losartan-potassium and Epilepsy

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecu

Topics: Acetylcysteine; Animals; Anticonvulsants; Antioxidants; Atorvastatin; Brain Injuries, Traumatic; Ceftriaxone; Dibenzazepines; Drug Repositioning; Epilepsy; Epilepsy, Post-Traumatic; Erythropoietin; Fingolimod Hydrochloride; GABA Agents; Gabapentin; Humans; Immunologic Factors; Inflammation; Interleukin 1 Receptor Antagonist Protein; Isoflurane; Levetiracetam; Losartan; Neuroprotective Agents; Oxidative Stress; Pregabalin; Pyrrolidinones; Sirolimus; Stroke; Topiramate; Translational Research, Biomedical; Vigabatrin

Perinatal asphyxia is characterized by oxygen deprivation and lack of perfusion in the perinatal period, leading to hypoxic-ischemic encephalopathy and sequelae such as cerebral palsy, mental retardation, cerebral visual impairment, epilepsy and learning disabilities. On cellular level PA is associated with a decrease in oxygen and glucose leading to ATP depletion and a compromised mitochondrial function. Upon reoxygenation and reperfusion, the renewed availability of oxygen gives rise to not only restoration of cell function, but also to the activation of multiple detrimental biochemical pathways, leading to secondary energy failure and ultimately, cell death. The formation of reactive oxygen species, nitric oxide and peroxynitrite plays a central role in the development of subsequent neurological damage. In this review we give insight into the pathophysiology of perinatal asphyxia, discuss its clinical relevance and summarize current neuroprotective strategies related to therapeutic hypothermia, ischemic postconditioning and pharmacological interventions. The review will also focus on the possible neuroprotective actions and molecular mechanisms of the selective neuronal and inducible nitric oxide synthase inhibitor 2-iminobiotin that may represent a novel therapeutic agent for the treatment of hypoxic-ischemic encephalopathy, both in combination with therapeutic hypothermia in middle- and high-income countries, as well as stand-alone treatment in low-income countries.

Topics: Allopurinol; Asphyxia Neonatorum; Biotin; Cerebral Palsy; Clinical Trials as Topic; Epilepsy; Erythropoietin; Female; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Intellectual Disability; Ischemic Postconditioning; Melatonin; Neuroprotective Agents; Pregnancy; Reactive Nitrogen Species; Reactive Oxygen Species

Epilepsy is a disorder characterised by recurrent seizures and molecular events, including the activation of early expression genes and the post-translational modifications of functional proteins. These events lead to changes in neurogenesis, mossy fibre sprouting, network reorganisation and neuronal death. The role of these events is currently a matter of great debate, especially as they relate to protection, repair, or further brain injury. In recent years, accumulating data have supported the idea that erythropoietin (EPO) regulates biological processes including neuroprotection and neurogenesis in several diseases, such as epilepsy. This review summarises the role of EPO in some of the molecular mechanisms involved in these events that could direct a more detailed approach for its use as a therapeutic alternative in reducing epileptic seizures.

Topics: Animals; Brain; Epilepsy; Erythropoietin; Humans; Models, Neurological; Neurogenesis; Neuroprotective Agents; Signal Transduction

Neuronal damage secondary to brain injuries such as cerebral hypoxia, seizures as well as neurodegenerative process, may include pro-inflammatory changes. The activation of a common mechanism related to survival or cell death, mediated by the stabilization and trans-activation of Hypoxia-Inducible Factor 1 (HIF-1), has been observed in these conditions. HIF-1 may induce over expression of P-glycoprotein, the product multidrug-resistance gene (MDR-1), both on blood-brain barrier as well as on the cerebral damaged cells, producing the refractoriness to therapeutic strategies for neuroprotection. However, in these same cells, HIF-1 can also induce the expression of erythropoietin receptor (Epo-R). Irrespective of its known properties on hematopoiesis, it was proposed that erythropoietin can trigger neuroprotective mechanisms mediated by Epo-R activation. Brain hypoxia, epilepsy, neurodegeneration and inflammation, can share the induction of Epo-R and several other growth factor receptors as well as signal transductions pathways after HIF-1 transactivation. Perhaps, the use of the intranasal route for the exogenous administration of Epo, (or other biological compounds) could help neuroprotection as well as to repair the brain areas damaged.

