Ironing out the Links: Ferroptosis in epilepsy and SUDEP.

Iron is a crucial element for almost all organisms because it plays a vital role in oxygen transport, enzymatic processes, and energy generation due to its electron transfer capabilities. However, its dysregulation can lead to a form of programmed cell death known as ferroptosis, which is characterized by cellular iron accumulation, reactive oxygen species (ROS) production, and unrestricted lipid peroxidation. Both iron and ferroptosis have been identified as key players in the pathogenesis of various neurodegenerative diseases. While in epilepsy this phenomenon remains relatively understudied, seizures can be considered hypoxic-ischemic episodes resulting in increased ROS production, lipid peroxidation, membrane disorganization, and cell death. All of this is accompanied by elevated intracellular free Fe2+ concentration and hemosiderin precipitation, as existing reports suggest a significant accumulation of iron in the brain and heart associated with epilepsy. Generalized tonic-clonic seizures (GTCS), a primary risk factor for Sudden Unexpected Death in Epilepsy (SUDEP), not only have an impact on the brain but also lead to cardiogenic dysfunctions associated with "Iron Overload and Cardiomyopathy" (IOC) and "Epileptic heart" characterized by electrical and mechanical dysfunction and a high risk of malignant bradycardia. In line with this phenomenon, studies conducted by our research group have demonstrated that recurrent seizures induce hypoxia in cardiomyocytes, resulting in P-glycoprotein (P-gp) overexpression, prolonged Q-T interval, severe bradycardia, and hemosiderin precipitation, correlating with an elevated spontaneous death ratio. In this article, we explore the intricate connections among ferroptosis, epilepsy, and SUDEP. By synthesizing current knowledge and drawing insights from recent publications, this study provides a comprehensive understanding of the molecular underpinnings. Furthermore, this review offers insights into potential therapeutic avenues and outlines future research directions.

Erythropoietin as a new therapeutic opportunity in brain inflammation and neurodegenerative diseases.

Highly expressed Erythropoietin Receptor (EPO-R) has been detected in several nonhematopoietic hypoxic cells, including cells from different brain areas in response to many different types of cell injury. In brain, hypoxia-ischemia (HI) can induce a wide spectrum of biologic responses, where inflammation and apoptosis are the main protagonists. Inflammation, as a primary brain insult, can induce a chronic hypoxic condition, producing the continuous cycle of inflammation-hypoxia that increases the apoptotic-cell number. It has also been demonstrated that administration of erythropoietin (EPO) prevented the neuronal death induced by HI, as well as the induction of lipid peroxidation in the hippocampus in a rodent model of Alzheimer's disease. Anti-apoptotic, anti-inflammatory, anti-oxidant, and/or cell-proliferative effects of EPO, have been observed in all type of cells expressing EPO-R, resulting in a potential tool for neuroprotection, neuroreparation, or neurogenesis of brain damaged areas. The nasal route is an alternative way of drugs administration that has been successfully exploited for bypassing the blood brain barrier, and subsequently delivering EPO and other molecules to central nervous system. Intranasal administration of EPO could be a new therapeutic opportunity in several brain damages that includes hypoxia, inflammation, neurodegenerative process, and apoptosis.

Cerebral arteritis following methylphenidate use.

Stroke is a well-documented complication of amphetamine abuse. Methylphenidate, chemically and pharmacologically similar to amphetamines, is widely used in the treatment of attention deficit disorder in children. The possibility of vasculitis connected to methylphenidate should not be surprising. A case is reported of stroke associated with ingestion of methylphenidate in an 8-year-old boy. Family history was negative and other causes of vasculitis were excluded. We draw your attention to the risk of using methylphenidate for a long period of time.

Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy.

Intractable seizures are the most common manifestation in severe cases of tuberous sclerosis. Multidrug resistance type 1 (MDR1) gene expression is directly linked to the resistance of tumor cells to chemotherapy as the major cause of treatment failure, but it has not been reported in tuberous sclerosis cells nor has the relationship between the MDR1 gene and antiepileptic drugs been described. A 4-month-old female is described with poorly controlled seizures secondary to tuberous sclerosis. The patient was treated with antiepileptic drugs, including phenytoin, phenobarbital, and lorazepam, without improvement of symptoms. Phenytoin blood levels were invariably subtherapeutic and ranged from 0.45 to 3.55 microg/mL, despite several consecutive intravenous loading doses. Surgical treatment with total resection of the brain lesions was performed as a last resort. Immunohistochemical analysis of the resected tissues revealed high levels of P-glycoprotein 170 expression, the product of the MDR1 gene. Both MDR1 gene expression and persistently low phenytoin levels likely share a common pathway liable to induce drug-resistant epilepsy.

Giant platelet disorder in a patient with type 2B von Willebrand's disease.

