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.

Stroke triggers a systemic inflammatory response that exacerbates the initial injury. Immunizing with peptides derived from CNS proteins can stimulate protective autoimmunity (PA). The most renowned of these peptides is copolymer-1 (Cop-1) also known as glatiramer acetate. This peptide has been approved for use in the treatment of multiple sclerosis. Cop-1-specific T cells cross the blood-brain barrier and secrete neurotrophins and anti-inflammatory cytokines that could stimulate proliferation of neural precursor cells and recruit them to the injury site; making it an ideal therapy for acute ischemic stroke. The aim of this work was to evaluate the effect of Cop-1 on neurogenesis and neurological recovery during the acute phase (7 days) and the chronic phase of stroke (60 days) in a rat model of transient middle cerebral artery occlusion (tMCAo). BDNF and NT-3 were quantified and infarct volumes were measured. We demonstrated that Cop-1 improves neurological deficit, enhances neurogenesis (at 7 and 60 days) in the SVZ, SGZ, and cerebral cortex through an increase in NT-3 production. It also decreased infarct volume even at the chronic phase of tMCAo. The present manuscript fortifies the support for the use of Cop-1 in acute ischemic stroke.

After an ischemic stroke, various harmful mechanisms contribute to tissue damage, including the inflammatory response. The increase in pro-inflammatory cytokines has been related to greater damage to the neural tissue and the promotion of neurological alterations, including cognitive impairment. Recent research has shown that the use of prebiotics and/or probiotics counteracts inflammation and improves cognitive function through the production of growth factors, such as brain-derived neurotrophic factor (BDNF), by reducing inflammatory molecules. Therefore, in this study, the effect of the symbiotic inulin and Enterococcus faecium on neuroprotection and memory improvement was evaluated in a rat model of transient middle cerebral artery occlusion (tMCAO). In order to accomplish this, the animals were subjected to ischemia; the experimental group was supplemented with the symbiotic and the control group with the vehicle. The neurological deficit as well as spatial and working memory were evaluated using the Zea Longa scale, Morris water maze, and the eight-arm maze tests, respectively. Infarct size, the levels of BDNF, and tumor necrosis factor-alpha (TNF-α) were also assessed. The results show that supplementation with the symbiotic significantly diminished the neurological deficit and infarct size, improved memory and learning, increased BDNF expression, and reduced TNF-α production. These findings provide new evidence about the therapeutic use of symbiotics for ischemic stroke and open up the possibilities for the design of further studies.

The rat is the most common animal model for the preclinical validation of neuroprotective therapies in spinal cord injury (SCI). Lipid peroxidation (LP) is a hallmark of the damage triggered after SCI. Free radicals react with fatty acids causing cellular and membrane disruption. LP accounts for a considerable amount of neuronal cell death after SCI. To better understand the implications of inbred and outbred rat strain selection on preclinical SCI research we evaluated LP after laminectomy sham surgery and a severe contusion of the T9 spinal cord in female Sprague-Dawley (SPD), Lewis (LEW) and Fischer 344 (F344) rats. Further analysis included locomotor recovery using the Basso, Beattie, and Bresnahan (BBB) scale and retrograde rubrospinal tract tracing. LEW had the highest levels of LP products 72 hours after sham surgery and SCI, significantly different from both F344 and SPD. SPD rats had the fastest functional recovery and highest BBB scores; these were not significantly different to F344. However, LEW rats achieved the lowest BBB scores throughout the two-month follow-up, yielding significant differences when compared to SPD and F344. To see if the improvement in locomotion was secondary to an increase in axon survival we evaluated rubrospinal neurons (RSN) via retrograde labeling of the rubrospinal tract and quantified cells at the red nuclei. The highest numbers of RSNs were observed in SPD rats then F344; the lowest counts were seen in LEW rats. The BBB scores significantly correlated with the amount of positively stained RSN in the red nuclei. It is critical to identify inter-strain variations as a potential confound in preclinical research. Multi-strain validation of neuroprotective therapies may increase chances of successful translation.