Topics: Animals; Epilepsy; Erythropoietin; Glutamic Acid; Humans; Hypoxia-Inducible Factor 1; Hypoxia, Brain; Neurodegenerative Diseases; Neuroprotective Agents; Receptors, Erythropoietin

The 39th Annual meeting of the Society for Neuroscience was held in Chicago, Illinois, USA from 17 to 21 October, 2009. The conference was attended by more than 33,000 delegates from across the globe including scientists from both basic and clinical settings. Co-incidentally, this year, the scientific community is commemorating the 200th anniversary of the birth of the famous English naturalist and biologist, Charles Darwin, who described the theory of natural selection. Keeping its traditions, the congress discussed various new advances in the area of neuroscience. The topics were divided into symposia, mini-symposia, nano-symposia, special lectures and poster sessions. The main areas of discussion were novel discoveries in Alzheimer's, Parkinson's, drug addiction, autism, epilepsy and major depression. According to the WHO, neurological disorders are one of the greatest threats to public health. There are many unknown and challenging facts in the field of neuroscience that needs exploration. It is unfortunate that despite the availability of various drugs for treating these disorders, a sizeable population still do not achieve complete remission. Therefore, organizing such events and addressing the latest developments may open new treatment vistas for patients suffering from these disorders. The present review discusses some of the outcomes of the deliberations in the field of epilepsy and major depression.

Topics: Administration, Inhalation; Adrenergic Uptake Inhibitors; Anti-Inflammatory Agents; Anticonvulsants; Antidepressive Agents; Depressive Disorder, Major; Dopamine Uptake Inhibitors; Epilepsy; Erythropoietin; Glutamates; Humans; Inflammation; Receptors, Cannabinoid; Recombinant Proteins; Selective Serotonin Reuptake Inhibitors; Signal Transduction; Wnt Proteins

Topics: Adolescent; Adult; Aged; Anemia; Anticonvulsants; Child; Dose-Response Relationship, Drug; Epilepsy; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

This study aimed to investigate the influence of recombinant human erythropoietin (rHuEPO) on pentylenetetrazol (PTZ)-induced neuronal apoptosis in epilepsy rats, and to explore the signaling pathways related to the action. Healthy Sprague-Dawley rats aged 8 weeks old were randomly divided into 5 groups, namely, control group, PTZ model group, PTZ + rHuEPO intervention group, PTZ + SB431542 + rHuEPO intervention group and PTZ + SB431542 (TGF-β/Smad inhibitor) intervention group. The expressions of apoptotic proteins [tumor necrosis factor receptor 1 (TNFR1) and caspase-3] and the transforming growth factor-beta (TGF-β)/Smad signaling pathway-related proteins [phosphorylated smad3 (p-smad3) and TGF-β1] in the brain tissues were determined via Western blotting (WB). Epilepsy was successfully induced by PTZ in the rats. The results of the TUNEL assay showed that the intervention with rHuEPO could remarkably reduce the number of PTZ-induced apoptotic neurons in the hippocampus, while SB431542 inhibitor could attenuate the protective effect of rHuEPO against neuronal apoptosis (P<0.05). In addition, the intraperitoneal injection of 50 μg/kg rHuEPO could activate the TGF-β/Smad signaling pathway, markedly up-regulate the expressions of TGF-β1 and p-smad3 (P<0.05), down-regulate the expressions of apoptotic proteins TNFR1 and caspase-3 (P<0.01) and reduce neuronal apoptosis. Moreover, SB431542 was able to notably repress the protective effect of rHuEPO against neuronal apoptosis, and down-regulate the expressions of p-smad3 and TGF-β1 (P<0.01). In conclusion, the inhibitory effect of rHuEPO on nerve cell apoptosis in epilepsy rats may be realized by activating the TGF-β/Smad signaling pathway, thus relieving neuronal apoptosis and ameliorating the symptoms of epilepsy.

Topics: Animals; Apoptosis; Caspase 3; Epilepsy; Erythropoietin; Humans; Rats; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Cerebral Palsy; Child, Preschool; Epilepsy; Erythropoietin; Female; Humans; Infant; Male; Recombinant Proteins; Seizures

