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Background: Currently, combined therapies could help to reduce long-term sequelae of spinal cord injury (SCI); stem cell therapy at the site of injury in combination with other therapies has shown very promising results that can be transferred to the clinical field. Nanoparticles (NPs) are versatile technologies with applications to medical research for treatments of SCI since they could deliver therapeutic molecules to the target tissue and may help to reduce the side effects of non-targeted therapies. This article's purpose is to analyze and concisely describe the diverse cellular therapies in combination with NPs and their regenerative effect after SCI. Methods: We reviewed the literature related to combinatory therapy for motor impairment following SCI that has been published by Web of Science, Scopus, EBSCO host, and PubMed databases. The research covers the databases from 2001 to December 2022. Result: Animal models of SCI have shown that the combination of NPs plus stem cells has a positive impact on neuroprotection and neuroregeneration. Further research is required to better understand the effects and benefits of SCI on a clinical level; therefore, it is necessary to find and select the most effective molecules that are capable of exacerbating the neurorestorative effects of the different stem cells and then try them out on patients after SCI. On the other hand, we consider that synthetic polymers such as poly [lactic-co-glycolic acid] (PLGA) could be a candidate for the design of the first therapeutic strategy that combines NPs with stem cells in patients with SCI. The reasons for the selection are that PLGA has shown important advantages over other NPs, such as being biodegradable, having low toxicity levels, and high biocompatibility; In addition, researchers could control the release time and the biodegradation kinetics, and most importantly, it could be used as NMs on other clinical pathologies (12 studies on www.clinicaltrials.gov) and has been approved by the Federal Food, Drug, and Cosmetic Act (FDA). Conclusion: The use of cellular therapy and NPs may be a worthwhile alternative for SCI therapy; however, it is expected that the data obtained from interventions after SCI reflect an important variability of molecules combined with NPs. Therefore, it is necessary to properly define the limits of this research to be able to continue to work on the same line. Consequently, the selection of a specific therapeutic molecule and type of NPs plus stem cells are crucial to evaluate its application in clinical trials.
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INTRODUCTION: The mechanism underlying the memory improvement induced by prebiotic and probiotic supplementation remains unclear. Glucagon-like peptide type 1 (GLP-1) could play an important role since it is induced by prebiotics and enhances memory and learning. AIMS: We correlated the levels of GLP-1 with spatial memory in senile animals to determine its role in memory improvement after prebiotic and probiotic supplementation. METHODS: Senile rats were randomly assigned to four groups: (1) water (control); (2) Enterococcus faecium (probiotic); (3) agave inulin (prebiotic); and (4) E. faecium + agave inulin (symbiotic). Each supplement was administered by an orogastric cannula for 5 weeks. In the fifth week, spatial memory was assessed using the Morris Water Maze test (MWM). We extracted the hippocampus, intestine, and serum. GLP-1 levels were quantified by enzyme-linked immunosorbent assay. RESULTS: A significant decrease in escape latency time in the MWM was observed in all groups treated with supplements. The symbiotic group achieved the highest reduction (15.13 s ± 6.40) (p < 0.01). We did not find a significant increase in GLP-1 levels nor a direct correlation of its levels with spatial memory improvement (p > 0.05). CONCLUSION: Prebiotic and probiotic supplementation improved spatial memory in senile animals. However, this beneficial effect did not correlate with GLP-1 levels.
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Prebióticos , Probióticos , Ratos , Animais , Peptídeo 1 Semelhante ao Glucagon , Inulina , Suplementos NutricionaisRESUMO
Neurogenesis in the adult state is the process of new neuron formation. This relatively infrequent phenomenon comprises four stages: cell proliferation, cell migration, differentiation, and the integration of these cells into an existing circuit. Recent reports suggest that neurogenesis can be found in different regions of the Central Nervous System (CNS), including the spinal cord (SC). This process can be observed in physiological settings; however, it is more evident in pathological conditions. After spinal cord injury (SCI), the activation of microglial cells and certain cytokines have shown to exert different modulatory effects depending on the presence of inflammation and on the specific region of the injury site. In these conditions, microglial cells and cytokines are considered to play an important role in the regulation of neurogenesis after SCI. The purpose of this article is to present an overview on neural progenitor cells and neurogenic and non-neurogenic zones as well as the cellular and molecular regulation of neurogenesis. Additionally, we will briefly describe the recent advances in the knowledge of neurogenesis after SCI.
