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Determining the role of endogenous factors as markers of chronic epileptic activity allows pathogenetically justifying new approaches to treating epilepsy. The aim of the work was the immunohistochemical study of the expression of the tumor necrosis factor-alpha (TNF-α) and nuclear factor p-NF-κB in the tissue of the dorsal parts of the hippocampus in rats with kindling seizures. Kindling was produced in 15 rats by three-week i.p. pentylenetetrazole (PTZ, 35.0 mg/kg) administration. 20 control group rats were injected with 0.9% NaCl solution. The avidin-biotin-peroxidase method was used in 10 control group rats for staining. The rest ten rats composed the negative control group and stained using only secondary antibodies. The color intensity of the brain sections of the control and kindling groups was compared with the color of the brain sections of the negative control group using the "Image J" program. In rats with PTZ-kindling, the level of TNF-α was 17.86+0.83 relative units (RU) and exceeded the corresponding indicator in the control group (4.78+0.14 RU), (p

Traumatic brain injury (TBI) is a debilitating acquired neurological disorder that afflicts nearly 74 million people worldwide annually. TBI has been classified as more than just a single insult because of its associated risk toward various long-term neurological and neurodegenerative disorders. This risk may be triggered by a series of postinjury secondary molecular and cellular pathology, which may be dependent on the severity of the TBI. Among the secondary injury mechanisms, neuroinflammation may be the most crucial as it may exacerbate brain damage and lead to fatal consequences when prolonged. This Review aimed to elucidate the influence of neuroinflammatory mediators on the TBI functional and pathological outcomes, particularly focusing on inflammatory cytokines which were associated with neuronal dysfunctions in the acute and chronic stages of TBI. These cytokines include interleukins (IL) such as IL-1(beta)β, IL-4, IL-6, IL8, IL-10, IL-18, IL-33 and tumor necrosis factor alpha (TNF-α), which have been extensively studied. Apart from these, IL-2, interferon gamma (IFN-γ), and transforming growth factor-beta (TGF-β) may also play a significant role in the pathogenesis of TBI. These neuroinflammatory mediators may trigger a series of pathological events such as cell death, microglial suppression, and increased catecholaminergic activity. Interestingly, in the acute phase of TBI, most of these mediators may also play a neuroprotective role by displaying anti-inflammatory properties, which may convert to a pro-inflammatory action in the chronic stages post TBI. Early identification and treatment of these mediators may help the development of more effective treatment options for TBI.

The aimof the study is to determine the level of HIF-1α, TNF-α, and NF-kB in the hippocampus of kindled rats treated with rapamycin and axitinib. Materials and methods.Kindling was produced in 29 rats by administration of three-week pentylenetetrazole (PTZ, 35.0 mg/kg, i.p.). Treatment with rapamycin (0.5 mg/kg, i.p.) and axitinib (2.5 mg/kg, i.p.) was performed for ten days in fully kindled rats. The avidin-biotin-peroxidase method was used for hippocampal slice staining. For negative control, staining was performed using only secondary antibodies. Results.The HIF-1α expression increased in kindled rats raised by 1.77 times compared to the control (p0.05), while axitinib – by 26.5 % (p Conclusions.PTZ-kindling resulted in an increase in the immunoreactivity of HIF-1α, TNF-α, and NF-kB in the hippocampus. Combined treatment with rapamycin and axitinib engendered prevention of generalized seizures and normalized the level of HIF-1α and NF-kB with a significant reduction of TNF-α. Effects of treatment favours of synergy action of rapamycin and axitinib

Epilepsy is a devastating neurological disorder characterized by recurrent seizures attributed to the disruption of the dynamic excitatory and inhibitory balance in the brain. Epilepsy has emerged as a global health concern affecting about 70 million people worldwide. Despite recent advances in pre-clinical and clinical research, its etiopathogenesis remains obscure, and there are still no treatment strategies modifying disease progression. Although the precise molecular mechanisms underlying epileptogenesis have not been clarified yet, the role of ion channels as regulators of cellular excitability has increasingly gained attention. In this regard, emerging evidence highlights the potential implication of inwardly rectifying potassium (Kir) channels in epileptogenesis. Kir channels consist of seven different subfamilies (Kir1-Kir7), and they are highly expressed in both neuronal and glial cells in the central nervous system. These channels control the cell volume and excitability. In this review, we discuss preclinical and clinical evidence on the role of the several subfamilies of Kir channels in epileptogenesis, aiming to shed more light on the pathogenesis of this disorder and pave the way for future novel therapeutic approaches.

