**4. The effect of copolymer-1 on inflammatory diseases**

The beneficial effects showed by copaxone in patients with MS, even though the knowledge of its immunomodulatory mechanisms is partial, encouraged the evaluation of its effect in other experimental models.

In the model of optic nerve lesion—which tries to reproduce the characteristics of secondary degeneration—Cop-1 demonstrated an interesting neuroprotective effect. Kipnis et al. [55] evaluated the effect of adoptive anti-Cop-1 T cell transfer and immunization with Cop-1 immediately after causing optic nerve contusion in Lewis rats; their results were very encouraging as they observed reduction in axonal degeneration, accumulation of T lymphocytes in injured areas and obtained a significant increase in IL-10 and BDNF *in-vitro*. In contrast, using a model of axon transection of the optic nerve, Blair and coworkers [56] found no beneficial effects of Cop-1. The difference in the results may be due to the different inflammatory response evoked by the type of injury (contusion or transection). Inflammation is more pronounced after contusion as compared to the one observed after a transection. It should be an issue to be studied by future investigations.

**147**

processes [73].

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

Parkinson's disease presents gradual reduction of dopaminergic neurons in the region of the substantia nigra and the striatum in the brain, it is not known the reason that causes the death of these neurons, but the pathology is characterized by a significant increase in oxidative stress, mitochondrial dysfunction, neuroinflammation, and cell death [57]. Patients with PD present an increase in TNF-β, IL-1β, and IL-6 and other inflammatory cytokines resulting from the activation of the macrophages and microglia towards a proinflammatory phenotype capable of releasing NO and superoxide radicals that further damage neural tissue facilitating

In the traditional model to induce Parkinson's disease in mice [induction by 1-1-methyl-1,2,3,6-tetrahydropyridine], it was observed that Cop-1 reduces the degeneration of dopaminergic cells. This effect is achieved since Cop-1 induces the up-regulation in the protein expression of tyrosine hydroxylase [59, 60]. Additionally, it has been reported an increase in glial cell-derived neurotrophic factor (GDNF), reduction of activated microglia markers, and restoration of BDNF [61]. Based in these findings, several research groups consider COP-1 as a pharmacological alterna-

Copolimer-1 has also been tested in models of Alzheimer's disease (AD). AD is a pathology that produces deposits of the β-amyloid protein, dystrophic neurites, loss of synapses and neurons, and elevated gliosis [63]. From the early stages of the pathology, it has been observed microgial activation toward a M2 neuroprotective phenotype that is modified as the disease progresses [64]. In advanced stages, a proinflammatory microenvironment characterized by the presence of cytokines

After Cop-1 administration, microglia modulation toward a M2 phenotype is observed, in such a way as to promote neuronal survival and neural tissue repair in AD models [66]. Butovsky and coworkers showed that Cop-1 immunizations lead to enhanced infiltration of monocyte-derived macrophages into neural tissue with an anti-inflammatory profile expressing minor levels of TNF-α and high levels of IL-10, TGF-β1, and IGF1. In this scenario, phagocytosis of preformed fibrillar amyloid-β by bone marrow-derived macrophages increased dramatically after the administration of Cop-1. Also, to demonstrate benefits on the preservation of cognitive function, the investigation showed an important synaptic protection, plaque removal, restriction of astrogliosis, and modulation of the immune molecu-

Another pathology that evidenced the beneficial effects produced by Cop-1 is amyotrophic lateral sclerosis (ALS). This is a neurodegenerative disease known by the progressive depletion of the upper and lower motor neurons [69]. During pathogenesis, glutamate excitotoxicity, structural and functional anomalies of mitochondria, damaged axonal structure, and oxidative stress conducted by free

In this case, Angelov and colleagues showed—in mouse models—that the

The beneficial effects of Cop-1 on ALS have been assessed in a Phase II trial conducted by Mosley. This investigation evaluated the cytokine response of ALS patients treated with copaxone and showed that copaxone is capable of inducing a