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Neurogênese/fisiologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/terapia , Animais , Diferenciação Celular , Movimento Celular , Proliferação de Células , Citocinas , Humanos , Microglia/fisiologia , Células-Tronco Neurais/patologia , Neurônios/patologia , Medula Espinal/patologiaRESUMO
AIMS: Immunization with neural-derived peptides (INDP) has demonstrated to be a promising therapy to achieve a regenerative effect in the chronic phase of the spinal cord injury (SCI). Nevertheless, INDP-induced neurogenic effects in the chronic stage of SCI have not been explored. METHODS AND RESULTS: In this study, we analyzed the effect of INDP on both motor and sensitive function recovery; afterward, we assessed neurogenesis and determined the production of cytokines (IL-4, IL-10, and TNF alpha) and neurotrophic factors (BDNF and GAP-43). During the chronic stage of SCI, rats subjected to INDP showed a significant increase in both motor and sensitive recovery when compared to the control group. Moreover, we found a significant increase in neurogenesis, mainly at the central canal and at both the dorsal and ventral horns of INDP-treated animals. Finally, INDP induced significant production of antiinflammatory and regeneration-associated proteins in the chronic stages of SCI. CONCLUSIONS: These findings suggest that INDP has a neurogenic effect that could improve motor and sensitive recovery in the chronic stage of SCI. Moreover, our results also envision the use of INDP as a possible therapeutic strategy for other trauma-related disorders like traumatic brain injury.
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Imunização/métodos , Neurogênese/efeitos dos fármacos , Neuropeptídeos/administração & dosagem , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/terapia , Animais , Feminino , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Neurogênese/fisiologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/imunologiaRESUMO
Immunization with neural derived peptides (INDP), as well as scar removal (SR) and the use of matrices with bone marrow-mesenchymal stem cells (MSCs), have been studied separately and proven to induce a functional and morphological improvement after spinal cord injury (SCI). Herein, we evaluated the therapeutic effects of INDP combined with SR and a fibrin glue matrix (FGM) with MSCs (FGM-MSCs), on motor recovery, axonal regeneration-associated molecules and cytokine expression, axonal regeneration (catecholaminergic and serotonergic fibers), and the induction of neurogenesis after a chronic SCI. For this purpose, female adult Sprague-Dawley rats were subjected to SCI, 60 days after lesion, rats were randomly distributed in four groups: (1) Rats immunized with complete Freund's adjuvant + PBS (vehicle; PBS-I); (2) Rats with SR+ FGM-MSCs; (3) Rats with SR+ INDP + FGM-MSCs; (4) Rats only with INDP. Afterwards, we evaluated motor recovery using the BBB locomotor test. Sixty days after the therapy, protein expression of TNFα, IL-4, IL-10, BDNF, and GAP-43 were evaluated using ELISA assay. The number of catecholaminergic and serotonergic fibers were also determined. Neurogenesis was evaluated through immunofluorescence. The results show that treatment with INDP alone significantly increased motor recovery, anti-inflammatory cytokines, regeneration-associated molecules, axonal regeneration, and neurogenesis when compared to the rest of the groups. Our findings suggest that the combination therapy (SR + INDP + FGM-MSCs) modifies the non-permissive microenvironment post SCI, but it is not capable of inducing an appropriate axonal regeneration or neurogenesis when compared to the treatment with INDP alone.
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BACKGROUND: The chronic phase of Spinal Cord (SC) injury is characterized by the presence of a hostile microenvironment that causes low activity and a progressive decline in neurological function; this phase is non-compatible with regeneration. Several treatment strategies have been investigated in chronic SC injury with no satisfactory results. OBJECTIVE- In this proof-of-concept study, we designed a combination therapy (Comb Tx) consisting of surgical glial scar removal plus scar inhibition, accompanied with implantation of mesenchymal stem cells (MSC), and immunization with neural-derived peptides (INDP). METHODS: This study was divided into three subsets, all in which Sprague Dawley rats were subjected to a complete SC transection. Sixty days after injury, animals were randomly allocated into two groups for therapeutic intervention: control group and animals receiving the Comb-Tx. Sixty-three days after treatment we carried out experiments analyzing motor recovery, presence of somatosensory evoked potentials, neural regeneration-related genes, and histological evaluation of serotoninergic fibers. RESULTS: Comb-Tx induced a significant locomotor and electrophysiological recovery. An increase in the expression of regeneration-associated genes and the percentage of 5-HT+ fibers was noted at the caudal stump of the SC of animals receiving the Comb-Tx. There was a significant correlation of locomotor recovery with positive electrophysiological activity, expression of GAP43, and percentage of 5-HT+ fibers. CONCLUSION: Comb-Tx promotes motor and electrophysiological recovery in the chronic phase of SC injury subsequent to a complete transection. Likewise, it is capable of inducing the permissive microenvironment to promote axonal regeneration.
