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The primary mechanism of traumatic spinal cord injury (SCI) comprises the initial mechanical trauma due to the transmission of energy to the spinal cord, subsequent deformity, and persistent compression. The secondary mechanism of injury, which involves structures that remained undamaged after the initial trauma, triggers alterations in microvascular perfusion, the liberation of free radicals and neurotransmitters, lipid peroxidation, alteration in ionic concentrations, and the consequent cell death by necrosis and apoptosis. Research in the treatment of SCI has sought to develop early therapeutic interventions that mitigate the effects of these pathophysiological mechanisms. Clinical and experimental evidence has demonstrated the therapeutic benefits of sex-steroid hormone administration after traumatic brain injury and SCI. The administration of estradiol, progesterone, and testosterone has been associated with neuroprotective effects, better neurological recovery, and decreased mortality after SCI. This review evaluated evidence supporting hormone-related neuroprotection over SCI and the possible underlying mechanisms in animal models. As neuroprotection has been associated with signaling pathways, the effects of these hormones are observed on astrocytes and microglia, modulating the inflammatory response, cerebral blood flow, and metabolism, mediating glutamate excitotoxicity, and their antioxidant effects. Based on the current evidence, it is essential to analyze the benefit of sex steroid hormone therapy in the clinical management of patients with SCI.
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Mild cognitive impairment (MCI) is defined as inter-stage between normal cognitive aging and major neurocognitive disorder (MND). This state of decay is a crucial factor in treatment to prevent the progression to MND. In this study, our group developed a virtual screening process to evaluate 2568 phytochemical compounds against 5 key proteins associated with MCI and MND. As a result, two potential candidates were identified: carpaine, found in Carica papaya leaves, and punicalagin, present in Punica granatum. A model of cognitive impairment (CI) was developed in 10-month-old male Sprague Dawley rats by administering aluminum chloride (AlCl3) at a dose of 100 mg/kg/day for 30 days. After AlCl3 administration period, one of the groups received carpaine and punicalagin in a phytochemical extract (PE) by oral gavage for 30 days. Novel object recognition test (NOR) was assessed at three different time points (T1 - before CI, T2 - after CI, and T3 - after PE treatment). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were identified in the hippocampus of rats at the end of the study period. After administration of AlCl3, a reduction in discrimination index vs control rats (CI = 0.012 ± 0.08 vs Control = 0.076 ± 0.03), was observed. After phytochemical extract treatment, a significant increase in discrimination index values was observed in the PE group 0.4643 ± 0.13 vs CI group 0.012 ± 0.08. Additionally, the evaluation of immunohistochemistry showed an increase in GFAP positivity in the hippocampus of the CI groups, while a slight decrease was observed in the PE group. This work addressed a comprehensive methodology that utilized in silico tools to identify phytochemical compounds (carpaine and punicalagin) as potential candidates for affecting key proteins in CI. The phytochemical extract containing carpaine and punicalagin resulted in a trend in the decrease of GFAP expression in the hippocampus and improved recognition memory in rats with CI induced by age and AlCl3 administration.
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Carica , Disfunción Cognitiva , Taninos Hidrolizables , Granada (Fruta) , Ratones , Ratas , Masculino , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Carica/química , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Disfunción Cognitiva/tratamiento farmacológico , Fitoquímicos , SemillasRESUMEN
Spinal cord injury (SCI) harms patients' health and social and economic well-being. Unfortunately, fully effective therapeutic strategies have yet to be developed to treat this disease, affecting millions worldwide. Apoptosis and autophagy are critical cell death signaling pathways after SCI that should be targeted for early therapeutic interventions to mitigate their adverse effects and promote functional recovery. Tibolone (TIB) is a selective tissue estrogen activity regulator (STEAR) with neuroprotective properties demonstrated in some experimental models. This study aimed to investigate the effect of TIB on apoptotic cell death and autophagy after SCI and verify whether TIB promotes motor function recovery. A moderate contusion SCI was produced at thoracic level 9 (T9) in male Sprague Dawley rats. Subsequently, animals received a daily dose of TIB orally and were sacrificed at 1, 3, 14 or 30 days post-injury. Tissue samples were collected for morphometric and immunofluorescence analysis to identify tissue damage and the percentage of neurons at the injury site. Autophagic (Beclin-1, LC3-I/LC3-II, p62) and apoptotic (Caspase 3) markers were also analyzed via Western blot. Finally, motor function was assessed using the BBB scale. TIB administration significantly increased the amount of preserved tissue (p < 0.05), improved the recovery of motor function (p < 0.001) and modulated the expression of autophagy markers in a time-dependent manner while consistently inhibiting apoptosis (p < 0.05). Therefore, TIB could be a therapeutic alternative for the recovery of motor function after SCI.
