Research Center Del Proyecto Camina Ac

Mexico City, Mexico

Research Center Del Proyecto Camina Ac

Mexico City, Mexico
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Arellano-Ruiz S.,Instituto Nacional Of Neurologia Y Neurocirugia Manuel Velasco Suarez Ssa | Arellano-Ruiz S.,Metropolitan Autonomous University | Rios C.,Instituto Nacional Of Neurologia Y Neurocirugia Manuel Velasco Suarez Ssa | Salgado-Ceballos H.,Hospital Of Especialidades | And 6 more authors.
Neuroscience Letters | Year: 2012

After spinal cord injury (SCI), a complex cascade of pathophysiological processes rapidly damages the nervous tissue. The initial damage spreads to the surrounding tissue by different mechanisms, including oxidative stress. We have recently reported that the induction of metallothionein (MT) protein is an endogenous rapid-response mechanism after SCI. Since the participation of MT in neuroprotective processes after SCI is still unknown, the aim of the present study was to evaluate the possible neuroprotective effect of exogenously administered MT-II during the acute phase after SCI in rats. Female Wistar rats weighing 200-250. g were submitted to spinal cord contusion by means of a computer-controlled device (NYU impactor). Rats received several doses of MT-II (3.2, 10 and 100. μg) at 2 and 8. h after SCI. Results of the BBB scale were statistically analysed using an ANOVA of repeated-measures, followed by Tukey's test. Among the three doses tested, only 10 and 100. μg were able to significantly increase (. p<. 0.05) BBB scale scores eight weeks after SCI from a mean of 7.88 in the control group, to means of 12.63 and 10.88 for the 10 and 100. μg doses of MT-II, respectively. The amount of spared tissue was also higher in the groups treated with 10 and 100. μg, as compared to the control group values. Results from the present study demonstrate a significant neuroprotective effect of exogenously administered MT-II. Further studies are needed in order to characterize the mechanisms involved in this neuroprotective action. © 2012 Elsevier Ireland Ltd.

Garcia E.,Anahuac University of North Mexico | Garcia E.,Research Center Del Proyecto Camina Ac | Silva-Garcia R.,Hospital Of Pediatria | Mestre H.,Anahuac University of North Mexico | And 5 more authors.
Journal of Neuroscience Research | Year: 2012

Immunization with neurally derived peptides (INDP) boosts the action of an autoreactive immune response that has been shown to induce neuroprotection in several neurodegenerative diseases, especially after spinal cord (SC) injury. This strategy provides an environment that promotes neuronal survival and tissue preservation. The mechanisms by which this autoreactive response exerts its protective effects is not totally understood at the moment. A recent study showed that INDP reduces lipid peroxidation. Lipid peroxidation is a neurodegenerative phenomenon caused by the increased production of reactive nitrogen species such as nitric oxide (NO). It is possible that INDP could be interfering with NO production. To test this hypothesis, we examined the effect of INDP on the amount of NO produced by glial cells when cocultured with autoreactive T cells. We also evaluated the amount of NO and the expression of the inducible form of nitric oxide synthase (iNOS) at the injury site of SC-injured animals. The neural-derived peptides A91 and Cop-1 were used to immunize mice and rats with SC injury. In vitro studies showed that INDP significantly reduces the production of NO by glial cells. This observation was substantiated by in vivo experiments demonstrating that INDP decreases the amount of NO and iNOS gene expression at the site of injury. The present study provides substantial evidence on the inhibitory effect of INDP on NO production, helpingour understanding of the mechanisms through which protective autoimmunity promotes neuroprotection. © 2011 Wiley Periodicals, Inc.

del Rayo Garrido M.,Anahuac University of North Mexico | del Rayo Garrido M.,Hospital Of Pediatria | Silva-Garcia R.,Hospital Of Pediatria | Garcia E.,Anahuac University of North Mexico | And 9 more authors.
Basic and Clinical Pharmacology and Toxicology | Year: 2013

