH-immunoreactivity than control males with no differences in the amount of TH-IR fibres. 17-OHPC also created a sex difference in which males had a lower TH-IR fibre density than females. We also examined microglia, brain macrophages that play a key role in sculpting dopaminergic axon outgrowth in development, using phenotype as an indirect measure of microglial activity. Females had a greater number of reactive stout microglia compared to males in the PL, and males had more active round microglia than females in the IL. 17-OHPC treatment abolished the sex differences in both regions. These findings demonstrate that developmental exposure to 17-OHPC can exert differential effects in males and females and may diminish sex differences in cortical maturation.