Copaxone is also tested in other pathologies at clinical settings. For instance, a phase III study on optic neuritis is now being conducted to evaluate the thickness of the layer of nerve fiber of the retina after 6 months of treatment. The results of this study have not been published. Finally, copaxone has been tested in Crohn's disease and various types of carcinomas, studies where copaxone is in evaluation

administration of Cop-1 promotes the survival of motor neurons [71].

temporary change in cytokines from Th1 to Th2 phenotype [72].

tive for this pathology which should be deeply studied [62].

such as IL-1β, TNF-α, IL-6 has been reported [65].

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

disease progression [58].

lar environment [67, 68].

radicals are strongly observed [70].

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

Parkinson's disease presents gradual reduction of dopaminergic neurons in the region of the substantia nigra and the striatum in the brain, it is not known the reason that causes the death of these neurons, but the pathology is characterized by a significant increase in oxidative stress, mitochondrial dysfunction, neuroinflammation, and cell death [57]. Patients with PD present an increase in TNF-β, IL-1β, and IL-6 and other inflammatory cytokines resulting from the activation of the macrophages and microglia towards a proinflammatory phenotype capable of releasing NO and superoxide radicals that further damage neural tissue facilitating disease progression [58].

In the traditional model to induce Parkinson's disease in mice [induction by 1-1-methyl-1,2,3,6-tetrahydropyridine], it was observed that Cop-1 reduces the degeneration of dopaminergic cells. This effect is achieved since Cop-1 induces the up-regulation in the protein expression of tyrosine hydroxylase [59, 60]. Additionally, it has been reported an increase in glial cell-derived neurotrophic factor (GDNF), reduction of activated microglia markers, and restoration of BDNF [61]. Based in these findings, several research groups consider COP-1 as a pharmacological alternative for this pathology which should be deeply studied [62].

Copolimer-1 has also been tested in models of Alzheimer's disease (AD). AD is a pathology that produces deposits of the β-amyloid protein, dystrophic neurites, loss of synapses and neurons, and elevated gliosis [63]. From the early stages of the pathology, it has been observed microgial activation toward a M2 neuroprotective phenotype that is modified as the disease progresses [64]. In advanced stages, a proinflammatory microenvironment characterized by the presence of cytokines such as IL-1β, TNF-α, IL-6 has been reported [65].

After Cop-1 administration, microglia modulation toward a M2 phenotype is observed, in such a way as to promote neuronal survival and neural tissue repair in AD models [66]. Butovsky and coworkers showed that Cop-1 immunizations lead to enhanced infiltration of monocyte-derived macrophages into neural tissue with an anti-inflammatory profile expressing minor levels of TNF-α and high levels of IL-10, TGF-β1, and IGF1. In this scenario, phagocytosis of preformed fibrillar amyloid-β by bone marrow-derived macrophages increased dramatically after the administration of Cop-1. Also, to demonstrate benefits on the preservation of cognitive function, the investigation showed an important synaptic protection, plaque removal, restriction of astrogliosis, and modulation of the immune molecular environment [67, 68].

Another pathology that evidenced the beneficial effects produced by Cop-1 is amyotrophic lateral sclerosis (ALS). This is a neurodegenerative disease known by the progressive depletion of the upper and lower motor neurons [69]. During pathogenesis, glutamate excitotoxicity, structural and functional anomalies of mitochondria, damaged axonal structure, and oxidative stress conducted by free radicals are strongly observed [70].

In this case, Angelov and colleagues showed—in mouse models—that the administration of Cop-1 promotes the survival of motor neurons [71].

The beneficial effects of Cop-1 on ALS have been assessed in a Phase II trial conducted by Mosley. This investigation evaluated the cytokine response of ALS patients treated with copaxone and showed that copaxone is capable of inducing a temporary change in cytokines from Th1 to Th2 phenotype [72].

