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Traumatic brain injury (TBI) results from direct penetrating and indirect non-penetrating forces that alters brain functions, affecting millions of individuals annually. Primary injury following TBI is exacerbated by secondary brain injury; foremost is the deleterious inflammatory response. One therapeutic intervention being increasingly explored for TBI is hyperbaric oxygen therapy (HBOT), which is already approved clinically for treating open wounds. HBOT consists of 100% oxygen administration, usually between 1.5 and 3 atm and has been found to increase brain oxygenation levels after hypoxia in addition to decreasing levels of inflammation, apoptosis, intracranial pressure, and edema, reducing subsequent secondary injury. The following review examines recent preclinical and clinical studies on HBOT in the context of TBI with a focus on contributing mechanisms and clinical potential. Several preclinical studies have identified pathways, such as TLR4/NF-kB, that are affected by HBOT and contribute to its therapeutic effect. Thus far, the mechanisms mediating HBOT treatment have yet to be fully elucidated and are of interest to researchers. Nonetheless, multiple clinical studies presented in this review have examined the safety of HBOT and demonstrated the improved neurological function of TBI patients after HBOT, deeming it a promising avenue for treatment.
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Lesões Encefálicas Traumáticas , Lesões Encefálicas , Oxigenoterapia Hiperbárica , Humanos , Oxigenoterapia Hiperbárica/métodos , Lesões Encefálicas Traumáticas/terapia , Lesões Encefálicas/terapia , Encéfalo , OxigênioRESUMO
Obesity has been linked to cognitive impairment through systemic low-grade inflammation. High fat and sugar diets (HFSDs) also induce systemic inflammation, either by induced Toll-like receptor 4 response, or by causing dysbiosis. This study aimed to evaluate the effect of symbiotics supplementation on spatial and working memory, butyrate concentration, neurogenesis, and electrophysiological recovery of HFSD-fed rats. In a first experiment, Sprague-Dawley male rats were given HFSD for 10 weeks, after which they were randomized into 2 groups (n = 10 per group): water (control), or Enterococcus faecium + inulin (symbiotic) administration, for 5 weeks. In the fifth week, spatial and working memory was analyzed through the Morris Water Maze (MWM) and Eight-Arm Radial Maze (RAM) tests, respectively, with 1 week apart between tests. At the end of the study, butyrate levels from feces and neurogenesis at hippocampus were determined. In a second experiment with similar characteristics, the hippocampus was extracted to perform electrophysiological studies. Symbiotic-supplemented rats showed a significantly better memory, butyrate concentrations, and neurogenesis. This group also presented an increased firing frequency in hippocampal neurons [and a larger N-methyl-d-aspartate (NMDA)/α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) current ratio] suggesting an increase in NMDA receptors, which in turn is associated with an enhancement in long-term potentiation and synaptic plasticity. Therefore, our results suggest that symbiotics could restore obesity-related memory impairment and promote synaptic plasticity.
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Agave , Memória Espacial , Ratos , Animais , Masculino , Agave/metabolismo , Inulina/farmacologia , Inulina/uso terapêutico , Ratos Sprague-Dawley , Hipocampo/metabolismo , Plasticidade Neuronal/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Aprendizagem em Labirinto/fisiologia , Obesidade/terapia , Suplementos Nutricionais , InflamaçãoRESUMO
Epilepsy stands as a life-threatening disease that is characterized by unprovoked seizures. However, an important characteristic of epilepsy that needs to be examined is the neuropsychiatric aspect. Epileptic patients endure aggression, depression, and other psychiatric illnesses. Therapies for epilepsy can be divided into two categories: antiepileptic medications and surgical resection. Antiepileptic drugs are used to attenuate heightened neuronal firing and to lessen seizure frequency. Alternatively, surgery can also be conducted to physically cut out the area of the brain that is assumed to be the root cause for the anomalous firing that triggers seizures. While both treatments serve as viable approaches that aim to regulate seizures and ameliorate the neurological detriments spurred by epilepsy, they do not serve to directly counteract epilepsy's neuropsychiatric traits. To address this concern, a potential new treatment involves the use of stem cells. Stem cell therapy has been employed in experimental models of neurological maladies, such as Parkinson's disease, and neuropsychiatric illnesses like depression. Cell-based treatments for epilepsy utilizing stem cells such as neural stem cells (NSCs), mesenchymal stem cells (MSCs), and interneuron grafts have been explored in preclinical and clinical settings, highlighting both the acute and chronic stages of epilepsy. However, it is difficult to create an animal model to capitalize on all the components of epilepsy due to the challenges in delineating the neuropsychiatric aspect. Therefore, further preclinical investigation into the safety and efficacy of stem cell therapy in addressing both the neurological and the neuropsychiatric components of epilepsy is warranted in order to optimize cell dosage, delivery, and timing of cell transplantation.