Background In recent years, the cerebellum and its nuclei have become important targets for understanding and suppressing the mechanisms of seizures. The aim of this study was to investigate the effects of electrical stimulation (ES) applied to the lateral cerebellar nucleus (LCN) in rats with early and fully developed pentylenetetrazol (PTZ)-kindled seizures. MethodsThe experimental groups were represented by rats kindled with PTZ (35.0 mg/kg, i.p.) to myoclonus (9-11 PTZ injections) and generalized tonic-clonic seizures (21 PTZ injections). Unilateral ES (100 Hz, 0.25 ms, 4.5-5.0 duration) was delivered daily for five days after the last kindled PTZ administration with PTZ seizure testing after the last ES. Results ES of LCN performed at the early stage of kindling facilitated the appearance of myoclonus and increased seizure severity by 30.2% - up to 2.25+0.46 scored points compared to the control group (P+0.31 scored points (PConclusion The data obtained showed that repeated ES of the LCN at the early kindling stage facilitates myoclonus appearance, while in fully PTZ-kindled rats causes suppression of generalized seizure fits, which were substituted with myoclonus.

Background:Aside from its pervasiveness, whereby it affects as much as 20% of the world's population, depression continues to be one of the most crucial psychiatric problems due to the loss of power it causes by disrupting daily life functioning, containing economic consequences, and having a high suicidal tendency. Major depression (MD) is a systemic and multifactorial disorder involving complex interactions between genetic predisposition and disturbances of various molecular pathways.Objectives:In our current study, we aimed to identify the proteins obtained from serum samples that change during depression with the MD model.Methods:The MD model was applied through the forced swim test in rats. 14 Winstar Albino male rats were divided into two equal groups as follows: depression and control groups. Serum samples were separated by chromatographic methods and then compared with two-dimensional (2D) electrophoresis.Results:A total of 9 potential diagnostic protein sequences were identified, which were distinguished with computer software. During the last phase of the study, the Matrix-Assisted Laser Desorption/ Ionization – Time of Flight (MALDI-TOF) analysis, the previous expression sequences identified among the groups were determined and classified. By comparing protein expressions, it was concluded that 9 different points could be used together as a potential biomarker.Conclusion:Results can help us identify a new diagnostic system that can be used to diagnose MD.

Boronic acids constitute an important class of synthetic intermediates due to their high chemical stability, ease of use, moderate organic Lewis acid properties, reduced reactivity profiles and numerous biological activities such as antibacterial and antioxidant. The present study documents the synthesis and characterization of a novel boronic ester compound (3,5,7-trihydroxy-2- (2-phenyl benzo [d] [1,3,2] dioxaborol-5-yl) -4H-chromen-4-a) which was derived from phenyl boronic acid and quercetin. The new boron-based compound was used in the cream formulation after evaluating its antioxidant, antibacterial, anti-enzyme, anticancer activities and electrochemical oxidation behaviour. Furthermore, the cream has been dermatologically and microbiologically tested. Also, histological evaluation of the agent was estimated on multiple rat organs by hematoxylin-eosin staining method. Antioxidant potential of the new compound was tested by ABTS cation radical (IC

Background The diagnosis of the rare genetic diseases has great importance in treating multisystemic conditions, preventing potential complications, and estimating disease risk for family members. The duration of obtaining genetic test results is varies. The demand to learn the diagnosis of a possible untreatable illness involves a struggle between uncertainty and a lifetime chronic disease. The current uncertainty of their child's condition and the long wait for a diagnosis may increase the parents' anxiety level and cause difficulties in the continuation of diagnostic procedures in some families. This study aimed to investigate the prediagnosis and postdiagnosis anxiety levels of parents who have a child with a rare genetic disease. Method The parents in this study, mothers or fathers, admitted their children to the Bezmialem Vakıf University Medical Genetics Clinic due to a suspected rare genetic disease (n = 40). Researchers created “The Sociodemographic Questionnaire” and used it to analyze the parents' sociodemographic status. In addition, they used the State-Trait Anxiety Inventory (STAI) to determine the anxiety levels of the parents. Results The state anxiety levels of parents decreased significantly after learning the diagnosis. However, there was no statistically significant decrease observed in trait anxiety levels. Conclusion Data from this study revealed that informing parents about their child's disease and properly explaining to them the expected difficulties might help to reduce their anxiety levels. Psychological support for parents is necessary to reduce their long-term stress, thus increasing the patient's compliance with treatment.