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Fármacos Neuroprotectores , Traumatismos de la Médula Espinal , Humanos , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/metabolismo , Apoptosis , Autofagia , Médula Espinal/metabolismo , Recuperación de la Función , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/metabolismoRESUMEN
Introduction: Spinal cord injury (SCI) can cause paralysis, for which effective therapeutic strategies have not been developed yet. The only accepted strategy for patients is rehabilitation (RB), although this does not allow complete recovery of lost functions, which makes it necessary to combine it with strategies such as plasma-synthesized polypyrrole/iodine (PPy/I), a biopolymer with different physicochemical properties than PPy synthesized by conventional methods. After SCI in rats, PPy/I promotes functional recovery. Therefore, the purpose of this study was to increase the beneficial effects of both strategies and identify which genes activate PPy/I when applied alone or in combination with a mixed scheme of RB by swimming and enriched environment (SW/EE) in rats with SCI. Methods: Microarray analysis was performed to identify mechanisms of action underlying the effects of PPy/I and PPy/I+SW/EE on motor function recovery as evaluated by the BBB scale. Results: Results showed robust upregulation by PPy/I in genes related to the developmental process, biogenesis, synapse, and synaptic vesicle trafficking. In addition, PPy/I+SW/EE increased the expression of genes related to proliferation, biogenesis, cell development, morphogenesis, cell differentiation, neurogenesis, neuron development, and synapse formation processes. Immunofluorescence analysis showed the expression of ß-III tubulin in all groups, a decreased expression of caspase-3 in the PPy/I group and GFAP in the PPy/I+SW/EE group (p < 0.05). Better preservation of nerve tissue was observed in PPy/I and PPy/SW/EE groups (p < 0.05). In the BBB scale, the control group scored 1.72 ± 0.41, animals with PPy/I treatment scored 4.23 ± 0.33, and those with PPy/I+SW/EE scored 9.13 ± 0.43 1 month after follow-up. Conclusion: Thus, PPy/I+SW/EE could represent a therapeutic alternative for motor function recovery after SCI.
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Inflammation and oxidative stress are critical events involved in neurodegeneration. In animal models, it has been shown that chronic consumption of a hypercaloric diet, which leads to inflammatory processes, affects the hippocampus, a brain region fundamental for learning and memory processes. In addition, advanced age and menopause are risk factors for neurodegeneration. Hormone replacement therapy (HRT) ameliorates menopause symptoms. Tibolone (TB), a synthetic hormone, exerts estrogenic, progestogenic and androgenic effects on different tissues. We aimed to determine the effect of short-term TB administration on oxidative stress and inflammation markers in the hippocampus of ovariectomized rats fed a high-fat-and-fructose diet (HFFD). Adult female rats were ovariectomized (OVX) and fed standard diet or HFFD-consisting of 10% lard supplemented chow and 20% high-fructose syrup in the drinking water-and administered vehicle or TB (1â mg/kg for seven days). Finally, we administered hormone receptor antagonists (MPP, RU486 or FLU) to each of the OVX + HFFD + TB groups. Bodyweight, triglycerides and cholesterol, oxidative stress and inflammation markers, and the activity and expression of antioxidant enzymes were quantified in the hippocampus of each experimental group. We observed that short-term TB administration significantly reduced body weight, AGEs, MDA levels, increased SOD and GPx activity, improved GSH/GSSG ratio, and reduced IL-6 and TNF-α. Our findings suggest that short-term administration of TB decreases oxidative stress and reduces inflammation caused by HFFD and early estrogenic decline. These effects occurred via estrogen receptor alpha.