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Stroke serves as a life-threatening disease and continues to face many challenges in the development of safe and effective therapeutic options. The use of hyperbaric oxygen therapy (HBOT) demonstrates pre-clinical effectiveness for the treatment of acute ischemic stroke and reports reductions in oxidative stress, inflammation, and neural apoptosis. These pathophysiological benefits contribute to improved functional recovery. Current pre-clinical and clinical studies are testing the applications of HBOT for stroke neuroprotection, including its use as a preconditioning regimen. Mild oxidative stress may be able to prime the brain to tolerate full extensive oxidative stress that occurs during a stroke, and HBOT preconditioning has displayed efficacy in establishing such ischemic tolerance. In this review, evidence on the use of HBOT following an ischemic stroke is examined, and the potential for HBOT preconditioning as a neuroprotective strategy. Additionally, HBOT as a stem cell preconditioning is also discussed as a promising strategy, thus maximizing the use of HBOT for ischemic stroke.
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Oxigenoterapia Hiperbárica/métodos , AVC Isquêmico/terapia , Fármacos Neuroprotetores/uso terapêutico , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Humanos , Precondicionamento Isquêmico/métodos , Óxido Nítrico/metabolismo , Respiração , Células-TroncoRESUMO
Although hyperbaric oxygen therapy (HBOT) is common as a treatment for injuries, this study aimed to research the ability of HBOT in preconditioning to diminish any potential damage. The hypothesis stated that HBOT preconditioning alleviated the death of cells in primary rat neuronal cells (PRNCs) by transferring mitochondria from astrocytes. In this experiment, PRNCs were given an HBOT treatment before a tumor necrosis factor-alpha or lipopolysaccharide injury which resembled cell death associated with stroke and traumatic brain injury (TBI). After being examined, the study found more cell viability in the PRNCs that had received HBOT precondition and a mitochondrial transfer. The mitochondrial transfer was visualized by a series of images showing the transfer after the HBOT treatment. This study demonstrated the ability of HBOT preconditioning as a treatment for inflammation in stroke and TBI, with the transfer of mitochondria from astrocytes to PRNCs reducing cell death. Along with discussion of the study, this review also focuses on different stroke treatments in comparison with HBOT.
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Returning veterans are frequently diagnosed with traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). Considering a recent case-controlled study of hyperbaric oxygen therapy (HBOT) reporting a reduction in suicidal ideation, we investigated retrospectively three veterans with chronic TBI/PTSD symptoms who were treated with multiple rounds of HBOT with neurophysiological testing performed before and after treatment. Improvements were detected on parameters within neurocognitive domains, including reductions in suicide-related symptoms. These findings independently confirm that HBOT may be effective in treating specific symptoms of TBI/PTSD that are not currently addressed with existing therapeutic approaches.