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Cicatriz/cirurgia , Terapia Combinada/métodos , Transplante de Células-Tronco Mesenquimais , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/imunologia , Traumatismos da Medula Espinal , 2,2'-Dipiridil/uso terapêutico , Animais , Potenciais Evocados/fisiologia , Feminino , Adjuvante de Freund/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Ratos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/cirurgia , Traumatismos da Medula Espinal/terapia , Triptofano/análogos & derivados , Triptofano/uso terapêuticoRESUMO
In the central nervous system (CNS), senescent astrocytes have been associated with neurodegeneration. Senescent cells secrete a complex mixture of pro-inflammatory factors, which are collectively called Senescence Associated Secretory Phenotype (SASP). The SASP components can vary depending on the cell type, senescence inducer and time. The SASP has been mainly studied in fibroblasts and epithelial cells, but little is known in the context of the CNS. Here, the SASP profile in senescent astrocytes isolated from Wistar newborn rats induced to senescence by oxidative stress or by proteasome inhibition was analyzed. Senescent astrocytes secreted predominantly chemokines and IL-1α, but no IL-6. The effect of the anti-inflammatory drugs, sulforaphane (SFN) and dehydroepiandrosterone (DHEA), on the SASP profile was evaluated. Our results showed that SFN and DHEA decreased IL-1α secretion while increasing IL-10, thus modifying the SASP to a less anti-inflammatory profile. Primary neurons were subjected to the conditioned media obtained from drug-treated senescent astrocytes, and their mitochondrial membrane potential was evaluated.
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Astrócitos , Senescência Celular , Sistema Nervoso Central , Desidroepiandrosterona/farmacologia , Isotiocianatos/farmacologia , Neurônios , Animais , Animais Recém-Nascidos , Anti-Inflamatórios/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Senescência Celular/efeitos dos fármacos , Senescência Celular/imunologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Inflamação , Interleucina-1alfa/imunologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Animais , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , SulfóxidosRESUMO
BACKGROUND: 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 α,α'-dipyridyl. RESULTS: 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 TNFα, IFNγ, IL4, TGFß, 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, TGFß, BDNF, IGF1, and GAP43 expression, but a decrease of TNFα and IFNγ. 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. CONCLUSIONS: 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.
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Cicatriz/metabolismo , Locomoção/efeitos dos fármacos , Neuropeptídeos/administração & dosagem , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/metabolismo , Vacinação , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Proteína GAP-43/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Interferon gama/metabolismo , Interleucina-4/metabolismo , Neuropeptídeos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/tratamento farmacológico , Regeneração da Medula Espinal/genética , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.
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Autoimunidade , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína Básica da Mielina/imunologia , Neurotrofina 3/metabolismo , Fragmentos de Peptídeos/imunologia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/terapia , Animais , Doença Crônica , Modelos Animais de Doenças , Feminino , Atividade Motora , Distribuição Aleatória , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Medula Espinal/imunologia , Fatores de Tempo , VacinaçãoRESUMO
Apoptosis is one of the most destructive mechanisms that develop after spinal cord (SC) injury. Immunization with neural-derived peptides (INDPs) such as A91 has shown to reduce the deleterious proinflammatory response and the amount of harmful compounds produced after SC injury. With the notion that the aforementioned elements are apoptotic inducers, we hypothesized that INDPs would reduce apoptosis after SC injury. In order to test this assumption, adult rats were subjected to SC contusion and immunized either with A91 or phosphate buffered saline (PBS; control group). Seven days after injury, animals were euthanized to evaluate the number of apoptotic cells at the injury site. Apoptosis was evaluated using DAPI and TUNEL techniques; caspase-3 activity was also evaluated. To further elucidate the mechanisms through which A91 exerts this antiapoptotic effects we quantified tumor necrosis factor-alpha (TNF-α). To also demonstrate that the decrease in apoptotic cells correlated with a functional improvement, locomotor recovery was evaluated. Immunization with A91 significantly reduced the number of apoptotic cells and decreased caspase-3 activity and TNF-α concentration. Immunization with A91 also improved the functional recovery of injured rats. The present study shows the beneficial effect of INDPs on preventing apoptosis and provides more evidence on the neuroprotective mechanisms exerted by this strategy.