Immunisation with neural-derived peptides is a promising strategy in models of spinal cord (SC) injury. Recent studies have also demonstrated that the addition of glutathione monoethyl ester (GHSE) to this strategy further improves motor recovery, tissue protection and neuronal survival after SC injury. As it is realistic to envision that this combination therapy could be tested in clinical trials, the therapeutic window should be experimentally explored before implementing its use in SC-injured human beings. For this purpose, 50 rats (10 per group) were subjected to a moderate SC contusion. The combined therapy was initiated at 10 min., 24, 72 or 120 hr after injury. Motor recovery and the survival of rubrospinal (RS) and ventral horn (VH) neurones were evaluated 60 days after injury. Results showed a significant motor improvement even if the combined therapy was initiated up to 72 hr after injury. BBB scores were as follows: 10 min.: 10.5 ± 0.7, 24 hr: 10.7 ± 0.5, 72 hr: 11.0 ± 1.3 and PBS: 6.7 ± 1 (mean ± S.D.). Initiation of combined therapy 120 hr after injury had no beneficial effect on motor recovery. Survival of RS and VH neurones was significantly higher in animals treated during the first 72 hr than those treated only with PBS. In this case again, animals treated with combined therapy 120 hr after injury did not present significant survival of neurones. Treatment with this combined strategy has a clinically feasible therapeutic window. This therapy provides enough time to transport and diagnose the patient and allows the concomitant use of other neuroprotective therapies. © 2012 Nordic Pharmacological Society.

Martinon S.,Anahuac University of North Mexico | Martinon S.,Research Center Del Proyecto Camina Ac | Martinon S.,Instituto Nacional Of Psiquiatria | Garcia-Vences E.,Anahuac University of North Mexico | And 7 more authors.
BMC Neuroscience | Year: 2016

Background: After spinal cord (SC)-injury, a non-modulated immune response contributes to the damage of neural tissue. Protective autoimmunity (PA) is a T cell mediated, neuroprotective response induced after SC-injury. Immunization with neural-derived peptides (INDP), such as A91, has shown to promote-in vitro-the production of neurotrophic factors. However, the production of these molecules has not been studied at the site of injury. Results: In order to evaluate these issues, we performed four experiments in adult female Sprague-Dawley rats. In the first one, brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) concentrations were evaluated at the site of lesion 21 days after SC-injury. BDNF and NT-3 were significantly increased in INDP-treated animals. In the second experiment, proliferation of anti-A91 T cells was assessed at chronic stages of injury. In this case, we found a significant proliferation of these cells in animals subjected to SC-injury + INDP. In the third experiment, we explored the amount of BDNF and NT3 at the site of injury in the chronic phase of rats subjected to either SC-contusion (SCC; moderate or severe) or SC-transection (SCT; complete or incomplete). The animals were treated with INDP immediately after injury. Rats subjected to moderate contusion or incomplete SCT showed significantly higher levels of BDNF and NT-3 as compared to PBS-immunized ones. In rats with severe SCC and complete SCT, BDNF and NT-3 concentrations were barely detected. Finally, in the fourth experiment we assessed motor function recovery in INDP-treated rats with moderate SC-injury. Rats immunized with A91 showed a significantly higher motor recovery from the first week and up to 4 months after SC-injury. Conclusions: The results of this study suggest that PA boosted by immunization with A91 after moderate SC-injury can exert its benefits even at chronic stages, as shown by long-term production of BDNF and NT-3 and a substantial improvement in motor recovery. © 2016 The Author(s).

Diaz-Ruiz A.,Instituto Nacional Of Neurologia Y Neurocirugia Manuel Velasco Suarez Ssa | Salgado-Ceballos H.,Hospital Of Especialidades | Salgado-Ceballos H.,Research Center Del Proyecto Camina Ac | Montes S.,Instituto Nacional Of Neurologia Y Neurocirugia Manuel Velasco Suarez Ssa | And 6 more authors.
Journal of Neuroscience Research | Year: 2011

After spinal cord injury (SCI), a complex cascade of pathophysiological processes increases the primary damage. The inflammatory response plays a key role in this pathology. Recent evidence suggests that myeloperoxidase (MPO), an enzyme produced and released by neutrophils, is of special importance in spreading tissue damage. Dapsone (4,4'-diaminodiphenylsulfone) is an irreversible inhibitor of MPO. Recently, we demonstrated, in a model of brain ischemia/reperfusion, that dapsone has antioxidant, antiinflammatory, and antiapoptotic effects. The effects of dapsone on MPO activity, lipid peroxidation (LP) processes, motor function recovery, and the amount of spared tissue were evaluated in a rat model of SCI. MPO activity had increased 24.5-fold 24 hr after SCI vs. the sham group, and it had diminished by 38% and 19% in the groups treated with dapsone at 3 and 5 hr after SCI, respectively. SCI increased LP by 45%, and this increase was blocked by dapsone. In rats treated with dapsone, a significant motor function recovery (Basso-Beattie-Bresnahan score, BBB) was observed beginning during the first week of evaluation and continuing until the end of the study. Spontaneous recovery 8 weeks after SCI was 9.2 ± 1.12, whereas, in the dapsone-treated groups, it reached 13.6 ± 1.04 and 12.9 ± 1.17. Spared tissue increased by 42% and 33% in the dapsone-treated groups (3 and 5 hr after SCI, respectively) vs. SCI without treatment. Dapsone significantly prevented mortality. The results show that inhibition of MPO by dapsone significantly protected the spinal cord from tissue damage and enhanced motor recovery after SCI. © 2011 Wiley-Liss, Inc.