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Lesões Encefálicas Traumáticas/terapia , Oxigenoterapia Hiperbárica/métodos , Transtornos de Estresse Pós-Traumáticos/terapia , Adulto , Feminino , Humanos , Masculino , Estudos Retrospectivos , VeteranosRESUMO
Traumatic brain injury (TBI) is associated with long-term disabilities and devastating chronic neurological complications including problems with cognition, motor function, sensory processing, as well as behavioral deficits and mental health problems such as anxiety, depression, personality change and social unsuitability. Clinical data suggest that disruption of the thalamo-cortical system including anatomical and metabolic changes in the thalamus following TBI might be responsible for some chronic neurological deficits following brain trauma. Detailed mechanisms of these pathological processes are not completely understood. The goal of this study was to evaluate changes in the thalamus following TBI focusing on cleaved-caspase-3, a specific effector of caspase pathway activation and myelin and microvascular pathologies using immuno- and histochemistry at different time points from 24 h to 3 months after controlled cortical impact (CCI) in adult Sprague-Dawley rats. Significant increases in cleaved-caspase-3 immunoreactivity in the thalamus were observed starting one month and persisting for at least three months following experimental TBI. Further, the study demonstrated an association of cleaved-caspase-3 with the demyelination of neuronal processes and tissue degeneration in the gray matter in the thalamus, as reflected in alterations of myelinated fiber integrity (luxol fast blue) and decreases in myelin basic protein (MBP) immunoreactivity. The immunofluorescent counterstaining of cleaved-caspase-3 with endothelial barrier antigen (EBA), a marker of blood-brain barrier, revealed limited direct and indirect associations of cleaved caspase-3 with blood-brain barrier damage. These results demonstrate for the first time a significant chronic upregulation of cleaved-caspase-3 in selected thalamic regions associated with cortical regions directly affected by CCI injury. Further, our study is also the first to report that significant upregulation of cleaved-caspase-3 in selected ipsilateral thalamic regions is associated with microvascular reorganization reflected in the significant increases in the number of microvessels with blood-brain barrier alterations detected by EBA staining. These findings provide new insights into potential mechanisms of TBI cell death involving chronic activation of caspase-3 associated with disrupted cortico-thalamic and thalamo-cortical connectivity. Moreover, this study offers the initial evidence that this upregulation of activated caspase-3, delayed degeneration of myelinated nerve fibers and microvascular reorganization with impaired blood-brain barrier integrity in the thalamus might represent reciprocal pathological processes affecting neuronal networks and brain function at the chronic stages of TBI.
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Lesões Encefálicas Traumáticas/metabolismo , Caspase 3/metabolismo , Microvasos/metabolismo , Bainha de Mielina/patologia , Tálamo/metabolismo , Animais , Antígenos de Superfície/metabolismo , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Humanos , Microvasos/patologia , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para CimaRESUMO
Tissue plasminogen activator (tPA) thrombolysis remains the gold standard treatment for ischemic stroke. A time-constrained therapeutic window, with the drug to be given within 4.5 h after stroke onset, and lethal side effects associated with delayed treatment, most notably hemorrhagic transformation (HT), limit the clinical use of tPA. Co-administering tPA with other agents, including drug or non-drug interventions, has been proposed as a practical strategy to address the limitations of tPA. Here, we discuss the pharmacological and non-drug approaches that were examined to mitigate the complications-especially HT-associated with delayed tPA treatment. The pharmacological treatments include those that preserve the blood-brain barrier (e.g., atovarstatin, batimastat, candesartan, cilostazol, fasudil, minocycline, etc.), enhance vascularization and protect the cerebrovasculature (e.g., coumarin derivate IMM-H004 and granulocyte-colony stimulating factor (G-CSF)), and exert their effects through other modes of action (e.g., oxygen transporters, ascorbic acid, etc.). The non-drug approaches include stem cell treatments and gas therapy with multi-pronged biological effects. Co-administering tPA with the abovementioned therapies showed promise in attenuating delayed tPA-induced side effects and stroke-induced neurological and behavioral deficits. Thus, adjunctive treatment approach is an innovative therapeutic modality that can address the limitations of tPA treatment and potentially expand the time window for ischemic stroke therapy.
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Isquemia Encefálica/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica/métodos , Animais , Isquemia Encefálica/terapia , Quimioterapia Adjuvante , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Fibrinolíticos/uso terapêutico , Humanos , Transplante de Células-Tronco/métodos , Acidente Vascular Cerebral/terapiaRESUMO
Traumatic brain injury (TBI) describes the presence of physical damage to the brain as a consequence of an insult and frequently possesses psychological and neurological symptoms depending on the severity of the injury. The recent increased military presence of US troops in Iraq and Afghanistan has coincided with greater use of improvised exploding devices, resulting in many returning soldiers suffering from some degree of TBI. A biphasic response is observed which is first directly injury-related, and second due to hypoxia, increased oxidative stress, and inflammation. A proportion of the returning soldiers also suffer from post-traumatic stress disorder (PTSD), and in some cases, this may be a consequence of TBI. Effective treatments are still being identified, and a possible therapeutic candidate is hyperbaric oxygen therapy (HBOT). Some clinical trials have been performed which suggest benefits with regard to survival and disease severity of TBI and/or PTSD, while several other studies do not see any improvement compared to a possibly poorly controlled sham. HBOT has been shown to reduce apoptosis, upregulate growth factors, promote antioxidant levels, and inhibit inflammatory cytokines in animal models, and hence, it is likely that HBOT could be advantageous in treating at least the secondary phase of TBI and PTSD. There is some evidence of a putative prophylactic or preconditioning benefit of HBOT exposure in animal models of brain injury, and the optimal time frame for treatment is yet to be determined. HBOT has potential side effects such as acute cerebral toxicity and more reactive oxygen species with long-term use, and therefore, optimizing exposure duration to maximize the reward and decrease the detrimental effects of HBOT is necessary. This review provides a summary of the current understanding of HBOT as well as suggests future directions including prophylactic use and chronic treatment.
