**1. Introduction**

Cerebral ischemia is the main disorder of cerebrovascular diseases; currently, according to data from the World Health Organization, it is the second main cause of death worldwide [1] and the third principal cause of disability. In the last 40 years alone, the incidence of this condition has more than doubled in people from low and middle-revenue countries [2].

The increment in the incidence of this condition is due to increased risk factors as diabetes mellitus, hypertension, obesity, hyperlipidemia, and increased longevity of the population [3]. These factors allow the development of atherosclerosis, which is the main cause of ischemia [4]; thereby, it is considered that for the coming years this scenario will be maintained while strategies to reduce these factors are progressing.

Stroke is distinguished by the brusque reduction of blood flow; therefore, the levels of oxygen and glucose are also reduced significantly, to the point of altering the metabolic activities of the neural tissue [5]. As a consequence of the latter, the low production of ATP and the acidification of the environment induce the

depolarization of the membranes causing the intracellular increase of Ca2+ that is added to the one released by the endoplasmic reticulum and mitochondria [6].

Neuronal depolarization causes the release of glutamate which, when bound to its ionotropic N-methyl-D-aspartate (NMDA) and -amino-3-hydroxy-5-methyl-4-isoxazolpropionic (AMPA) receptors, achieves greater depolarization and, as a consequence, conditions of excitotoxicity [7]. These conditions are coupled with the production of free radicals [8] and lead to cell death by the activation of molecules that induce necrosis and apoptosis [9].

Along with the lesion caused by the decrease in blood flow, the immune response is added to the events involved in both the detriment of the tissue and its protection.

#### **2. Immunological response in stroke**

Inflammation is usually present before the development of arterial obstruction that gives rise to the ischemic event. The development of atherosclerosis is accompanied by the production of oxygen free radicals (ROS), expression of cell adhesion molecules, and production of proinflammatory cytokines as IL-1β and tumor necrosis factor-α (TNF-α) by endothelial cells [10].

Shortly after occlusion, endothelial cells express a greater amount of intercellular adhesion molecules (ICAM), deposition of mannose binding lectin molecules that trigger activation of the complement pathway [11], producing higher amounts of ROS. The overproduction of ROS activates the prostaglandin pathway that stimulates the production of matrix metalloproteinases (MMP) that even though degrading constituents of the extracellular matrix, reshape the vascular endothelium seeking to protect of the blood brain barrier (BBB) [12].

The release of chemokines such as CCL2 allows endothelial permeability [13], leading to the translocation of P-selectin from Weibel-Palade bodies, as well as the expression of ICAM-1 and vascular cell adhesion molecule (VCAM)-1 and E-selectin, on the endothelial surface [14]. Theses phenomena, together with the damage of the extracellular matrix facilitate the extravasation of macromolecules and water, which causes the development of vasogenic edema [15]. Peripheral immune cells then enter the injured cerebral parenchyma [16] facilitating the loss of the integrity of the BBB.

Neutrophils are the first leukocytes that migrate to the cerebral parenchyma; they have been detected since the first hour after ischemia and reach their maximum peak in 1–3 days [17]. In the clinic, it has been observed that the higher blood neutrophil count is associated with higher infarction volumes in patients with acute stroke [18].

The second cell type that enters the neural tissue are monocytes, these infiltrate within 24 h of the onset of the ischemic event reaching its peak on day 3 [19]; their differentiation process toward macrophages and their activation will be determined by the molecular environment to which they arrive. This process is similar to that experienced by T lymphocytes, which reach the parenchyma 24–96 h post-ischemia [20].

At the same time, the cells of the injured cerebral parenchyma release damage associated molecular patterns (DAMPs) that activate the microglia. Depending on the activation environment, the microglia can acquire a proinflammatory (M1) or anti-inflammatory (M2) phenotype [21]. In the M1 phenotype, the microglia acquires phagocytic capacity, produces NO, free radicals, and proinflammatory cytokines (e.g. TNF-α, IL-12 and IL-6) [22]. Some regions in the ischemic penumbra present an activation of M2 microglia distinguished by the production of anti-inflammatory and repair molecules, such as insulin growth factor 1 (IGF-1), IL-10, and arginase 1 [23].