Recurrent seizures can result in neuronal death, cognitive deficits and intellectual disability, which causes devastating damage in children. Recombinant human erythropoietin (rhEPO) is considered a neuroprotective factor in many nervous system diseases. However, the precise mechanisms through which rhEPO exerts its neuroprotective effects on epilepsy remain unknown. Thus, in this study, we determined whether rhEPO protects against brain injury by inducing cortical neuronal autophagy through blunting the mammalian target of rapamycin complex 1 (mTORC1) pathway in the developing brains of rats with seizures.. We used kainic acid to induce recurrent seizures in rats. Nissl staining and TUNEL analysis were used to evaluate the neuronal damage and apoptotic cells. Western blot analysis was employed to evaluate the phospho-mammalian target of rapamycin (p-mTOR)/mTOR protein ratio, the phospho-ribosomal protein S6 (S6)/S6 protein ratio, the microtubule-associated protein light chain 3 (LC3) II/I protein ratio and sequestosome 1 (P62/SQSTM1) protein expression levels.. rhEPO reversed the decrease in the number of Nissl-positive neurons and the increase in the number of apoptotic cells in the kainic acid group. Notably, rhEPO induced autophagy and inhibited the mTORC1 pathway to protect against brain injury in rats with seizures. Treating rats with rapamycin blocked the mTORC1 pathway and masked the abovementioned effects of rhEPO.. Based on these results, rhEPO protects against brain injury by activating autophagy through blunting the mTORC1 pathway in developing rats with seizures.

Topics: Animals; Autophagy; Brain; Brain Injuries; Epilepsy; Erythropoietin; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Neurons; Neuroprotection; Neuroprotective Agents; Rats, Sprague-Dawley; Recombinant Proteins; Seizures; Signal Transduction

Epilepsy is among the most common neurological disorders. Recurrent seizures result in neuronal death, cognitive deficits and intellectual disabilities in children. Currently, recombinant human erythropoietin (rhEPO) is considered to play a neuroprotective role in nervous system disorders. However, the precise mechanisms through which rhEPO modulates epilepsy remain unknown. Based on results from numerous studies, we hypothesized that rhEPO protects against hippocampal damage in developing rats with seizures probably by modulating autophagy via the ribosomal protein S6 (S6) in a time-dependent manner. First, we observed that rats with recurrent seizures displayed neuronal loss in the hippocampal CA1 region. Second, rhEPO injection reduced neuronal loss and decreased the number of apoptotic cells in the hippocampal CA1 region. Moreover, rhEPO increased the Bcl-2 protein expression levels and decreased the ratio of cleaved caspase-3/caspase-3 in the hippocampus. Finally, rhEPO modulated autophagy in the hippocampus in a time-dependent manner, probably via the S6 protein. In summary, rhEPO protects against hippocampal damage in developing rats with seizures by modulating autophagy in a time-dependent manner, probably via the S6 protein. Consequently, rhEPO is a likely drug candidate that is capable of attenuating brain injury.

Topics: Animals; Autophagy; Brain Injuries; Epilepsy; Erythropoietin; Hippocampus; Humans; Male; Neurons; Neuroprotective Agents; Rats, Sprague-Dawley; Recombinant Proteins; Ribosomal Protein S6 Kinases; Seizures; Time Factors

Klotho, which is a life extension factor, and erythropoietin (EPO) have been introduced as effective neuroprotective factors in several neurological disorders. The present study is an attempt to examine the potential role of klotho and EPO in therapeutic effect of curcumin-loaded nanoparticles (NPs) in pentylenetetrazol (PTZ)-induced kindling model. In order to induce the kindling model, PTZ was administrated intraperitoneally (i.p.) at dose of 36.5 mg/kg every other day for 20 days. Male NMRI mice received pre-treatment of free curcumin or curcumin-loaded NPs (12.5 mg/kg, i.p.) 10 days before PTZ injection and this was continued until 1 h before each PTZ injection. Immunostaining against NeuN, as a marker of neuronal maturation, and EPO was performed on hippocampal brain sections. Quantitative real time polymerase chain reaction (qRT-PCR) was conducted to assess the expression levels of tumor necrosis factor-α (TNF-α), klotho and EPO in the hippocampus. Immunostaining data indicated that treatment with curcumin-loaded NPs significantly alleviates the neuronal cell death in PTZ receiving animals. Curcumin-loaded NPs effectively upregulated the levels of EPO and klotho in PTZ receiving animals. Furthermore, mRNA level of TNF-α was considerably reduced in animals undergone curcumin-loaded NPs treatment. Overall, the results of this study suggest that downregulation of TNF-α and consequent upregulation of klotho and EPO might contribute to the neuroprotective effect of curcumin-loaded NPs in experimental model of epilepsy.