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The last three decades have documented preclinical and clinical data supporting the use of acupuncture in relieving symptoms of many diseases, including allergies, infections, and neurological disorders. The advent of electroacupuncture has not only modernized the practice of acupuncture, but also has improved its efficacy, especially for producing analgesic-like effects. Although the mechanism of action of acupuncture-induced analgesia remains largely unknown, several lines of investigation have implicated modulation of pain processes via brain opioid signaling and neuroimmunoregulatory pathways. Here, we review key findings demonstrating the efficacy and underlying mechanisms of acupuncture-induced analgesia. In particular, we discuss potent analgesic effects of acupuncture via neural pain processes through inhibition of microglial activation. The safe and effective use of acupuncture stands as a nonpharmacological alternative for induction of analgesia, which has direct clinical applications, especially for pain-related diseases.
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Analgesia por Acupuntura , Microglia/imunologia , Neuroimunomodulação , Manejo da Dor , Dor/imunologia , HumanosRESUMO
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone derived from the pineal gland that has a wide range of clinical applications. While melatonin was originally assessed as a hormone specializing in regulation of the normal circadian rhythm in mammals, it now has been shown to be an effective free radical scavenger and antioxidant. Current research has focused on central nervous system (CNS) disorders, stroke in particular, for potential melatonin-based therapeutics. As of now, the realm of potential therapy regimens is focused on three main treatments: exogenously delivered melatonin, pineal gland grafting, and melatonin-mediated stem cell therapy. All therapies contain both costs and benefits, and current research is still focused on finding the best treatment plan. While comprehensive research has been conducted, more research regarding the safety of such therapies is needed in order to transition into the clinical level of testing. Antioxidants such as traditional Chinese medicine, (-)-epigallocatechin-3-gallate (EGCG), and lavender oil, which have been used for thousands of years as treatment, are now gaining recognition as effective melatonin treatment alternatives. This review will further discuss relevant studies assessing melatonin-based therapeutics and provide evidence of other natural melatonin treatment alternatives for the treatment of stroke.
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Antioxidantes/uso terapêutico , Melatonina/uso terapêutico , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Transplante de Células-Tronco , Acidente Vascular Cerebral/prevenção & controle , Animais , Catequina/análogos & derivados , Catequina/uso terapêutico , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Glândula Pineal/metabolismo , Glândula Pineal/transplante , Receptores de Melatonina/metabolismo , Células-Tronco/citologiaRESUMO
CONTEXT: Telomerase is a critical enzyme that is involved in aging and cancer and that is thought to be a part of multiple neurological diseases. OBJECTIVE: To investigate the telomerase response in the brain to acupuncture, the study examined the levels of expression of brain-derived neurotrophic factor (BDNF) and its downstream signaling molecules, including tyrosine kinase receptor Β (TrkB), p75 neurotrophin receptor (p75NTR), protein kinase B (Akt), extracellular signal-regulated protein kinase (ERK1/2), and nuclear factor κΒ (NF-κΒ). DESIGN: Both telomerase-deficient (Tercâ»/â») mice (Tercâ»/â» group) and normal, wild-type (WT) mice (WT group) were randomly assigned to 1 of 3 subgroups, 1 receiving acupuncture (acupuncture subgroup), 1 receiving sham acupuncture therapy (sham subgroup), and 1 receiving no treatment (control subgroup). SETTING: The study occurred at the University of South Florida Health Byrd Alzheimer's Institute (Tampa, FL, USA). INTERVENTION: The 2 acupuncture subgroups received acupuncture at the stomach 36 (ST-36) position for 30 min/d for 4 d. For the 2 sham groups, the sham point was set at a location approximately 3 mm to the lateral side of the tail on the gluteus muscle following the same schedule. OUTCOME MEASURES: After 4 d, the mice were sacrificed, and the brain tissues were collected. The protein levels in the hippocampus and dentate gyrus (DG) of each mouse were determined by western blotting and immunostaining assays. RESULTS: The Tercâ»/â» group showed downregulated hippocampal BDNF expression compared with the WT mice. Acupuncture at ST-36 for 4 d upregulated BDNF, TrkB, p75NTR, Akt, and ERK1/2 in the DG and hippocampus of the telomerase-deficient mice, but that result was not seen in the WT mice with normally functioning telomerase. CONCLUSIONS: The use of acupuncture in pathologies associated with telomerase deficiencies, such as Alzheimer's disease (AD) and Parkinson's disease (PD), may provide some benefit in terms of eliciting better clinical responses. The research team believes that result occurs through the activation of BDNF and its downstream signaling pathways in populations of patients who exhibit low telomerase activity.