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Fructosa , Estrés Oxidativo , Ratas , Femenino , Animales , Fructosa/efectos adversos , Inflamación/metabolismo , Dieta Alta en Grasa/efectos adversos , Peso Corporal , Hipocampo/metabolismo , Hormonas/metabolismo , Hormonas/farmacologíaRESUMEN
Spinal cord injury (SCI) is a significant cause of disability, and treatment alternatives that generate beneficial outcomes and have no side effects are urgently needed. SCI may be treatable if intervention is initiated promptly. Therefore, several treatment proposals are currently being evaluated. Inflammation is part of a complex physiological response to injury or harmful stimuli induced by mechanical, chemical, or immunological agents. Neuroinflammation is one of the principal secondary changes following SCI and plays a crucial role in modulating the pathological progression of acute and chronic SCI. This review describes the main inflammatory events occurring after SCI and discusses recently proposed potential treatments and therapeutic agents that regulate inflammation after insult in animal models.
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Traumatismos de la Médula Espinal , Animales , Factores Inmunológicos/uso terapéutico , Inflamación/complicaciones , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/tratamiento farmacológicoRESUMEN
INTRODUCTION: In the central nervous system (CNS), tibolone actions are mainly modulated through its interaction with estrogen, progesterone, and androgen receptors. Several studies have reported the expression of sex hormone receptors in the CNS using the RT-PCR endpoint technique. Although some studies have validated reference genes for rat brain tissue in different experimental conditions, no suitable reference genes have been reported in brain tissue from ovariectomized rats treated with tibolone. OBJECTIVE: The aim of this investigation was to evaluate the expression of different housekeeping genes in several brain regions in ovariectomized rats treated with tibolone to determine the stability of a single housekeeping gene and a combination of two housekeeping genes under these experimental conditions. METHODS: Adult female Sprague-Dawley rats were ovariectomized. Seven days after the surgery, animals were administered a single dose of vehicle (water) or tibolone (10 mg/kg/weight). Twenty-four hours later, animals were sacrificed, and the hypothalamus, hippocampus, prefrontal cortex, and cerebellum were dissected. Total RNA was extracted from these tissues, and RT-qPCR was performed to amplify Ppia, Hprt1, Rpl32, and Gapdh housekeeping genes. RESULTS: Ppia was the most stable gene in the hypothalamus and cerebellum, whereas Hprt1 was the most stable gene in the prefrontal cortex. For the analysis of the combination of two genes, the most stable combination was Ppia and Hrpt1 for the prefrontal cortex and Ppia and Rpl32 for the cerebellum. CONCLUSION: In ovariectomized rats treated with tibolone, Hprt1 and Ppia genes showed high stability as housekeeping genes for qPCR analysis.
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Encéfalo/efectos de los fármacos , Moduladores de los Receptores de Estrógeno/farmacología , Genes Esenciales , Norpregnenos/farmacología , Ovariectomía , Animales , Encéfalo/metabolismo , Femenino , Ratas , Ratas Sprague-DawleyRESUMEN
Estrogen replacement therapy decreases some risk factors of the metabolic syndrome but increases the risk of some types of cancer. Tibolone (TIB) has shown similar neuroprotective effects as estrogens. This study aimed to evaluate the effects of TIB on metabolic parameters and the expression of sex hormone receptors in the CNS in ovariectomised rats fed with a hypercaloric diet. Sprague-Dawley female rats were ovariectomised and fed for 30 days with a standard diet (SD) or high-fat high-fructose diet (HFFD) and treated with TIB (1 mg/kg) or vehicle. At the end of the treatments, HFFD increased body weight, glucose tolerance, triglycerides and cholesterol levels, while TIB treatment decreased these parameters. Subsequently, the hippocampus, the hypothalamus and the frontal cortex were dissected. RT-PCR was performed for progesterone receptor (PR), androgen receptor (AR), estrogen receptors alpha and beta (ERα, ERß), insulin receptor (IR) and insulin-like growth factor 1 (IGF-1). HFFD altered the expression of sex hormone receptors in specific brain structures involved in the regulation of homeostasis and cognition, which highlights the importance of a healthy diet. In turn, TIB modulated the expression of these receptors, particularly in the hypothalamus.
