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.
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.