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Terapia por Acupuntura/métodos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , RNA/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Telomerase/metabolismo , Animais , Camundongos , Camundongos Knockout , Distribuição Aleatória , Transdução de SinaisRESUMO
Recent studies have been conducted to examine the neuroprotective effects of acupuncture in many neurological disorders. Although the neuroprotective effects of acupuncture has been linked to changes in signaling pathways, accumulating evidence suggest the participation of endogenous biological mediators, such as the neurotrophin (NT) family of proteins, specifically, the brain derived neurotrophic factor (BDNF). Accordingly, acupuncture can inhibit neurodegeneration via expression and activation of BDNF. Moreover, recent studies have reported that acupuncture can increase ATP levels at local stimulated points. We have also demonstrated that acupuncture could activate monocytes and increase the expression of BDNF via the stimulation of ATP. The purpose of this article is to review the recent findings and ongoing studies on the neuroprotective roles of acupuncture and therapeutic implications of acupuncture-induced activation of BDNF and its signaling pathway.
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Terapia por Acupuntura , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Trifosfato de Adenosina/metabolismo , Animais , Humanos , Proteínas Tirosina Quinases/metabolismoRESUMO
Stroke remains the number one cause of disability in the adult population. Despite scientific progress in our understanding of stroke pathology, only one treatment (tissue plasminogen activator or tPA) is able to afford benefits but to less than 3% of ischemic stroke patients. The development of experimental dietary supplement therapeutics designed to stimulate endogenous mechanisms that confer neuroprotection is likely to open new avenues for exploring stroke therapies. The present review article evaluates the recent literature supporting the benefits of dietary supplementation for the therapy of ischemic stroke. This article focuses on discussing the medical benefits of NT-020 as an adjunct agent for stroke therapy. Based on our preliminary data, a pre-stroke treatment with dietary supplementation promotes neuroprotection by decreasing inflammation and enhancing neurogenesis. However, we recognize that a pre-stroke treatment holds weak clinical relevance. Thus, the main goal of this article is to provide information about recent data that support the assumption of natural compounds as neuroprotective and to evaluate the therapeutic effects of a dietary supplement called NT-020 as in a stroke model. We focus on a systematic assessment of practical treatment parameters so that NT-020 and other dietary supplementations can be developed as an adjunct agent for the prevention or treatment of chronic diseases. We offer rationale for determining the optimal dosage, therapeutic window, and mechanism of action of NT-020 as a dietary supplement to produce neuroprotection when administered immediately after stroke onset. We highlight our long-standing principle in championing both translational and basic science approaches in an effort to fully reveal the therapeutic potential of NT-020 as dietary supplementation in the treatment of stroke. We envision dietary supplementation as an adjunct therapy for stroke at acute, subacute, and even chronic periods.