Ibarra A.,Anahuac University of North Mexico | Ibarra A.,Research Center Del Proyecto Camina Ac | Garcia E.,Anahuac University of North Mexico | Garcia E.,Research Center Del Proyecto Camina Ac | And 5 more authors.
Neuroscience Letters | Year: 2010

Lipid peroxidation (LP) is one of the most harmful mechanisms developed after spinal cord (SC) injury. Several strategies have been explored in order to control this phenomenon. Protective autoimmunity is a physiological process based on the modulation of inflammatory cells that can be boosted by immunizing with neural-derived peptides, such as A91. Since inflammatory cells are among the main contributors to lipid peroxidation, we hypothesized that protective autoimmunity could reduce LP after SC injury. In order to test this hypothesis, we designed two experiments in SC contused rats. First, animals were immunized with a neural-derived peptide seven days before injury. With the aim of inducing the functional elimination of CNS-specific T cells, for the second experiment, animals were tolerized against SC-protein extract and thereafter subjected to a SC injury. The lipid-soluble fluorescent products were used as an index of lipid peroxidation and were assessed after injury. Immunization with neural-derived peptides reduced lipid peroxidation after SC injury. Functional elimination of CNS-specific T cells avoided the beneficial effect induced by protective autoimmunity. The present study demonstrates the beneficial effect of immunizing with neural-derived peptides on lipid peroxidation inhibition; besides this, it also provides evidence on the neuroprotective mechanisms exerted by protective autoimmunity. © 2010 Elsevier Ireland Ltd.

Morales I.-I.,Anahuac University of North Mexico | Toscano-Tejeida D.,Anahuac University of North Mexico | Ibarra A.,Anahuac University of North Mexico | Ibarra A.,Research Center Del Proyecto Camina Ac
Current Pharmaceutical Design | Year: 2016

Spinal cord injury (SCI) is a complex condition that can result in functional impairment and paralysis, and occurs more frequently in young men. Several studies tested diverse treatments; however none achieved effective neuronal regeneration or improvement in neural function. Current research is being performed in areas such as cellular therapy (Schwann cells, embryonic stem cells, pluripotent stem cells, mesenchymal stem cells and olfactory cells), growth factors (BDNF), inhibitory molecules, fibroglial scar, gene therapies, etc. Some strategies have provided encouraging results by themselves, others have been tested as a combination, showing an improved out-come after SCI. Combined strategies could be more effective than individual therapies; for instance, co transplantation of cells at the injury site to maximize their effect has been used, and it has demonstrated a greater efficacy in comparison to grafts of stem cells or of a particular cell type. The combination of neurotrophic factors such as BDNF and NT-3 enhances axonal regeneration and myelination; other therapies include the use of biological matrices in combination with inhibitors of glial scar formation. Chondroitinase ABC (ChABC) has shown synergistic effects with other strategies, specifically to improve regeneration and functional recovery after SCI. Experimental evidence suggests that it is possible to obtain better results with a combination of strategies, which justifies further research for therapeutic approaches. This review intends to compile the most relevant information about available up-to-date therapeutic strategies that are administered alone or in combination with others, and have offered the best results in neural regeneration after spinal cord injury. © 2016 Bentham Science Publishers.

PubMed | National Autonomous University of Mexico, Hospital Of Pediatria Cmn Siglo Xxi, UIMEN, Laboratory Bioenergetica y Envejecimiento Celular and 2 more.
Type: Journal Article | Journal: BMC neuroscience | Year: 2017