Copaxone is also tested in other pathologies at clinical settings. For instance, a phase III study on optic neuritis is now being conducted to evaluate the thickness of the layer of nerve fiber of the retina after 6 months of treatment. The results of this study have not been published. Finally, copaxone has been tested in Crohn's disease and various types of carcinomas, studies where copaxone is in evaluation processes [73].

*Neuroprotection - New Approaches and Prospects*

patients with multiple sclerosis [45, 46].

mechanisms such as memory and learning.

lia, and astrocytes.

as COX2 and iNOS [52].

the synthesis of growth factors.

TGF-β [53].

The Cop-1 response is distinguished by increased synthesis of IL-4, IL-5, IL-10, IL-13, and TGF-β [33, 40–43]. Cop-1 has also been observed to increase the presence of regulatory T lymphocytes [44] and regulatory CD8+ T lymphocytes in

Another important effect of copolymer-1 is the production of growth factors, among which stand out; the brain derived neurotrophic factor [BDNF] [47, 48], IGF-1, [49] and neurotrophins NT-3 and NT-4 [47]. It is known that, in addition to inducing neuroprotection and neurorestoration, these growth factors are related to

The molecular basis by which Cop-1 exerts its neuroprotective effect has been evaluated in several *in-vitro* assays. The most explanatory results have been obtained in the analysis of the effect of Cop-1 on APC such as monocytes, microg-

It has been showed that through the blockade of the nuclear factor kappa B [NFkB], Cop-1 reduces the expression of the chemokine CCL5 [RANTES], which is upregulated by the presence of IL-1β [50] and TNF-α in human astroglial cells [51]. A similar effect has also been observed on the monocyte chemotactic protein-1 [MPC-1] and adhesion molecules VCAM-1 and selectin E in endothelial cells as well

It has also been observed that Cop-1 induces differentiation of type II monocytes independently of the binding of Cop-1 to MHCII. Weber et al. demonstrated that this differentiation is due to the fact that Cop-1 reduces the phosphorylation of the transcription factor STAT-1 by stimulating the expression of IL-10 and

On the other hand, it has also been observed that Cop-1 has a direct effect on glial cells [microglia and astrocytes] which are activated in conjunction with T cells reducing STAT-1 and STAT-3 phosphorylation through increased expression of cytokine signaling suppressor (SOCS-1) and independently of IFNϒR, accompa-

Even though the molecular pathways by which Cop-1 acts are not yet completely established, the microenvironment induced by this compound is capable of allowing neuroprotection since it reduces the deleterious scenario that leads to neural death. Additionally, the new conditions could facilitate tissue restoration through

The beneficial effects showed by copaxone in patients with MS, even though the knowledge of its immunomodulatory mechanisms is partial, encouraged the evalu-

In the model of optic nerve lesion—which tries to reproduce the characteristics of secondary degeneration—Cop-1 demonstrated an interesting neuroprotective effect. Kipnis et al. [55] evaluated the effect of adoptive anti-Cop-1 T cell transfer and immunization with Cop-1 immediately after causing optic nerve contusion in Lewis rats; their results were very encouraging as they observed reduction in axonal degeneration, accumulation of T lymphocytes in injured areas and obtained a significant increase in IL-10 and BDNF *in-vitro*. In contrast, using a model of axon transection of the optic nerve, Blair and coworkers [56] found no beneficial effects of Cop-1. The difference in the results may be due to the different inflammatory response evoked by the type of injury (contusion or transection). Inflammation is more pronounced after contusion as compared to the one observed after a transec-

nied by a reduction of IL-12 by CD4+ T lymphocytes [54].

**4. The effect of copolymer-1 on inflammatory diseases**

tion. It should be an issue to be studied by future investigations.

ation of its effect in other experimental models.

**146**

The ability of Cop-1 to modify the proinflammatory milieu and to stimulate the production of growth factors encourages the idea of testing this compound on other pathologies with characteristics of secondary degeneration caused by inflammation. In line with this, the use of Cop-1 after stroke envisions an optimistic result.