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Isquemia Encefálica/dietoterapia , Suplementos Nutricionais , Alimentos Formulados , Acidente Vascular Cerebral/dietoterapia , Animais , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Humanos , Ratos , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologiaRESUMO
The present study explored the prophylactic and restorative benefits of cacao and red sage using both in vitro and in vivo models of stroke. For the in vitro study, we initially exposed primary rat cells to the established oxygen-glucose deprivation (OGD) stroke model followed by reperfusion under normoxic conditions, then added different cacao and sage concentrations to the cell culture media. Trypan blue cell viability results revealed specific cacao and sage dosages exerted significant therapeutic effects against OGD-induced cell death compared to cultured cells treated with extract vehicle. We next embarked on testing the therapeutic effects of cacao and sage in an in vivo model of stroke when extract treatment commenced either prior to or after transient middle cerebral artery occlusion (MCAo). Significant reduction in ischemic cell death within the peri-infarct area coupled with better performance in routine motor and neurological tasks were demonstrated by stroke animals that received cacao or sage extracts prior to MCAo compared to those that received the extracts or vehicle after MCAo. In summary, the present results demonstrate that neuroprotective effects were afforded by plant extract treatment, and that the in vitro stroke paradigm approximates in vivo efficacy when considering prophylactic treatment for stroke.
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BACKGROUND: Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, has been shown to promote therapeutic benefits in experimental stroke. However, equally compelling evidence demonstrates that the drug exerts variable and even detrimental effects in many neurological disease models. Assessment of the mechanism underlying minocycline neuroprotection should clarify the drug's clinical value in acute stroke setting. RESULTS: Here, we demonstrate that minocycline attenuates both in vitro (oxygen glucose deprivation) and in vivo (middle cerebral artery occlusion) experimentally induced ischemic deficits by direct inhibition of apoptotic-like neuronal cell death involving the anti-apoptotic Bcl-2/cytochrome c pathway. Such anti-apoptotic effect of minocycline is seen in neurons, but not apparent in astrocytes. Our data further indicate that the neuroprotection is dose-dependent, in that only low dose minocycline inhibits neuronal cell death cascades at the acute stroke phase, whereas the high dose exacerbates the ischemic injury. CONCLUSION: The present study advises our community to proceed with caution to use the minimally invasive intravenous delivery of low dose minocycline in order to afford neuroprotection that is safe for stroke.
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Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Minociclina/farmacologia , Neurônios/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Western Blotting , Contagem de Células , Células Cultivadas , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Citocromos c/metabolismo , Citoproteção , Relação Dose-Resposta a Droga , Glucose/deficiência , Hipóxia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Minociclina/uso terapêutico , Destreza Motora/efeitos dos fármacos , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
This study examined whether dietary supplementation can be used to protect against ischemic stroke. Two groups of adult male Sprague-Dawley rats initially received NT-020, a proprietary formulation of blueberry, green tea, Vitamin D3, and carnosine (n = 8), or vehicle (n = 7). Dosing for NT-020 and vehicle consisted of daily oral administration (using a gavage) over a 2-week period. On day 14 following the last drug treatment, all animals underwent the stroke surgery using the transient 1-hour suture occlusion of middle cerebral artery (MCAo). To reveal the functional effects of NT-020, animals were subjected to established behavioral tests just prior to stroke surgery and again on day 14 post-stroke. ANOVA revealed significant treatment effects (p < 0.05), characterized by reductions of 11.8% and 24.4% in motor asymmetry and neurologic dysfunction, respectively, in NT-020-treated stroke animals compared to vehicle-treated stroke animals. Evaluation of cerebral infarction revealed a significant 75% decrement in mean glial scar area in the ischemic striatum of NT-020-treated stroke animals compared to that of vehicle-treated stroke animals (p < 0.0005). Quantitative analysis of subventricular zone's cell proliferative activity revealed at least a one-fold increment in the number of BrdU-positive cells in the NT-020-treated stroke brains compared to vehicle-treated stroke brains (p < 0.0005). Similarly, quantitative analysis of BrdU labeling in the ischemic striatal penumbra revealed at least a three-fold increase in the number of BrdU-positive cells in the NT-020-treated stroke brains compared to vehicle-treated stroke brains (p < 0.0001). In addition, widespread double labeling of cells with BrdU and doublecortin was detected in NT-020-treated stroke brains (intact side 17% and ischemic side 75%), which was significantly higher than those seen in vehicle-treated stroke brains (intact side 5% and ischemic side 13%) (p < 0.05). In contrast, only a small number of cells in NT-020-treated stroke brains double labeled with BrdU and GFAP (intact side 1% and ischemic side 2%), which was significantly lower than those vehicle-treated stroke brains (intact side 18% and ischemic side 35%) (p < 0.0001). Endogenous neurogenic factors were also significantly upregulated in the ischemic brains of NT-020-treated stroke animals. These data demonstrate the remarkable neuroprotective effects of NT-020 when given prior to stroke, possibly acting via its neurogenic potential.