KCNMA1 located on chromosome 10q22.3, encodes the pore-forming α subunit of the “Big K+” (BK) large conductance calcium and voltage-activated K + channel. BK channels are widely distributed across tissues, including both excitable and non excitable cells. Numerous evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with different symptoms, such as paroxysmal non kinesigenic dyskinesia with gain of function and ataxia with loss of function. Functional classifications revealed two major patterns, gain of function and loss of function effects on channel properties in different cell lines. In the literature, two mutations have been shown to confer gain of function properties to BK channels: D434G and N995S. On the other hand 10 mutations have been classified as loss of function (S351Y,G354S, G356R, G375R, C413Y/N449fs, I663V, P805L, and D984N) or putative loss of function (premature truncation mutations: Y676Lfs*7 and Arg458Ter). In this study, we report the functional characterization of a variant which was previously reported the whole exome sequencing revealed bi-allelic nonsense variation (NM_001161352.1 (ENST00000286628.8):c.1372C > T; Arg458*) of the cytoplasmic domain of calcium-activated potassium channel subunit alpha-1 protein. To detect functional consequences of the variation immunostaining and electrophysiological studies were conducted. In this study, we conducted patch-clamp recordings on WT and R458X mutant cells. We found the gain of function effect for the mutation. This is the first functional study observing an increased current in the KCNMA1 gene resulting from a truncating mutation

Highlights • COVID-19 has neuro-invasion potential independently of the critical disease process. • Cerebrovascular diseases such as ischemia may develop in the course of disease. • Increased inflammation may be predicted by CRP and D-dimer levels. • The elder Covid-19 patients with prothrombotic risk factors should also be considered for the signs of stroke., Coronaviruses are revealed to target the human respiratory system mainly. However, they also have neuro-invasive abilities and might spread from the respiratory system to the central nervous system. Herein, we report four patients with COVID-19 simultaneously diagnosed with acute ischemic stroke. There were four stroke cases with simultaneously diagnosis of Covid-19 till the April 14, 2020 in the city of Sakarya, Turkey. They were aged between 45 to 77 years. All four cases were likely to have contracted the virus in Sakarya. The patients had all commonly reported symptoms of Covid-19. Three patients have elevated D-dimer levels, and two of them had high C-reactive protein (CRP) levels. They were managed symptomatically for both the infection and the stroke. Our findings suggest that ischemic cerebrovascular diseases may simultaneously develop in the course of Covid-19 independently of the critical disease process. Increased inflammation predicted by CRP and D-dimer levels may play a role in the formation of ischemia. In particular, elder patients with prothrombotic risk factors should also be considered for the signs of cerebrovascular events in addition to infectious symptoms.

Clinical and experimental studies show that epilepsy affects cardiac function; however, the underlying molecular mechanism has not been fully elucidated. Inwardly-rectifying potassium (Kir) channels transport K+ ions into excitable cells such as neurons and cardiomyocytes; they control the cell excitability by acting towards the repolarization phase of cardiac action potential. Kir channel expression has been previously shown to vary in epileptic brains, at the same time seizures are known to affect the autonomic nervous system. Kir channel expression in cardiac tissue is a possible mechanism for the explanation of cardiac pathology in epilepsy. We investigate the expression of Kir channels in epileptic cardiac tissue by using pentylenetetrazole (PTZ)-kindling model in rats. Our molecular analyses showed significant decrease in cardiac Kir channel mRNA and protein expression of PTZ-kindled rats. Interestingly, both Kir2.x, which directs IK1 flux in ventricular tissue and Kir3.x, which is responsible for IKACh in the atria, were observed to decrease significantly. Kir channel expression also differs between females and males. This is the first study to our knowledge in epileptic cardiac tissue showing the expression of Kir channels. Our results show that Kir channels may play a role in cardiac pathology associated with epilepsy.