Topics: Animals; Chronic Disease; Curcumin; Disease Models, Animal; DNA-Binding Proteins; Drug Carriers; Epilepsy; Erythropoietin; Glucuronidase; Hippocampus; Kindling, Neurologic; Klotho Proteins; Male; Mice; Nanoparticles; Nerve Tissue Proteins; Neurons; Neuroprotection; Neuroprotective Agents; Nuclear Proteins; Pentylenetetrazole; Random Allocation; Tumor Necrosis Factor-alpha; Up-Regulation

Erythropoietin (EPO) suppresses epileptogenesis and limits the neuronal damage associated with recurrent seizures, but the neurocellular mechanism is unclear. Dysregulation of intracellular calcium homeostasis is a key pathogenic event leading to the progression of epileptic activity, suggesting that EPO may suppress seizures by stabilizing intracellular calcium. In this study, we examined the effects of EPO on voltage-gated Ca(2+) influx in cultured rat hippocampal neurons and population spike (PS) amplitude in kainic acid (KA)-induced rats and the mechanisms responsible. KA injection markedly increased EPO and EPO receptor expression and the amplitude of PS in the hippocampal CA3 region, evoked by perforant pathway stimulation. Intracerebroventricular injection of exogenous rat recombinant EPO reversed KA-induced PS amplitude in the hippocampal CA3 region. Similarly, rat recombinant EPO pretreatment attenuates the increased voltage-gated calcium current's (I(Ca)) amplitude and density induced by KA in cultured hippocampal neurons. In contrast, transient transfection of rat EPO small interfering RNS (siRNA) further enhanced I(Ca) amplitude and density in the presence of KA, whereas a scrambled control siRNA had no effect. Further, EPO activates the PI3K and ERK1/2 pathways in cultured hippocampal neurons, and the PI3K/Akt inhibitor LY294002 and ERK1/2 inhibitor U0126 both blocked, at least in part, the suppressive effect of exogenous EPO on KA-induced calcium currents. This study indicates that both endogenous and exogenous EPO decrease KA-sensitive calcium influx and concomitant hyperexcitability in hippocampal neurons. The results also demonstrate that the PI3K/Akt and ERK1/2 signaling pathways mediate the EPO-modulated calcium influx in KA-induced epilepsy.

Topics: Animals; Blotting, Western; CA3 Region, Hippocampal; Calcium; Cells, Cultured; Electrophysiological Phenomena; Epilepsy; Erythropoietin; Evoked Potentials; Excitatory Amino Acid Agonists; Hippocampus; Kainic Acid; Male; MAP Kinase Signaling System; Neurons; Oncogene Protein v-akt; Patch-Clamp Techniques; Phosphatidylinositol 3-Kinases; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Recombinant Proteins; Signal Transduction; Transfection

Topics: Animals; Anticonvulsants; Brain Injuries; Epilepsy; Erythropoietin; Humans; Neuroprotective Agents

To investigate the effect of intranasal administration of low dosage recombinant human erythropoietin (r-HuEPO) on seizure in rats.. After intranasal or intraperitoneal administration of r-HuEPO, the behavioral and electroencephalographic changes were observed in pentylenetetrazol (PTZ) and maximal electroshock (MES) induced seizure or electrical amygdaloid-kindled seizure of rats.. Intranasal administration of low dosage r-HuEPO increased the seizure latency, and decreased the seizure grade and duration, and the number of convulsive episodes in PTZ induced seizure, with the most potential dosage of 2.4 IU. Intraperitoneal administration of r-HuEPO (3 000, 4 000 IU/kg) only decreased the seizure duration and number of convulsive episodes. The seizure grade, forelimb or hindlimb extension duration were decreased in MES-induced seizure by intranasal administration of 2.4 IU r-HuEPO. In addition, intranasal administration of 2.4 IU r-HuEPO decreased the seizure grade, generalized seizure duration and afterdischarge in electrical amygdaloid-kindled rats stimulated with generalized seizure threshold.. Intranasal administration of low dosage r-HuEPO can inhibit the seizure in rats.

Topics: Administration, Intranasal; Animals; Anticonvulsants; Epilepsy; Erythropoietin; Humans; Male; Pentylenetetrazole; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Brain injury evolves over time, often taking days or even weeks to fully develop. It is a dynamic process that involves immediate oxidative stress and excitotoxicity followed by inflammation and preprogrammed cell death. This article presents a brief overview of mechanisms of neuroprotection in the developing brain. Although the focus is on ischemic injury, the conclusions drawn apply to any type of brain insult-epileptic seizures, trauma, or ischemia. Strategies of neuroprotection include salvaging neurons through the use of targeted pharmacotherapies, protecting neurons through preconditioning, and repairing neurons by enhancing neurogenesis. Drug therapies that dampen the impact of immediate and downstream postinjury events are only modestly effective in protecting the brain from ischemic injury. In experimental models, complete or true protection can be achieved only through preconditioning, a process during which an animal develops tolerance to an otherwise lethal stressor. Although of no clinical use, preconditioning models have provided valuable insight into how repair systems work in the brain. Cumulative evidence indicates that the same genes that are upregulated during preconditioning, those mediating true protection, are also upregulated during injury and repair. Specifically, hypoxic preconditioning and hypoxic-ischemic insult have been shown to induce hypoxia inducible factor-1 (HIF-1) and its target survival genes, vascular endothelial growth factor (VEGF), and erythropoietin (Epo) in rodents. Of particular interest is the upregulation of Epo, a growth factor that may have therapeutic potential in the treatment of ischemic stroke. At this time, however, the postinjury enhancement of neurogenesis appears to offer the best hope for long-lasting functional recovery following brain injury.