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Isquemia Encefálica/patologia , Suplementos Nutricionais , Medicamentos de Ervas Chinesas/farmacologia , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/patologia , Animais , Mirtilos Azuis (Planta)/química , Carnosina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Colecalciferol/farmacologia , Modelos Animais de Doenças , Proteína Duplacortina , Medicamentos de Ervas Chinesas/uso terapêutico , Masculino , Doenças do Sistema Nervoso/prevenção & controle , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Chá/químicaRESUMO
BACKGROUND: We describe a rare case of severe rhabdomyolysis provoked by ingestion of a performance-enhancer herbal supplement containing ephedra. CASE REPORT: A healthy 21-year-old Army soldier complained of "complete muscle failure" after collapsing at the end of Army Physical Fitness Test. The patient was found to be tachycardic and hypotensive, but his vital signs quickly stabilized after receiving sodium chloride in the ambulance. Physical examination of the patient, including a thorough neuromuscular exam, was unremarkable. Urine tested positive for myoglobin. Initial creatinine kinase was 426 U/L, which increased to a maximum creatinine kinase of 241,418 ti/IL by hospital day 6. The patient also developed acute renal failure secondary to pigment-induced actute tubular necrosis. He was treated with bicarbonate-containing fluid. The patient's creatinine kinase and renal function had normalized at one month follow-up. A muscle biopsy was negative for underlying neuromuscular disease. His past medical history was only notable for the patient having taken 2 tablets of an herbal supplement containing ephedra every day for a month leading to his physical fitness test. CONCLUSIONS: Rhabdomvolvsis and myoglobinuric renal failure associated with ephedra use are a very uncommion occurrence, but a significant clinical event that should be closely monitored due to rampant use by young adults of ephedra-containing dietary supplements.
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Suplementos Nutricionais/efeitos adversos , Ephedra sinica/efeitos adversos , Exercício Físico , Preparações de Plantas/efeitos adversos , Rabdomiólise/diagnóstico , Rabdomiólise/etiologia , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Adulto , Humanos , MasculinoRESUMO
BACKGROUND: Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally. The aim of this study was to determine if minocycline was effective at reducing infarct size in a Temporary Middle Cerebral Artery Occlusion model (TMCAO) when given at lower intravenous (IV) doses that correspond to human clinical exposure regimens. METHODS: Rats underwent 90 minutes of TMCAO. Minocycline or saline placebo was administered IV starting at 4, 5, or 6 hours post TMCAO. Infarct volume and neurofunctional tests were carried out at 24 hr after TMCAO using 2,3,5-triphenyltetrazolium chloride (TTC) brain staining and Neurological Score evaluation. Pharmacokinetic studies and hemodynamic monitoring were performed on minocycline-treated rats. RESULTS: Minocycline at doses of 3 mg/kg and 10 mg/kg IV was effective at reducing infarct size when administered at 4 hours post TMCAO. At doses of 3 mg/kg, minocycline reduced infarct size by 42% while 10 mg/kg reduced infarct size by 56%. Minocycline at a dose of 10 mg/kg significantly reduced infarct size at 5 hours by 40% and the 3 mg/kg dose significantly reduced infarct size by 34%. With a 6 hour time window there was a non-significant trend in infarct reduction. There was a significant difference in neurological scores favoring minocycline in both the 3 mg/kg and 10 mg/kg doses at 4 hours and at the 10 mg/kg dose at 5 hours. Minocycline did not significantly affect hemodynamic and physiological variables. A 3 mg/kg IV dose of minocycline resulted in serum levels similar to that achieved in humans after a standard 200 mg dose. CONCLUSIONS: The neuroprotective action of minocycline at clinically suitable dosing regimens and at a therapeutic time window of at least 4-5 hours merits consideration of phase I trials in humans in view of developing this drug for treatment of stroke.