**145**

*Neuroprotective and Neurorestorative Properties of Copolymer-1: Its Immunomodulating Effects…*

Some researchers suggest that the M2 phenotype is initially activated during the acute phase in the peripheral zone to the infarction [24], since it has been determined that the levels of IL-10, TGF-β, and CD206 increase from the first day after the lesion and reach the maximum point between 4 and 6 days, possibly trying to keep the viability of tissue. In addition, TGF-β induces the antiinflammatory phenotype of microglia, related with enhanced proliferation and

In contrast, some authors suggest that the first response is proinflammatory [27], due to the loss of regulatory mechanisms; when a stroke occurs there is an important

Although contradictory, both positions could be correct. The fact is that, M1 and M2 phenotypes actively participate in the response observed after ischemic event; however, in normal conditions, there is an important prevalence of the M1 phenotype leading the response to a proinflammatory reaction that, instead of helping,

On the other hand, perivascular macrophages and monocytes of peripheral origin that arrive at the injured parenchyma induce the synthesis of chemokines like CXCL1 and CXCL2, which are fundamental for recruiting more neutrophils to the injury site [29, 30]. The dendritic cells (DC) present a greater expression of the major histocompatibility complex II (MHCII) and the co-stimulant molecule CD80. This causes an important enhance in the interaction of T cells around and within

When T lymphocytes are activated by antigen-presenting cells (APCs) toward a Th1 phenotype, the secretion of proinflammatory cytokines like as IFN-γ, TNF, and LT-α [lymphotoxin] increases. This cytokine profile, intensify proinflammatory response and thereby, tissue damage. Contrarily, when T cells are activated toward a Th2 phenotype they produce anti-inflammatory cytokines such as IL-4 and IL-10 [32]. These cytokines have been associated with tissue protection mechanisms and even increased neurogenesis. This immune response that exerts protective effects and limits the damage caused by ischemia [19] can be stimulated by immunomodu-

Copolymer-1 [Cop-1], also known as glatiramer acetate (GA) or copaxone [trade

Cop-1 was originally synthesized from mylelin basic protein (MBP) to identify the precise immunogenic sequence and provoke experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS); however, it did not present encephalitogenic characteristics [34]; on the contrary, it has suppressive and protective effects on EAE [35]. In the clinic, copaxone is able to diminish the relapse rate and improve the disability of patients with relapsing-remitting MS [36]. Copaxone obtained its approvement by the Food and Drugs Administration [FDA]

At this time, the exact mechanism by which Cop-1 exerts its protective effects is not known at all. Studies carried out in EAE suggest that Cop-1 has greater affinity for the MHCII binding site of APC when competing with peptide complexes derived from the MBP, specifically with the epitope 82–100 [37]. This competition may also be present among the complexes for the TCR binding site of the lympho-

name], is a blend of peptides formed by random sequences of four amino acids: glutamic acid, lysine, alanine, and tyrosine; these have a variable length from 45 to

200 amino acid residues and a molecular weight of 4000–9000 Da [33].

the damaged areas inducing then a stronger immune response [31].

*DOI: http://dx.doi.org/10.5772/intechopen.91343*

activation of the M1 microglial phenotype [28].

neuroprotection [25, 26].

promotes more damage.

latory molecules such as copolymer-1.

of U.S.A. in 1996 and in Europe in 2001 [33].

cytes [38] that, when activated, induces a Th2 response [39].

**3. Copolymer-1**

#### *Neuroprotective and Neurorestorative Properties of Copolymer-1: Its Immunomodulating Effects… DOI: http://dx.doi.org/10.5772/intechopen.91343*

Some researchers suggest that the M2 phenotype is initially activated during the acute phase in the peripheral zone to the infarction [24], since it has been determined that the levels of IL-10, TGF-β, and CD206 increase from the first day after the lesion and reach the maximum point between 4 and 6 days, possibly trying to keep the viability of tissue. In addition, TGF-β induces the antiinflammatory phenotype of microglia, related with enhanced proliferation and neuroprotection [25, 26].

In contrast, some authors suggest that the first response is proinflammatory [27], due to the loss of regulatory mechanisms; when a stroke occurs there is an important activation of the M1 microglial phenotype [28].

Although contradictory, both positions could be correct. The fact is that, M1 and M2 phenotypes actively participate in the response observed after ischemic event; however, in normal conditions, there is an important prevalence of the M1 phenotype leading the response to a proinflammatory reaction that, instead of helping, promotes more damage.

On the other hand, perivascular macrophages and monocytes of peripheral origin that arrive at the injured parenchyma induce the synthesis of chemokines like CXCL1 and CXCL2, which are fundamental for recruiting more neutrophils to the injury site [29, 30]. The dendritic cells (DC) present a greater expression of the major histocompatibility complex II (MHCII) and the co-stimulant molecule CD80. This causes an important enhance in the interaction of T cells around and within the damaged areas inducing then a stronger immune response [31].

When T lymphocytes are activated by antigen-presenting cells (APCs) toward a Th1 phenotype, the secretion of proinflammatory cytokines like as IFN-γ, TNF, and LT-α [lymphotoxin] increases. This cytokine profile, intensify proinflammatory response and thereby, tissue damage. Contrarily, when T cells are activated toward a Th2 phenotype they produce anti-inflammatory cytokines such as IL-4 and IL-10 [32]. These cytokines have been associated with tissue protection mechanisms and even increased neurogenesis. This immune response that exerts protective effects and limits the damage caused by ischemia [19] can be stimulated by immunomodulatory molecules such as copolymer-1.
