Innate immune receptors, key actors in cardiovascular diseases

Cardiovascular diseases (CVDs) are the leading cause of death in the industrialized world. Most CVDs are associated with increased inflammation that arises mainly from innate immune system activation related to cardiac damage. Sustained activation of the innate immune system frequently results in maladaptive inflammatory responses that promote cardiovascular dysfunction and remodeling. Much research has focused on determining whether some mediators of the innate immune system are potential targets for CVD therapy. The innate immune system has specific receptors—termed pattern recognition receptors (PRRs)—that not only recognize pathogen-associated molecular patterns, but also sense danger-associated molecular signals. Activation of PRRs triggers the inflammatory response in different physiological systems, including the cardiovascular system. The classic PRRs, toll-like receptors (TLRs), and the more recently discovered nucleotide-binding oligomerization domain-like receptors (NLRs), have been recently proposed as key partners in the progression of several CVDs (e.g., atherosclerosis and heart failure). The present review discusses the key findings related to the involvement of TLRs and NLRs in the progression of several vascular and cardiac diseases, with a focus on whether some NLR subtypes (nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing receptor 3 and nucleotide-binding oligomerization domain-containing protein 1) can be candidates for the development of new therapeutic strategies for several CVDs

BML‐111 treatment prevents cardiac apoptosis and oxidative stress in a mouse model of autoimmune myocarditis.

Myocarditis is an inflammation of the myocardium that can progress to a more severe phenotype of dilated cardiomyopathy (DCM). Three main harmful factors determine this progression: inflammation, cell death, and oxidative stress. Lipoxins and their derivatives are endogenous proresolving mediators that induce the resolution of the inflammatory process. This study aims to determine whether these mediators play a protective role in a murine model of experimental autoimmune myocarditis (EAM) by treating with the lipoxin A4 analog BML‐111. We observed that EAM mice presented extensive infiltration areas that correlated with higher levels of inflammatory and cardiac damage markers. Both parameters were significantly reduced in BML‐treated EAM mice. Consistently, cardiac dysfunction, hypertrophy, and emerging fibrosis detected in EAM mice was prevented by BML‐111 treatment. At the molecular level, we demonstrated that treatment with BML‐111 hampered apoptosis and oxidative stress induction by EAM. Moreover, both in vivo and in vitro studies revealed that these beneficial effects were mediated by activation of Nrf2 pathway through CaMKK2‐AMPKα kinase pathway. Altogether, our data indicate that treatment with the lipoxin derivative BML‐111 effectively alleviates EAM outcome and prevents cardiac dysfunction, thus, underscoring the therapeutic potential of lipoxins and their derivatives to treat myocarditis and other inflammatory cardiovascular diseases.pre-print325 K

Protective effect of lipoxin A4 analog BML-111 on a murine model of autoimmune myocarditis

Resumen del póster presentado al 42nd Congress of the Spanish Society of Biochemistry and Molecular Biology (SEBBM), celebrado en Madrid del 16 al 19 de julio de 2019.Myocarditis is a cardiovascular disease characterized by a chronic inflammation of the myocardium that causes cardiac dysfunction. In the majority of patients this disease leads to dilated cardiomyopathy and represents the major cause of sudden cardiac death in young adults. Although it is a clinically severe disease, current treatments are inefficient and unspecific. In search for new therapies, lipoxins and their derivatives arise as a more effective and safer alternative thanks to their pro-resolving properties. The present work aimed to evaluate the effect of BML-111, a lipoxin A4 synthetic analog, in a murine model of autoimmune myocarditis (EAM) through molecular, histological and echocardiographic studies. We discovered that BML-111 treatment significantly improved cardiac function and reduced cardiac hypertrophy of myocarditisinduced mice. Furthermore, BML-111 also diminished infiltration of inflammatory cells in the heart and prevented the fibrotic process associated to cardiac remodeling. Lastly, we also observed that the levels of pro-inflammatory and pro-fibrotic molecular mediators (TGFβ, IL-6, TNFα and Galectin-3) in the heart decreased upon treatment. Together, these results demonstrate that BML-111 mitigates cardiac alterations associated to myocarditis by restoring cardiac function and reducing adverse cardiac remodeling. These findings highlight the therapeutic potential of lipoxins to treat myocarditis and provide new insights on the development of future therapies to alleviate the outcome of inflammatory heart diseases.Peer reviewe