Topics: Animals; Apoptosis; Brain; Brain Ischemia; Disease Models, Animal; Epilepsy; Erythropoietin; Humans; Hypoxia-Ischemia, Brain; Ischemic Preconditioning; Neuronal Plasticity; Neurons; Neuroprotective Agents; Oxidative Stress; Stroke; Up-Regulation

Topics: Epilepsy; Erythropoietin; Humans; Renal Dialysis

Butyrate, a four-carbon fatty acid, and its two-carbon metabolic product, acetate, are inducers of gamma-globin synthesis. To test whether other short-chain fatty acids share this property, we first examined whether propionic acid, a three-carbon fatty acid that is not catabolized to acetate, induces gamma-globin expression. Sodium propionate increased the frequency of fetal hemoglobin containing erythroblasts and the gamma/gamma + beta mRNA ratios in adult erythroid cell cultures and F reticulocyte production in a nonanemic juvenile baboon. Short-chain fatty acids containing five (pentanoic), six (hexanoic), seven (heptanoic), eight (octanoic), and nine (nonanoic) carbons induced gamma-globin expression (as measured by increase in gamma-positive erythroblasts and gamma/gamma + beta mRNA ratios) in adult erythroid burst-forming unit cultures. There was a clear-cut relationship between the concentration of fatty acids in culture and the degree of induction of gamma-globin expression. Three-, four-, and five-carbon fatty acids were better inducers of gamma globin in culture as compared with six- to nine-carbon fatty acids. These results suggest that all short-chain fatty acids share the property of gamma-globin gene inducibility. The fact that valproic acid, a derivative of pentanoic acid, also induces gamma-globin expression suggests that short-chain fatty acid derivatives that are already approved for human use may possess the property of gamma-globin inducibility and may be of therapeutic relevance to the beta-chain hemoglobinopathies.

Topics: Adult; Anemia, Sickle Cell; Animals; Anticonvulsants; Butyrates; Butyric Acid; Cells, Cultured; Epilepsy; Erythroid Precursor Cells; Erythropoietin; Fatty Acids, Volatile; Fetal Hemoglobin; Gene Expression Regulation; Globins; Hemoglobinopathies; Humans; Papio; Pentanoic Acids; Propionates; Reticulocytes; RNA, Messenger; Structure-Activity Relationship; Valproic Acid

Human erythropoietin in concert with intraoperative hemodilution, tumor embolization, and surgical staging was used to manage a red blood cell mass in an anemic Jehovah's Witness patient with a hypervascular meningioma. Erythropoietin (3000 U thrice weekly) and oral iron (1300 mg daily) were given for 1 month prior to surgery, raising the hemoglobin level from 11.8 to 14.1 gm/100 ml. A posterior fossa craniectomy combined with a temporal craniectomy was then performed so that partial petrosectomy, section of the transverse sinus, incision of the tentorium, and exposure of the lesion could be carried out. The first stage of the surgery was terminated immediately prior to tumor mobilization. Isovolemic hemodilution was initiated just before the skin incision. Postoperatively, the hemoglobin concentration dropped to 11.5 gm/100 ml. The erythropoietin dose was doubled and administration of oral iron continued, leading to a hemoglobin level of 14.0 gm/100 ml at 1 month after the first operation. The tumor was embolized using superselective catheterization. The next day, at the second stage of the surgery, the tumor was extirpated, again employing isovolemic hemodilution. By the 4th postoperative day, the hemoglobin level had dropped to 9.4 gm/100 ml. The patient made an uncomplicated recovery. Erythropoietin therapy contributed substantially to the successful outcome of this case. Since erythropoietin has the potential to augment all other forms of autologous banking, its role in elective neurosurgery may become increasingly important in an era of heightened concern about heterologous transfusion.

Topics: Blood Transfusion, Autologous; Christianity; Cranial Fossa, Posterior; Craniotomy; Embolization, Therapeutic; Epilepsy; Erythropoietin; Female; Hemodilution; Humans; Magnetic Resonance Imaging; Meningeal Neoplasms; Meningioma; Middle Aged