Neuroprotective and immunomodulatory roles of anti‐inflammatory neuropeptides on central nervous system disorders

Abstract

Nervous system disorders affect to more than one billion people worldwide and constitute around 35% of the total pool of all diseases in Europe. Due to their high severity and incidence, Multiple Sclerosis (MS) and Parkinson’s disease (PD) are two important diseases of central nervous system (CNS). MS is a neurodegenerative and autoimmune disease characterized by a chronic inflammatory demyelination and axonal damage of the CNS, being the main cause of non‐traumatic disability in young adults. MS pathology is mediated by a Th1/Th17 autoreactive response against the myelin sheath. On the other hand, PD is the second most common neurodegenerative disorder in adults over the age of 65. It is characterized by a progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) and their projections to the striatum. In the last years it has been accepted that the immune system also has a role in PD, where neuroinflammation seems to be a hallmark of its pathogenesis. Due to their complex pathophysiology, there is no effective cure for both disorders, being necessary looking for new treatments that act through a multitarget approach. In the last years, our lab has identified several neuropeptides that show anti‐inflammatory and immunomodulatory profiles. Among them, adrenomedullin and cortistatin seem also to have neuroprotective roles. The aim of the present study is to investigate the role of both neuropeptides in diseases of the CNS characterized by a disrupted immune response leading to neuroinflammation and neurodegeneration. We used a well‐established pre‐clinic model of MS, the experimental autoimmune encephalomyelitis (EAE) to assay the therapeutic potential of adrenomedullin. We demonstrated that adrenomedullin is able to reduce the incidence and severity of the disease, even when the disease was fully established. Moreover, the treatment of mice suffering EAE with adrenomedullin reduced the inflammatory infiltration, the number of demyelinating plaques, and the production of pro‐inflammatory mediators in spinal cord and/or brain. Furthermore, adrenomedullin was able to modulate the Th1/Th17 autoreactive response in the lymphoid organs and in the CNS. Interestingly, this effect was specific of the encephalitogenic antigent, and it seems to be related with the fact that the treatment with adrenomedullin generated immune tolerance by inducing regulatory T (Treg) cells and tolerogenic dendritic cells that were able to control the progression of the disease. Additionally, adrenomedullin promoted neuroprotective responses by up‐regulating the expression of neurotrophic factors. Accordingly, using a focal model of demyelination induced by the injection of the toxin lysolecithin, we demonstrated that adrenomedullin decreased the demyelinating area and increased the number of oligodendrocytes, suggesting a role on remyelination. Otherwise, adrenomedullin inactivates resident cells of CNS in presence of pro‐inflammatory stimulus. On the other hand, we previously described the beneficial effect of cortistatin in EAE. Therefore, we decided to analyze the potential therapeutic effect of this neuropeptide in a preclinical mouse model of PD induced by acute exposure to the neurotoxin MPTP. We observed that treatment with cortistatin reduced the loss of dopaminergic neurons in the SNpc and their projections to the striatum caused by MPTP injection. This effect correlated with an improvement in the locomotor activity. Furthermore, in an in vitro model of PD, cortistatin decreased cell death of dopaminergic neurons caused by MPP+. Moreover, cortistatin diminished the presence and activation of microglia cells and astrocytes in the SNpc of MPTP‐mice, suggesting a role of this neuropeptide in the regulation of neuroinflammation associated to this disorder. Furthermore, cortistatin induced the expression of neurotrophic factors. We also observed that cortistatin modulated the immune response of glial cells in the presence of α‐synuclein, as extracellular stimuli. Finally, animals deficient in cortistatin also revealed the relevance of this neuropeptide in the development and progression of this neurodegenerative disorder. Together, our results suggest that adrenomedullin and cortistatin emerge as potential new therapeutic agents that combine their anti‐inflammatory, immunomodulatory and neuroprotective properties to regulate at multiple levels the progression of CNS disorders.

Las enfermedades del sistema nervioso central (SNC) afectan a más de mil millones de personas en todo el mundo, y constituyen alrededor del 35% del total de enfermedades en Europa. Entre ellas, destacan la esclerosis múltiple (EM) y la enfermedad de Parkinson (EP) debido a su alta severidad e incidencia. La EM es una enfermedad neurodegenerativa y autoinmune caracterizada por una desmielinización e inflamación crónica, que cursa con daño axonal en el SNC, siendo la principal causa de discapacidad no traumática en jóvenes adultos. La patología de la EM está mediada por una respuesta autoreactiva tipo Th1/Th17 contra la vaina de la mielina. Por otra parte, la EP es el segundo desorden neurodegenerativo más común, por detrás de la enfermedad de Alzheimer, que afecta a personas mayores de 65 años. Se caracteriza por una degeneración progresiva de neuronas dopaminérgicas de la sustancia negra pars compacta (SNpc) y sus proyecciones en el estriado. En los últimos años se ha demostrado que el sistema inmunitario juega un papel importante en el desarrollo de la EP, siendo la neuroinflammación un proceso importante en su patogénesis. Debido a sus complejas patofisiologías no existe una cura eficaz para estas enfermedades. Por este motivo se hace necesaria la búsqueda de nuevos tratamientos que tengan varias dianas simultáneas con un papel relevante en la progresión y desarrollo de estos desórdenes. En los últimos años, nuestro laboratorio ha identificado distintos neuropéptidos con un perfil anti‐inflamatorio e inmunomodulador. Entre ellos se encuentran adrenomedulina y cortistatina, de los que además se ha demostrado un potencial papel neuroprotector. En esta tesis, hemos trabajado con ambos neuropéptidos caracterizando su potencial terapéutico en EM y EP.