Immunization with Cop-1 promotes neuroprotection and neurogenesis after ischemic stroke

In rats and since we have NO strategy from our fucking failures of stroke associations this will probably never be tested in humans. You're not only screwed, you're fucked over by the incredible display of incompetence in the stroke world.
http://www.nrronline.org/article.asp?issn=1673-5374;year=2015;volume=10;issue=11;spage=1733;epage=1734;aulast=Cruz
Correspondence Address:
Antonio Ibarra
Facultad de Ciencias de la Salud, Universidad Anáhuac México Norte, Av. Universidad Anáhuac No. 46, Col. Lomas Anáhuac, C.P.52786, Huixquilucan Edo. de México; Proyecto CAMINA A.C., Tlalpan No. 4430 Col. Toriello Guerra, C.P. 14050, México City
Mexico

Source of Support: None, Conflict of Interest: None
DOI: 10.4103/1673-5374.165288

How to cite this article: Cruz Y, Suárez-Meade P, Ibarra A. Immunization with Cop-1 promotes neuroprotection and neurogenesis after ischemic stroke. Neural Regen Res 2015;10:1733-4

How to cite this URL: Cruz Y, Suárez-Meade P, Ibarra A. Immunization with Cop-1 promotes neuroprotection and neurogenesis after ischemic stroke. Neural Regen Res [serial online] 2015 [cited 2015 Dec 15];10:1733-4. Available from: http://www.nrronline.org/text.asp?2015/10/11/1733/165288

Cerebrovascular diseases are considered to be amongst the most serious public health issues, since they are the third leading cause of death (WHO, 2014) and the most common cause of disability worldwide. Its monetary significance is evidenced by the economic burden imposed on health care systems, given that the cost of medical care for a patient that has suffered a stroke is around $25,741 US dollars every 5 years (Luengo-Fernandez et al., 2012). A stroke occurs as a result of a disturbance or interruption of cerebral blood flow that significantly reduces the supply of oxygen and glucose to the neural tissue. Consequently, several cell death mechanisms (secondary lesion mechanisms) such as necrosis, excitotoxicity, free radical production and inflammation are triggered (Castillo, 2000). Over the last decades, a variety of therapies with thrombolytic, neuroprotective, and restorative properties have been investigated. However, the results of these studies appear to be limited. That is the case of the tissue plasminogen activator (tPA) - the first line of treatment for decades - which is associated with low rates of recanalization and high rates of morbidity. Also, endovascular intervention, particularly mechanical thrombectomy, has been proposed as a promising therapeutic adjunct to tPA for the treatment of stroke; however, until recently, the efficacy of this therapeutic approach has been controversial (Ding, 2015). Innovative theurapeutic options are currently being developed in order to restore affected neuronal circuits following a cerebral ischemic event. Some of these innovative therapeutic approaches are based on stem cell transplantation and/or induction of neurogenesis.

After stroke; astrocytes, microglia, and endothelial cells induce an early response in gene expression through the activation of nuclear factor-κB (NF-κB). This event promotes a pro-inflammatory environment characterized by the expression of interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNF-α) and several chemokines (Fumagalli et al., 2015). These proteins activate adhesion molecules and produce a subsequent infiltration of inflammatory cells, especially T lymphocytes specific to neural constituents. Recruitment and activation of immune cells increase the presence of lytic enzymes and neurotoxic mediators (e.g., free radicals) which in turn, cause secondary damage to the neural tissue.

The immune system plays an essential role in the pathophysiology of some neurodegenerative diseases. It has previously been associated with disease exacerbation (Castillo, 2000). Nevertheless, recent work suggests that inflammatory cells and even autoimmune T lymphocytes could have the ability to promote neuroprotection (Schwartz and Shechter, 2010). These findings provide the basis to conceive a new therapeutic paradigm: Protective autoimmunity (PA), a physiological phenomenon that develops after central nervous system (CNS) damage (Hauben et al., 2000). Paradoxically, the beneficial effect of this immune response is exerted by autoreactive T cells directed against neural contituents (Schwartz and Shechter, 2010). In this light, PA might have beneficial effects over the secondary mechanisms of stroke and cerebrovascular diseases, nonetheless in order to exert these, it must be modulated. Evidence suggests that PA could be modulated by active inmunization with neural-derived peptides (NDP) in favor of protecting neural tissue after CNS damage (Cruz et al., 2015). Copolymer-1 (Cop-1; Copaxone, glatiramer acetate) is a synthetic polypeptide consisting of four amino acids: L-alanine, L-glutamic acid, L-lysine, and L-tyrosine in a fixed molar ratio of 6.0:1.9:4.7:1.0 and a molecular weight ranging from 4.7 to 11 kDa. Cop-1 has demonstrated to positively modulate PA and induce a strong effect over the immune response by binding to the MHC class II molecules on the surface of antigen-presenting cells, without being processed. Vaccination with Cop-1 stimulates T cells, which are activated by determinants common to Cop-1 and myelin basic protein (MBP); suggesting that it has a strong cross-reaction with MBP peptides. Cop-1 increases Th2/3 cytokine secretion patterns, regulatory T cells (Aharoni et al., 2003), IL-4, IL-10, and transforming growth factor-β (TGF-β), a cytokine type that by itself possesses immunomodulatory properties and inhibitis the production of inflammatory cytokines such as INF-γ, TNF-α and IL-12. Moreover, Cop-1 immunization has the ability to exert neuroregenerative properties. It has proven to increase the production of brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1) and neurotrophin 3 and 4 (NT-3 and 4) in models of experimental autoimmune encephalomyelitis (EAE) and schizophrenia (Aharoni et al., 2003; Kipnis et al., 2004). Together, these findings suggest that modulation of PA -through Cop-1 inmunization- could promote a neuroprotective and neurorestorative environment. Therefore, our group decided to investigate the neuroprotective and neuroregenerative effects of this strategy in a focal cerebral ischemia/reperfusion model.

In order to evaluate the neuroprotective effect of Cop-1, a model of transient middle cerebral artery occlusion (tMCAo) was developed in our laboratory. Animals were injected with 200 µg of Cop-1 dissolved in saline solution and emulsified in an equal volume of complete Freund's adjuvant. Immunization was applied subcutaneously at the interscapular space immediately after reperfusion (acute phase). In a first study, Cop-1 immunized animals presented a significant neurological recovery when compared to controls 7 days after ischemia (Ibarra et al., 2007). Additionally, histopathological findings had a significant correlation with neurological recovery: rats receiving Cop-1 immunization presented a smaller infarct volume after stroke. Such reduction in infarct volume could be related to increased neuroprotection, resulting in less tissue necrosis or inhibition of growth of the ischemic core [Figure 1]A). According to recent evidence, these results suggest that Cop-1 specific immune modulation could be the primary source of neuroprotection after ischemia.