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Dieta Alta en Grasa , Carbohidratos de la Dieta , Moduladores de los Receptores de Estrógeno/farmacología , Lóbulo Frontal/metabolismo , Hipocampo/metabolismo , Hipotálamo/metabolismo , Norpregnenos/farmacología , Animales , Femenino , Lóbulo Frontal/efectos de los fármacos , Fructosa , Hipocampo/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Ovariectomía , Ratas , Ratas Sprague-Dawley , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
Traumatic spinal cord injury (TSCI) can cause paralysis and permanent disability. Rehabilitation (RB) is currently the only accepted treatment, although its beneficial effect is limited. The development of biomaterials has provided therapeutic possibilities for TSCI, where our research group previously showed that the plasma-synthesized polypyrrole/iodine (PPy/I), a biopolymer with different physicochemical characteristics than those of the PPy synthesized by conventional methods, promotes recovery of motor function after TSCI. The present study evaluated if the plasma-synthesized PPy/I applied in combination with RB could increase its beneficial effects and the mechanisms involved. Adult rats with TSCI were divided into no treatment (control); biopolymer (PPy/I); mixed RB by swimming and enriched environment (SW/EE); and combined treatment (PPy/I + SW/EE) groups. Eight weeks after TSCI, the general health of the animals that received any of the treatments was better than the control animals. Functional recovery evaluated by two scales was better and was achieved in less time with the PPy/I + SW/EE combination. All treatments significantly increased ßIII-tubulin (nerve plasticity) expression, but only PPy/I increased GAP-43 (nerve regeneration) and MBP (myelination) expression when were analyzed by immunohistochemistry. The expression of GFAP (glial scar) decreased in treated groups when determined by histochemistry, while morphometric analysis showed that tissue was better preserved when PPy/I and PPy/I + SW/EE were administered. The application of PPy/I + SW/EE, promotes the preservation of nervous tissue, and the expression of molecules related to plasticity as ßIII-tubulin, reduces the glial scar, improves general health and allows the recovery of motor function after TSCI. The implant of the biomaterial polypyrrole/iodine (PPy/I) synthesized by plasma (an unconventional synthesis method), in combination with a mixed rehabilitation scheme with swimming and enriched environment applied after a traumatic spinal cord injury, promotes expression of GAP-43 and ßIII-tubulin (molecules related to plasticity and nerve regeneration) and reduces the expression of GFAP (molecule related to the formation of the glial scar). Both effects together allow the formation of nerve fibers, the reconnection of the spinal cord in the area of injury and the recovery of lost motor function. The figure shows the colocalization (yellow) of ßIII-tubilin (red) and GAP-43 (green) in fibers crossing the epicenter of the injury (arrowheads) that reconnect the rostral and caudal ends of the injured spinal cord and allowed recovery of motor function.
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Materiales Biocompatibles , Terapia por Ejercicio/métodos , Yodo/química , Polímeros/química , Pirroles/química , Traumatismos de la Médula Espinal/rehabilitación , Traumatismos de la Médula Espinal/cirugía , Animales , Coagulación con Plasma de Argón/métodos , Materiales Biocompatibles/administración & dosificación , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Materiales Biocompatibles/efectos de la radiación , Precipitación Química/efectos de la radiación , Terapia Combinada , Modelos Animales de Enfermedad , Planificación Ambiental , Femenino , Inyecciones Espinales , Yodo/administración & dosificación , Yodo/efectos de la radiación , Laminectomía , Láseres de Gas/uso terapéutico , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/fisiología , Polímeros/administración & dosificación , Polímeros/síntesis química , Polímeros/efectos de la radiación , Pirroles/administración & dosificación , Pirroles/síntesis química , Pirroles/efectos de la radiación , Ratas , Ratas Long-Evans , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/patología , Regeneración de la Medula Espinal/efectos de los fármacos , NataciónRESUMEN
In addition to oxidative stress due to the increase of free radicals, estrogen deficiency is associated with changes in enzymatic activity, glutathione redox ratio (GSH/GSSG), and the content of oxidative markers such as malondialdehyde. Tibolone, a synthetic steroid, has been used as an elective treatment for the relief of menopausal symptoms. However, the acute effects of hormonal therapy with tibolone on metabolic parameters and oxidative stress markers associated with the first stages of estrogen deficiency are still unknown. The study aimed to evaluate if the acute administration of tibolone reduces oxidative stress in ovariectomized rats fed high-fat-and-fructose diet. Rats were fed a standard diet or a diet consisting of 10% lard-supplemented chow and 20% high-fructose syrup in the drinking water plus tibolone or vehicle for seven days. Weight, cholesterol, triglycerides, and glucose levels, as well as antioxidant enzymes and oxidative stress markers were quantified in the serum of each experimental group. It was observed that seven days of diet and tibolone treatment in the ovariectomized group reduced weight, triglycerides, cholesterol, glucose levels and advanced glycation end products but did not change GSH/GSSG ratio nor the enzymatic activity of superoxide dismutase. Also, both glutathione peroxidase and glutathione reductase activity decreased, as well as malondialdehyde levels. These results suggest that the acute treatment with tibolone prevented the changes in the metabolic parameters analyzed as well as the increase in the levels of malondialdehyde and AGEs induced by ovariectomy and high-fat diet.