Experiencia clínica con los cannabinoides en la terapia de la espasticidad en la esclerosis múltiple

Resumen: Introducción: La espasticidad es un síntoma muy frecuente entre los pacientes con esclerosis múltiple (EM). El objetivo del presente estudio es evaluar la efectividad y la seguridad de la combinación de delta-9-tetrahidrocannabinol (THC) y cannabidiol (CBD) en la práctica clínica del tratamiento de la espasticidad en EM. Métodos: Estudio observacional retrospectivo con los pacientes tratados con THC/CBD inhalado de abril del 2008 a marzo del 2012. Se recogieron variables descriptivas de paciente y tratamiento. La respuesta se evaluó mediante impresión global de respuesta terapéutica analizada por el médico. Resultados: Cincuenta y seis pacientes iniciaron tratamiento, 6 fueron excluidos por falta de datos. Se evaluó a 50 pacientes (42% hombres), mediana de edad 47,8 años, el 38% de ellos diagnosticados de EM primaria progresiva, el 44% de EM secundaria progresiva y el 18% de EM remitente recurrente. El motivo de prescripción fue espasticidad (44%), dolor (10%) o ambos (46%). Se suspendió tratamiento en 16 pacientes por inefectividad (7 pacientes), abandono (4) y efectos adversos (5). La mediana de tiempo de exposición de los pacientes que suspendieron tratamiento fue 30 días y 174 días para los que continuaban tratamiento al final del estudio. THC/CBD fue efectivo en un 80% de pacientes, con dosis mediana de 5 (2-10) pulverizaciones/día. El perfil de efectos adversos fue: mareo (11 pacientes), somnolencia (6), debilidad muscular (7), molestias bucales (2), diarrea (3), sequedad de boca (2), visión borrosa (2), agitación (1), náuseas (1), ideas paranoides (1). Conclusiones: THC/CBD se muestra como una buena alternativa al tratamiento habitual mejorando la espasticidad refractaria en la EM con perfil de toxicidad aceptable. Abstract: Introduction: Spasticity is a common symptom among patients with multiple sclerosis (MS).This study aims to assess the effectiveness and safety of the combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in clinical practice for the treatment of spasticity in MS. Methods: Retrospective observational study with patients treated with inhaled THC/CBD between April 2008 and March 2012. Descriptive patient and treatment variables were collected. Therapeutic response was evaluated based on the doctor's analysis and overall impression. Results: Of the 56 patients who started treatment with THC/CBD, 6 were excluded because of missing data. We evaluated 50 patients (42% male) with a median age 47.8 years (25.6-76.8); 38% were diagnosed with primary progressive MS, 44% with secondary progressive MS, and 18% with relapsing-remitting MS. The reason for prescribing the drug was spasticity (44%), pain (10%), or both (46%). Treatment was discontinued in 16 patients because of ineffectiveness (7 patients), withdrawal (4), and adverse effects (5). The median exposure time in patients whose treatment was discontinued was 30 days vs 174 days in those whose treatment continued at the end of the study. THC/CBD was effective in 80% of patients at a median dose of 5 (2-10) inhalations/day. The adverse event profile consisted of dizziness (11 patients), somnolence (6), muscle weakness (7), oral discomfort (2), diarrhoea (3), dry mouth (2), blurred vision (2), agitation (1), nausea (1), and paranoid ideation (1). Conclusions: THC/CBD appears to be a good alternative to standard treatment as it improves refractory spasticity in MS and has an acceptable toxicity profile. Palabras clave: Cannabidiol, Cannabinoides, Delta-9-tetrahidrocannabinol, Efectividad, Esclerosis múltiple, Espasticidad, Keywords: Cannabidiol, Cannabinoids, Delta-9-tetrahydrocannabinol, Effectiveness, Multiple sclerosis, Spasticit