Epilepsy is a debilitating disorder of uncontrollable recurrent seizures that occurs as a result of imbalances in the brain excitatory and inhibitory neuronal signals, that could stem from a range of functional and structural neuronal impairments. Globally, nearly 70 million people are negatively impacted by epilepsy and its comorbidities. One such comorbidity is the effect epilepsy has on the autonomic nervous system (ANS), which plays a role in the control of blood circulation, respiration and gastrointestinal function. These epilepsy-induced impairments in the circulatory and respiratory systems may contribute toward sudden unexpected death in epilepsy (SUDEP). Although, various hypotheses have been proposed regarding the role of epilepsy on ANS, the linking pathological mechanism still remains unclear. Channelopathies and seizure-induced damages in ANS-control brain structures were some of the causal/pathological candidates of cardiorespiratory comorbidities in epilepsy patients, especially in those who were drug resistant. However, emerging preclinical research suggest that neurotransmitter/receptor dysfunction and synaptic changes in the ANS may also contribute to the epilepsy-related autonomic disorders. Thus, pathological mechanisms of cardiorespiratory dysfunction should be elucidated by considering the modifications in anatomy and physiology of the autonomic system caused by seizures. In this regard, we present a comprehensive review of the current literature, both clinical and preclinical animal studies, on the cardiorespiratory findings in epilepsy and elucidate the possible pathological mechanisms of these findings, in hopes to prevent SUDEP especially in patients who are drug resistant.

Epilepsy is a result of unprovoked, uncontrollable, and repetitive outburst of abnormal and excessive electrical discharges, known as seizures, in the neurons. Epilepsy is a devastating neurological condition that affects 70 million people globally. Unfortunately, only two-thirds of epilepsy patients respond to antiepileptic drugs while others become drug resistant and may be more prone to epilepsy comorbidities such as SUDEP. Oxidative stress, mitochondrial dysfunction, imbalance in the excitatory and inhibitory neurotransmitters, and neuroinflammation are some of the common pathologies of neurological disorders and epilepsy. Studies suggests that melatonin, a pineal hormone that governs sleep-wake cycles, may be neuroprotective against neurological disorders and thus may be translated as an antiepileptic as well. Melatonin has been shown to be an antioxidant, antiexcitotoxic, and anti-inflammatory hormone/molecule in neurodegenerative diseases, which may contribute to its antiepileptic and neuroprotective properties in epilepsy as well. In addition, melatonin has evidently been shown to play a regulatory role in the cardiorespiratory system and sleep-wake cycles, which may have positive implications toward epilepsy associated comorbidities, such as SUDEP. However, studies investigating the changes in melatonin release due to epilepsy and melatonin's antiepileptic role have been inconclusive and scarce, respectively. Thus, this comprehensive review aims to summarize and elucidate the potential role of melatonin in the pathogenesis of epilepsy and its comorbidities, in hopes to develop new diagnostic and therapeutic approaches that will improve the lives of epileptic patients, particularly those who are drug resistant.

Over the decades, various interventions have been developed and utilized to treat epilepsy. However, the majority of epileptic patients are often first prescribed anti-epileptic drugs (AED), now known as anti-seizure drugs (ASD), as the first line of defense to suppress their seizures and regain their quality of life. ASDs exert their anti-convulsant effects through various mechanisms of action, including regulation of ion channels, blocking glutamate-mediated stimulating neurotransmitter interaction, and enhancing the inhibitory GABA transmission. About one-third of epileptic patients are often resistant to anti-convulsant drugs, while others develop numerous side effects, which may lead to treatment discontinuation and further deterioration of quality of life. Common side effects of ASDs include headache, nausea and dizziness. However, more adverse effects, such as auditory and visual problems, skin problems, liver dysfunction, pancreatitis and kidney disorders may also be witnessed. Some ASDs may even result in life-threatening conditions as well as serious abnormalities, especially in patients with comorbidities and in pregnant women. Nevertheless, some clinicians had observed a reduction in the development of side effects post individualized ASD treatment. This suggests that a careful and well-informed ASD recommendation to patients may be crucial for an effective and side-effect-free control of their seizures. Therefore, this review aimed to elucidate the anticonvulsant effects of ASDs as well as their side effect profile by discussing their mechanism of action and reported adverse effects based on clinical and preclinical studies, thereby providing clinicians with a greater understanding of the safety of current ASDs.