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Carbohidratos de la Dieta/efectos adversos , Grasas de la Dieta/efectos adversos , Fructosa/efectos adversos , Norpregnenos/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Carbohidratos de la Dieta/farmacología , Grasas de la Dieta/farmacología , Femenino , Fructosa/farmacología , Ovariectomía , Ratas , Ratas Sprague-DawleyRESUMEN
Patients with spinal cord injury (SCI) face devastating health, social, and financial consequences, as well as their families and caregivers. Reducing the levels of reactive oxygen species (ROS) and oxidative stress are essential strategies for SCI treatment. Some compounds from traditional medicine could be useful to decrease ROS generated after SCI. This review is aimed at highlighting the importance of some natural compounds with antioxidant capacity used in traditional medicine to treat traumatic SCI. An electronic search of published articles describing animal models of SCI treated with natural compounds from traditional medicine was conducted using the following terms: Spinal Cord Injuries (MeSH terms) AND Models, Animal (MeSH terms) AND [Reactive Oxygen Species (MeSH terms) AND/OR Oxidative Stress (MeSH term)] AND Medicine, Traditional (MeSH terms). Articles reported from 2010 to 2018 were included. The results were further screened by title and abstract for studies performed in rats, mice, and nonhuman primates. The effects of these natural compounds are discussed, including their antioxidant, anti-inflammatory, and antiapoptotic properties. Moreover, the antioxidant properties of natural compounds were emphasized since oxidative stress has a fundamental role in the generation and progression of several pathologies of the nervous system. The use of these compounds diminishes toxic effects due to their high antioxidant capacity. These compounds have been tested in animal models with promising results; however, no clinical studies have been conducted in humans. Further research of these natural compounds is crucial to a better understanding of their effects in patients with SCI.
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Antiinflamatorios/farmacología , Antioxidantes/farmacología , Medicamentos Herbarios Chinos/farmacología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/uso terapéutico , Peroxidación de Lípido/efectos de los fármacos , Medicina Tradicional China , Ratones , Fármacos Neuroprotectores/uso terapéutico , Ácido Peroxinitroso/metabolismo , Primates , Ratas , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1 (MAP1), MAP2, neurofilament 38 (NF38) by different mechanisms of action and at different levels: neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects.
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We studied the effects of estradiol (E2) and progesterone (P) on progesterone receptor (PR) isoforms gene expression in the brain of ovariectomised female and gonadectomised male rats by RT-PCR analysis. In female rats, the expression of both PR isoforms was induced by E2 and down-regulated by P in the hypothalamus, whereas in the preoptic area these changes were only observed in PR-B isoform. On the contrary, in the hippocampus and the olfactory bulb, PR-A was the isoform induced by E2. In these regions, P did not modify the expression of any PR isoform. In the cerebellum and the frontal cortex of female rats, no treatment modified PR isoforms expression. In contrast with female rats, in the male rat brain, PR isoforms expression was only modified in the cerebellum, where PR-A was induced by E2. These results demonstrate a clear sexual dimorphism in the regulation of PR isoforms expression by sex steroid hormones in the rat brain, suggesting that this sex difference contributes to the sexually dimorphic effects of P in the rat brain.