Release of interleukin-10 and neurotrophic factors in the choroid plexus: possible inductors of neurogenesis following copolymer-1 immunization after cerebral ischemia

Abstract

Copolymer-1 (Cop-1) is a peptide with immunomodulatory properties, approved by the Food and Drug Administration of United States in the treatment of multiple sclerosis. Cop-1 has been shown to exert neuroprotective effects and induce neurogenesis in cerebral ischemia models. Nevertheless, the mechanism involved in the neurogenic action of this compound remains unknown. The choroid plexus (CP) is a network of cells that constitute the interphase between the immune and central nervous systems, with the ability to mediate neurogenesis through the release of cytokines and growth factors. Therefore, the CP could play a role in Cop-1-induced neurogenesis. In order to determine the participation of the CP in the induction of neurogenesis after Cop-1 immunization, we evaluated the gene expression of various growth factors (brain-derived neurotrophic factor, insulin-like growth factor 1, neurotrophin-3) and cytokines (tumor necrosis factor alpha, interferon-gamma, interleukin-4 (IL-4), IL-10 and IL-17), in the CP at 14 days after ischemia. Furthermore, we analyzed the correlation between the expression of these genes and neurogenesis. Our results showed that Cop-1 was capable of stimulating an upregulation in the expression of the genes encoding for brain-derived neurotrophic factor, insulin-like growth factor 1, neurotrophin-3 and IL-10 in the CP, which correlated with an increase in neurogenesis in the subventricular and subgranular zone. As well, we observed a downregulation of IL-17 gene expression. This study demonstrates the effect of Cop-1 on the expression of growth factors and IL-10 in the CP, in the same way, presents a possible mechanism involved in the neurogenic effect of Cop-1.

Neuroprotective and Neurorestorative Properties of Copolymer-1: Its Immunomodulating Effects on Ischemic Stroke

“…In this experiment, we again proved a significant increase of neurogenesis in the groups treated with Cop-1 in both, the SVZ and SGZ [83]. This data was similar to that previously reported [79].…”

“…With respect to anti-inflammatory cytokines, only IL-10 was significantly increased. In this investigation, we also found a significant increase of growth factors (BDNF, NT-3, and IGF-1) in the CP [83]. Both growth factors and IL-10 have been reported to be directly involved in the stimulation of SVZ and SGZ stem cells; specifically, IL-10 has been observed to induce stem cell proliferation but not differentiation in primary cultures [84].…”

Immunomodulation induced by central nervous system‐related peptides as a therapeutic strategy for neurodegenerative disorders

“…46,78 These effects are attributed to PA stimulation that alters the proinflammatory cytokine profile observed after cerebral ischemia, inducing neuroprotection, and neurogenesis. 47 The authors suggest that a possible GA-induced mechanism to promote neurogenesis is through modulating the microenvironment of choroid plexus by the upregulation and release of BDNF, IGF-1, NT-3, and IL-10 and downregulation of IL-17. 47 However, the immunization with high doses of GA immediately after cerebral ischemia did not show a protective effect.…”

“…47 The authors suggest that a possible GA-induced mechanism to promote neurogenesis is through modulating the microenvironment of choroid plexus by the upregulation and release of BDNF, IGF-1, NT-3, and IL-10 and downregulation of IL-17. 47 However, the immunization with high doses of GA immediately after cerebral ischemia did not show a protective effect. No reduction in infarct volume or improvement in the neural deficit was observed despite a significant increase in neurogenesis and a decrease in microglial activation.…”

Thinking Outside the Ischemia Box: Advancements in the Use of Multiple Sclerosis Drugs in Ischemic Stroke

“…Cruz et al delved into the pro-neurogenetic potential of the choroid plexus (CP), in mice assessed 14 days after TMCAO. Cop-1 significantly reduced neurological deficits, and increased neurogenesis in the "typical" neurogenetic sites (lateral ventricle walls/the subventricular zone and the sub-granular hippocampal zone), and the production of pro-neurogenetic factors and cytokines in the CP, the level of which was associated with the noted neurogenesis [52]. Mangin et al (2019) took their research one step further, by bringing diabetes mellitus into the picture.…”