Clinical experiences with cannabinoids in spasticity management in multiple sclerosis

Introduction: Spasticity is a common symptom among patients with multiple sclerosis (MS).This study aims to assess the effectiveness and safety of the combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in clinical practice for the treatment of spasticity in MS. Methods: Retrospective observational study with patients treated with inhaled THC/CBD between April 2008 and March 2012. Descriptive patient and treatment variables were collected. Therapeutic response was evaluated based on the doctor's analysis and overall impression. Results: Of the 56 patients who started treatment with THC/CBD, 6 were excluded because of missing data. We evaluated 50 patients (42% male) with a median age of 47.8 years (25.6–76.8); 38% were diagnosed with primary progressive MS, 44% with secondary progressive MS, and 18% with relapsing-remitting MS. The reason for prescribing the drug was spasticity (44%), pain (10%), or both (46%). Treatment was discontinued in 16 patients because of ineffectiveness (7 patients), withdrawal (4), and adverse effects (5). The median exposure time in patients whose treatment was discontinued was 30 days vs 174 days in those whose treatment continued at the end of the study. THC/CBD was effective in 80% of the patients at a median dose of 5 (2-10) inhalations/day. The adverse event profile consisted of dizziness (11 patients), somnolence (6), muscle weakness (7), oral discomfort (2), diarrhoea (3), dry mouth (2), blurred vision (2), agitation (1), nausea (1), and paranoid ideation (1). Conclusions: THC/CBD appears to be a good alternative to standard treatment as it improves refractory spasticity in MS and has an acceptable toxicity profile. Resumen: Introducción: La espasticidad es un síntoma muy frecuente entre los pacientes con esclerosis múltiple (EM). El objetivo del presente estudio es evaluar la efectividad y la seguridad de la combinación de delta-9-tetrahidrocannabinol (THC) y cannabidiol (CBD) en la práctica clínica del tratamiento de la espasticidad en EM. Métodos: Estudio observacional retrospectivo con los pacientes tratados con THC/CBD inhalado de abril del 2008 a marzo del 2012. Se recogieron variables descriptivas de paciente y tratamiento. La respuesta se evaluó mediante impresión global de respuesta terapéutica analizada por el médico. Resultados: Cincuenta y seis pacientes iniciaron tratamiento, 6 fueron excluidos por falta de datos. Se evaluó a 50 pacientes (42% hombres), mediana de edad 47,8 años, el 38% de ellos diagnosticados de EM primaria progresiva, el 44% de EM secundaria progresiva y el 18% de EM remitente recurrente. El motivo de prescripción fue espasticidad (44%), dolor (10%) o ambos (46%). Se suspendió tratamiento en 16 pacientes por inefectividad (7 pacientes), abandono (4) y efectos adversos (5). La mediana de tiempo de exposición de los pacientes que suspendieron tratamiento fue 30 días y 174 días para los que continuaban tratamiento al final del estudio. THC/CBD fue efectivo en un 80% de pacientes, con dosis mediana de 5 (2-10) pulverizaciones/día. El perfil de efectos adversos fue: mareo (11 pacientes), somnolencia (6), debilidad muscular (7), molestias bucales (2), diarrea (3), sequedad de boca (2), visión borrosa (2), agitación (1), náuseas (1), ideas paranoides (1). Conclusiones: THC/CBD se muestra como una buena alternativa al tratamiento habitual mejorando la espasticidad refractaria en la EM con perfil de toxicidad aceptable. Keywords: Cannabidiol, Cannabinoids, Delta-9-tetrahydrocannabinol, Effectiveness, Multiple sclerosis, Spasticity, Palabras clave: Cannabidiol, Cannabinoides, Delta-9-tetrahidrocannabinol, Efectividad, Esclerosis múltiple, Espasticida