Epilepsy is a neurological disease characterized by abnormal electrical activity and recurrent seizures in the central nervous system (CNS). Changes in hypoxia and iron metabolism can stimulate seizures through the CNS and cardiac system. Cardiovascular system disorders such as arrhythmias also accompany this process. It was aimed to examine the genes of TFRC-1 and TIM-2, which contribute to ion homeostasis by providing hypoxia inducible factor (HIF) -1 and intracellular iron flow, through the kindled model of pentylenetetrazol (PTZ). HIF-1α, TFRC-1 and TIM-2 gene expressions were investigated in both brain and heart tissue by RT-PCR method. As a result of the data, TIM-2 expression significantly decreased in the brain (p

Epilepsies are a diverse group of neurological disorders characterized by an unprovoked seizure and a brain that has an enduring predisposition to seizures. The lack of disease-modifying treatment strategies against the same has led to the exploration of novel treatment strategies that could halt epileptic seizures. In this regard, environmental enrichment (EE) has gained increased attention in recent days. EE modulates the effects of interactions between the genes and the environment on the structure and function of the brain. EE therapy can improve seizure-related symptoms in neurological diseases such as epilepsy. EE therapy can have a significant effect on cognitive disorders such as learning and memory impairments associated with seizures. EE therapy in epileptic hippocampus tissue can improve seizure-related symptoms by inducing enhanced neurogenesis and neuroprotective mechanisms. In this context, the efficiency of EE is regulated in the epilepsy by the brain-derived neurotrophic factor (BDNF)/extracellular signal-regulated kinase (ERK) signaling pathway regulated by extracellular signaling. Herein, we provide experimental evidence supporting the beneficial effects of EE in epileptic seizures and its underlying mechanism.

Epilepsy is a neurologicaldisorder characterized by persistent predisposition to recurrent seizurescaused by abnormal neuronal activity in the brain. Epileptic seizures maydevelop due to a relative imbalance of excitatory and inhibitory neurotransmitters. Expressional alterations of receptors and ion channelsactivated by neurotransmitters can lead to epilepsy pathogenesis. Aims In this updated comprehensive review, we discuss the emerging implication of mutations in neurotransmitter-mediated receptors and ion channels. We aim to provide critical findings of the current literature about the role of neurotransmitters in epilepsy. Materials and methods A comprehensive literature review was conducted to identify and critically evaluate studies analyzing the possible relationship between epilepsy and neurotransmitters. The PubMed database was searched for related research articles. Key findings Glutamate and gamma-aminobutyric acid (GABA) are the main neurotransmitters playing a critical role in the pathophysiology of this balance, and irreversible neuronal damage may occur as a result of abnormal changes in these molecules. Acetylcholine (ACh), the main stimulant of the autonomic nervous system, mediates signal transmission through cholinergic and nicotinic receptors. Accumulating evidence indicates that dysfunction of nicotinic ACh receptors, which are widely expressed in hippocampal and cortical neurons, may be significantly implicated in the pathogenesis of epilepsy. The dopamine-norepinephrine-epinephrine cycle activates hormonal and neuronal pathways; serotonin, norepinephrine, histamine, and melatonin can act as both hormones and neurotransmitters. Recent reports have demonstrated that nitric oxide mediates cognitive and memory-related functions via stimulating neuronal transmission. Significance The elucidation of the role of the main mediators and receptors in epilepsy is crucial for developing new diagnostic and therapeutic approaches.

WOS:000558679700028 PubMed: 33040832 Skeletal system and some organs development changes in rat fetuses with 30 and 60 mg/kg caffeine and melatonin's (10 mg/kg) protective role against rat fetuses were investigated. Groups (n = 4) were formed as Control, LDC, HDC, LDC+melatonin, HDC+melatonin and melatonin. Fetuses were taken by cesarean section and stained using dual skeletal staining method and FESEM. TRAP and AP immune-reactivity concentrations were calculated. Oxidative stress and inflammatory markers were also measured by liver, bone and placenta samples. TNT-alpha, IL-1 beta, IL-6, VEGF-A, SOST and Fetuin-A levels were measured in tissue by using ELISA. TBARS, SOD, GSH, GSSG, TOS, TAS, measured by spectrophotometric assay method. The mRNA levels of Agtr2 gene expressed in placental tissues of control rats and in placental tissues of rats exposed to HDC, LDC, MEL, HDC+MEL, LDC+MEL were analyzed by Real-time PCR. The gene expressions of Agtr2 were significantly upregulated in the placentas exposed to HDC. MEL. HDC+MEL and LDC+MEL (P0,05). According to these data, caffeine used during pregnancy delayed ossification; melatonin, a powerful antioxidant, was found to eliminate this effect. Besides, changes in angiotensin receptor expression observed in response to a caffeine and melatonin exposure result from high dose and join effect. Yozgat Bozok University Project Coordination Application and Research Center [6602c-TF/18-144] I would like to express my gratitude to Yozgat Bozok University Project Coordination Application and Research Center for supporting this project with BAP project number 6602c-TF/18-144.