Immunization with neural derived peptides (INDP) as well as scar removal-separately-have shown to induce morphological and functional improvement after spinal cord injury (SCI). In the present study, we compared the effect of INDP alone versus INDP with scar removal on motor recovery, regeneration-associated and cytokine gene expression, and axonal regeneration after chronic SCI. Scar removal was conducted through a single incision with a double-bladed scalpel along the stump, and scar renewal was halted by adding ,-dipyridyl.During the chronic injury stage, two experiments were undertaken. The first experiment was aimed at testing the therapeutic effect of INDP combined with scar removal. Sixty days after therapeutic intervention, the expression of genes encoding for TNF, IFN, IL4, TGF, BDNF, IGF1, and GAP43 was evaluated at the site of injury. Tyrosine hydroxylase and 5-hydroxytryptamine positive fibers were also studied. Locomotor evaluations showed a significant recovery in the group treated with scar removal+INDP. Moreover; this group presented a significant increase in IL4, TGF, BDNF, IGF1, and GAP43 expression, but a decrease of TNF and IFN. Also, the spinal cord of animals receiving both treatments presented a significant increase of serotonergic and catecholaminergic fibers as compared to other the groups. The second experiment compared the results of the combined approach versus INDP alone. Rats receiving INDP likewise showed improved motor recovery, although on a lesser scale than those who received the combined treatment. An increase in inflammation and regeneration-associated gene expression, as well as in the percentage of serotonergic and catecholaminergic fibers was observed in INDP-treated rats to a lesser degree than those in the combined therapy group.These findings suggest that INDP, both alone and in combination with scar removal, could modify the non-permissive microenvironment prevailing at the chronic phase of SCI, providing the opportunity of improving motor recovery.

Zajarias-Fainsod D.,Anahuac University of North Mexico | Carrillo-Ruiz J.,Anahuac University of North Mexico | Carrillo-Ruiz J.,Hospital General Of Mexico Od | Mestre H.,Anahuac University of North Mexico | And 6 more authors.
European Spine Journal | Year: 2012

Introduction Previous studies have shown the existence of either cellular or humoral MBP-reactive elements up to 5 years after spinal cord injury (SCI), but not the presence of both after 10 years. Materials and methods Twelve SCI patients, with more than 10 years of evolution, and 18 healthy blood donors were studied. Lymphocyte proliferation (colorimetric- BrdU ELISA assay) and antibody titers against MBP (ELISA Human IgG MBP-specific assay) were assessed. Results SCI patients presented a significant T-cell proliferation against MBP (lymphocyte proliferation index: 3.7 ± 1.5, mean ± SD) compared to control individuals (0.7 ± 0.3; P<0.001). Humoral response analysis yielded a significant difference (P<0.0001) between the antibody titers of controls and SCI patients. A significant correlation between cellular and humoral responses was observed. Finally, patients with an ASIA B presented the highest immune responses. Conclusion This work demonstrates, for the first time, the existence of both cellular and humoral responses against MBP in the chronic stages (>10 years) of injury. © 2011 Springer-Verlag.

Martinon S.,Research Center Del Proyecto Camina Ac | Garcia E.,Research Center Del Proyecto Camina Ac | Garcia E.,Anahuac University of North Mexico | Gutierrez-Ospina G.,National Autonomous University of Mexico | And 3 more authors.
PLoS ONE | Year: 2012

Protective autoimmunity (PA) is a physiological response to central nervous system trauma that has demonstrated to promote neuroprotection after spinal cord injury (SCI). To reach its beneficial effect, PA should be boosted by immunizing with neural constituents or neural-derived peptides such as A91. Immunizing with A91 has shown to promote neuroprotection after SCI and its use has proven to be feasible in a clinical setting. The broad applications of neural-derived peptides make it important to determine the main features of this anti-A91 response. For this purpose, adult Sprague-Dawley rats were subjected to a spinal cord contusion (SCC; moderate or severe) or a spinal cord transection (SCT; complete or incomplete). Immediately after injury, animals were immunized with PBS or A91. Motor recovery, T cell-specific response against A91 and the levels of IL-4, IFN-γ and brain-derived neurotrophic factor (BDNF) released by A91-specific T (T A91) cells were evaluated. Rats with moderate SCC, presented a better motor recovery after A91 immunization. Animals with moderate SCC or incomplete SCT showed significant T cell proliferation against A91 that was characterized chiefly by the predominant production of IL-4 and the release of BDNF. In contrast, immunization with A91 did not promote a better motor recovery in animals with severe SCC or complete SCT. In fact, T cell proliferation against A91 was diminished in these animals. The present results suggest that the effective development of PA and, consequently, the beneficial effects of immunizing with A91 significantly depend on the severity of SCI. This could mainly be attributed to the lack of T A91 cells which predominantly showed to have a Th2 phenotype capable of producing BDNF, further promoting neuroprotection. © 2012 Martiñón et al.

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