While patients with type 2B von Willebrand's disease often exhibit thrombocytopenia, platelet morphology is typically normal. We describe a 44-year-old Jamaican man with thrombocytopenia and a history of bleeding, who had giant platelets on his peripheral blood film. Functional studies and von Willebrand factor gene sequencing showed him to have type 2B von Willebrand's disease with a heterozygous point mutation resulting in a V553M (V1316M in the new von Willebrand factor gene mutation nomenclature) amino acid substitution. Family studies showed one of his two sisters to have an ill-defined giant-platelet-syndrome with mild thrombocytopenia, but not von Willebrand's disease, indicating that the association of giant platelets and von Willebrand's disease in our patient was most likely coincidental. This report describes the rare concurrence of two uncommon disorders. It also demonstrates how the thrombocytopenia of type 2B von Willebrand's disease can be misdiagnosed as ITP, leading to unnecessary and potentially harmful therapeutic interventions.

Use of antiepileptic drugs in nontraumatic neurosurgical procedures. Is there any best route and time of administration?

We assessed in 15 consecutive patients the best route and time of administration for phenytoin (PHT) prophylaxis in neurosurgical procedures. We also correlated PHT levels in serum and cerebrospinal fluid after oral and parenteral loading doses. The mean PHT level was 13.9 micrograms/ml in serum and 2.03 micrograms/ml in cerebrospinal fluid (CSF), with a significant correlation between levels in both compartments (r = 0.73, p < 0.01). Mean PHT levels among the different groups were not statistically significant. We conclude that therapeutic levels of PHT in CSF can be achieved independently of the route of administration, as long as accepted loading doses are used.

Expression of gelatinase/type IV collagenase in tumor necrosis correlates with cell detachment and tumor invasion.

We have previously observed that acellular extracts from necrotic areas (NE) of the non-metastatic murine mammary adenocarcinoma M3, enhance in vitro cell detachment and spontaneous lung metastases. In the present study, using different proteinase inhibitors along with NE, only the calcium chelator EDTA could significantly abrogate the enhanced cell detachment from M3 produced by NE. The typical cleavage products of type IV collagenase were detected inside the tumor necrotic area, mainly in association with necrobiotic cells, as evaluated by Western blot analysis and immunohistochemical assays. Zymography revealed the presence of 72- and 92-kDa gelatinase/type IV collagenase in NE. Moreover, NE increased the in vitro invasive ability of cultured M3 cells. The use of specific antibodies against both 72- and 92-kDa type IV collagenases in the invasion assay showed that only the latter was able to revert the enhanced invasiveness to the baseline. It can be concluded that tumor necrosis is an important source of gelatinase/type IV collagenase, mainly in its 92 kDa form, and plays a major role in tumor invasion.

Ferritina serica: su aplicacion en clinica. / Serum ferritin: its clinical use

La determinacion de ferritina serica (FS) por metodos IRM permite la medicion directa de una fraccion del "pool" de ferritina corporal.La FS es un buen indice del hierro de los depositos en los sujetos normales. En ciertas condiciones que determinan aumento de la sintesis de ferritina (inflamacion, hepatopatia, malignidad, cronicidad, eritropoyesis inefectiva, ferroterapia en curso) puede no reflejar fielmente el hierro de reserva del organismo. En la anemia hiposideremica, la concentracion de FS permite separar las causadas por deficiencia de hierro de las provocadas por procesos cronicos. Aseguradas la calidad del ensayo, su valor es incuestionable cuando resultan concentraciones subnormales. Se halla especialmente indicada en estudios de un numero grande de sujetos. Ha sido investigada como posible marcador tumoral. Su determinacion combinada a la de alfa-fetoproteina serica aumentaria la especificidad del serodiagnostico de hepatoma. Los resultados de la determinacion de FS deben interpretarse teniendo en cuenta la posible concurrencia de situaciones que modifican los depositos de hierro y aquellas que llevan a un aumento en la sintesis de ferritina

Ferritina serica: su aplicacion en clinica. / Serum ferritin: its clinical use

La determinacion de ferritina serica (FS) por metodos IRM permite la medicion directa de una fraccion del "pool" de ferritina corporal.La FS es un buen indice del hierro de los depositos en los sujetos normales. En ciertas condiciones que determinan aumento de la sintesis de ferritina (inflamacion, hepatopatia, malignidad, cronicidad, eritropoyesis inefectiva, ferroterapia en curso) puede no reflejar fielmente el hierro de reserva del organismo. En la anemia hiposideremica, la concentracion de FS permite separar las causadas por deficiencia de hierro de las provocadas por procesos cronicos. Aseguradas la calidad del ensayo, su valor es incuestionable cuando resultan concentraciones subnormales. Se halla especialmente indicada en estudios de un numero grande de sujetos. Ha sido investigada como posible marcador tumoral. Su determinacion combinada a la de alfa-fetoproteina serica aumentaria la especificidad del serodiagnostico de hepatoma. Los resultados de la determinacion de FS deben interpretarse teniendo en cuenta la posible concurrencia de situaciones que modifican los depositos de hierro y aquellas que llevan a un aumento en la sintesis de ferritina