Experimental and clinical studies of cardiac pathology associated with epilepsy have demonstrated an impact on the autonomic nervous system (ANS). However, the underlying molecular mechanism has not been fully elucidated. Molecular investigation of the neurotransmitters related receptor and ion channel directing ANS might help in understanding the associated mechanism. In this paper, we investigated the role of acetylcholine (ACh), which demonstrates both sympathetic and parasympathetic roles in targeted expression in terms of the relevant receptor and ion channel. Inwardly rectifying potassium (Kir) channels play a significant role in maintaining the resting membrane potential and controlling cell excitability and are prominently expressed in both the excitable and non-excitable tissues. The immunoreactivity of ACh-activated Kir3.1 channel and muscarinic ACh receptors (M2) in autonomic centers such as the brainstem, vagus nerve (VN) and atria of heart was confirmed by both histological staining and pathological tissue analysis. Significant upregulations of Kir3.1 and M2 receptors were observed in pentylenetetrazol (PTZ)-kindled epileptic rats for all related tissues investigated, whereas no pathological difference was observed. These findings provide proof-of-concept that changes in ACh-associated immunoreactivity might be linked to the ANS dysfunctions associated with epilepsy.

Background: Sepsis is a serious clinical condition characterized by damage to the immune system as a result of an uncontrolled response to infection. Septic patients show complications such as fever, cardiovascular shock, and/or systemic organ failure. Acute organ failure formed in sepsis mostly affects the respiratory and cardiovascular systems. In sepsis, responses including pro-inflammatory and anti-inflammatory processes in addition to the Toll-Like Receptor 4 (TLR4) signals leading to the release of inflammatory mediators have been suggested to be fundamental pathways in the pathophysiology of sepsis. Purpose: In this context, unregulated levels of sepsis-associated inflammatory mediators may increase the risk of mortality. In sepsis, infection-induced pathogens lead to a systemic inflammatory response. These systemic responses may contribute to septic shock and organ dysfunction. In the unfavorable clinical course of sepsis, an uncontrolled inflammatory response is observed. Accordingly, the mechanism of inflammatory mediators such as cytokines and chemokines in sepsis might increase. Neurotransmitters and gene regulators affect inflammatory mediators and control the inflammatory response. In this review, we aimed to show the new therapeutic targets in sepsis treatment with current studies. New clinical implications targeting inflammatory mediators in high mortality affected by the uncontrolled inflammatory response in sepsis can contribute to the understanding of the symptoms.

In recent years, there is an increased research interest for plants which are natural sources of antioxidants. Lepidium sativum Subsp spinescens L., commonly found in South West Asia, is a plant known as a healthy nutritional source containing bio-molecules that carry anti-hypertensive, hypoglycemic, anti-asthmatic, antispasmodic, hepato-protective, chemoprotective, anti-inflammatory and anti-oxidant effects. In this study, we aimed to investigate the antioxidant content and activity of Lepidium sativum Subsp spinescens L. methanol extract on cancer cells. Methanol extract of dried Lepidium sativum Subsp spinescens L. was prepared. Total amount of phenolic compounds was determined by Slinkard and Singleton method using Folin-Ciocalteu reagent. Total flavonoid amount was determined according to Zhishen method. Antioxidant activity of the extract was evaluated by CUPRAC and ABTS radical scavenging activity assays. Cytotoxic effects of the plant extract on colon and endometrium cancer cells, and human peripheral lymphocyte cells were investigated in vitro by MTT and neutral red assays. Furthermore, the plant extract was investigated for necrotic effects by LDH assay; apoptotic activity by DNA ladder fragmentation, ELISA and acridine orange/ethidium bromide staining; and genotoxic effect by comet assay methods. Methanol extract of Lepidium sativum Subsp spinescens L. was found to have a high content of phenolic and flavonoid compounds. The extract showed significant antioxidant activity and also cytotoxic activity on colon and endometrium cancer cells in a concentration-dependent manner. Apoptotic activity and genotoxic effects were significantly increased, especially with 200 μg/ml concentrations at 48 hours incubation. In conclusion, it was determined that the extract evaluated in this study could be a natural source of antioxidants. Further molecular studies explaining chemo-preventive and chemotherapeutic effects on cancer cells are required to support anticancer efficacy of the plant.

Aim Diabetes mellitus (DM) is characterized by insulin resistance or hyperglycemia caused by insufficient insulin secretion. Acetylcholine (ACh) can stimulate insulin release depending on glucose while hyperglycemia in DM pathology can cause cellular hypoxia. Adaptive responses to hypoxia in DM are associated with stimulation of hypoxia-inducible factor 1-alpha (HIF-1α) signal due to hyperglycemia. Hypoxia affects potassium (K+) concentration by increasing excitability in K+ ion channels. In our study, we aimed to evaluate the immunoexpression of adaptive responses to hypoxia that develops with DM in pancreatic and cardiac tissues. Materials and methods In this study, 14 Balb/C female mice were divided into control and type 1 DM groups. Streptozotocin (STZ; 150 mg/kg/bw) was injected intraperitoneally in mice to create a type 1 diabetes model. During the experiment, diabetic mice with a daily blood-glucose value higher than 250 mg/dl were injected subcutaneously with 1 U/day insulin. Two weeks after STZ injection, the mice were euthanized by cervical dislocation and the heart and pancreatic tissues were removed and prepared for histological and immunohistochemical analysis for TNF-α, HIF-1α, Kir6.2, Kir3.1, and M2 muscarinic receptor. Key findings Significant increase of TNF-α, HIF-1α, and Kir6.2 immunoreactivity was observed in both cardiac and pancreatic tissues of type 1 DM mice. And also, cardiac Kir3.1 and M2 muscarinic receptor and pancreatic M2 muscarinic receptor immunoreactivities significantly increased. Significance Our study can contribute to understanding the role of Kir3.1, Kir6.2 channels, and hypoxia biomarkers in the type 1 DM mechanism.

The new aggregate data analyses revealed the earlier missing role of cerebellum long-term electrical stimulation in the absence epilepsy. Neurophysiologic data gained by authors favor that cerebellar serial deep brain stimulation (DBS) (100 Hz) causes the transformation of penicillin-induced cortical focal discharges into prolonged 3,5–3,75 sec oscillations resembling spike-wave discharges (SWD) in cats. Such SWDs were not organized in the form of bursts and persisted continuously after stimulation. Therefore, the appearance of prolonged periods of SWD is regarded as a tonic cerebellar influence upon pacemaker of SWD and might be caused by the long-lasting DBS-induced increase of GABA-ergic extrasynaptic inhibition in the forebrain networks. The absence seizure facilitation caused by cerebellar DBS was discussed with the reviewed data on optogenetic stimulation, neuronal activity of cerebellar structures, and imaging data.

Sudden unexpected death in epilepsy (SUDEP) is the major cause of death that affects patients with epilepsy. The risk of SUDEP increases according to the frequency and severity of uncontrolled seizures; therefore, SUDEP risk is higher in patients with refractory epilepsy (RE), in whom most antiepileptic drugs (AEDs) are ineffective for both seizure control and SUDEP prevention. Consequently, RE and SUDEP share a multidrug resistance (MDR) phenotype, which is mainly associated with brain overexpression of ABC-transporters such as P-glycoprotein (P-gp). The activity of P-gp can also contribute to membrane depolarization and affect the normal function of neurons and cardiomyocytes. Other molecular regulators of membrane potential are the inwardly rectifying potassium channels (Kir), whose genetic variants have been related to both epilepsy and heart dysfunctions. Although it has been suggested that dysfunctions of the cardiac, respiratory, and brainstem arousal systems are the causes of SUDEP, the molecular basis for explaining its dysfunctions remain unknown. In rats, repetitive seizures or status epilepticus induced high expression of P-gp and loss Kir expression in the brain and heart, and promoted membrane depolarization, malignant bradycardia, and the high rate of mortality. Here we reviewed clinical and experimental evidences suggesting that abnormal expression of depolarizing/repolarizing factors as P-gp and Kir could favor persistent depolarization of membranes without any rapid functional recovery capacity. This condition induced by convulsive stress could be the molecular mechanism leading to acquired severe bradycardia, as an ineffective heart response generating the appropriate scenario for SUDEP development. This article is part of the Special Issue "NEWroscience 2018".

Epilepsy is a devastating neurological disorder characterized by the repeated occurrence of epileptic seizures. Epilepsy stands as a global health concern affecting around 70 million people worldwide. The mainstream antiepileptic drugs (AEDs) only exert symptomatic relief and drug-resistant epilepsy occurs in up to 33 percent of patients. Hence, the investigation of novel therapeutic strategies against epileptic seizures that could exert disease modifying effects is of paramount importance. In this context, compounds of natural origin with potential antiepileptic properties have recently gained increasing attention. Quercetin is a plant-derived flavonoid with several pharmacological activities. Emerging evidence has demonstrated the antiepileptic potential of quercetin as well. Herein, based on the available evidence, we discuss the neuroprotective effects of quercetin against epileptic seizures and further analyze the plausible underlying molecular mechanisms. Our review suggests that quercetin might be a potential therapeutic candidate against epilepsy that deserves further investigation, and paves the way for the development of plant-derived antiepileptic treatment approaches.

Understanding the interplay between the innate immune system, neuroinflammation, and epilepsy might offer a novel perspective in the quest of exploring new treatment strategies. Due to the complex pathology underlying epileptogenesis, no disease-modifying treatment is currently available that might prevent epilepsy after a plausible epileptogenic insult despite the advances in pre-clinical and clinical research. Neuroinflammation underlies the etiopathogenesis of epilepsy and convulsive disorders with Toll-like receptor (TLR) signal transduction being highly involved. Among TLR family members, TLR4 is an innate immune system receptor and lipopolysaccharide (LPS) sensor that has been reported to contribute to epileptogenesis by regulating neuronal excitability. Herein, we discuss available evidence on the role of TLR4 and its endogenous ligands, the high mobility group box 1 (HMGB1) protein, the heat shock proteins (HSPs) and the myeloid related protein 8 (MRP8), in epileptogenesis and post-traumatic epilepsy (PTE). Moreover, we provide an account of the promising findings of TLR4 modulation/inhibition in experimental animal models with therapeutic impact on seizures.

Objective: Aquaporin-4 (AQP-4) is a water channel protein which is the most abundant aquaporin isoform in the brain. Recent studies indicate the relationship between AQP-4 with epileptogenesis . Therefore, w e examined the potential effect of the AQP-4 inhibitor TGN-020 on penicillin-induced epileptiform activity in rats. Material and Method: Epileptiform activity was induced by intracortical (i.c.) administration of penicillin (200 IU, 1 μl). TGN-020, at doses of 25 µg, 50 µg, 100 µg and 200 µg, was administered by intracerebroventricular (i.c.v.) 30 minutes after penicillin injection. The epileptiform activity was verified by electrocorticographic (ECoG) recordings. Twenty four hours later, animals are decapitated for the collection of blood samples and brain tissue. Results: The dose of 100 µg TGN-020 decreased the mean spike frequency of epileptiform activity in the 30 min after the injection without changing the amplitude (p < 0.05). Serum neuropeptide Y level was up-regulated by 25 µg TGN-020 in comparison with the other groups (p

Background: The KCNMA1 gene encodes the α-subunit of the large conductance, voltage, and calcium-sensitive potassium channel (BK channels) that plays a critical role in neuronal excitability. Heterozygous mutations in KCNMA1 were first illustrated in a large family with generalized epilepsy and paroxysmal nonkinesigenic dyskinesia. Recent research has established homozygous KCNMA1 mutations accountable for the phenotype of cerebellar atrophy, developmental delay, and seizures. Case report: Here, we report the case of a patient with a novel homozygous truncating mutation in KCNMA1 (p.Arg458Ter) presenting with both the loss- and gain-of-function phenotype with paroxysmal dyskinesia, epilepsy, intellectual delay, and corticospinal–cerebellar tract atrophy. Conclusion: This report extends the KNCMA1 mutation phenotype with a patient who carries a novel frameshift variant, presenting with both the gain- and loss-of-function phenotypes along with spinal tract involvement as a novel characteristic.