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- Dynamics of interictal spikes and high-frequency oscillations during epileptogenesis in temporal lobe epilepsy. [JOURNAL ARTICLE]
- Neurobiol Dis 2014 Mar 28.:97-106.
Mesial temporal lobe epilepsy (MTLE) is characterized in humans and in animal models by a seizure-free latent phase that follows an initial brain insult; this period is presumably associated to plastic changes in temporal lobe excitability and connectivity. Here, we analyzed the occurrence of interictal spikes and high frequency oscillations (HFOs; ripples: 80-200Hz and fast ripples: 250-500Hz) from 48h before to 96h after the first seizure in the rat pilocarpine model of MTLE. Interictal spikes recorded with depth EEG electrodes from the hippocampus CA3 area and entorhinal cortex (EC) were classified as type 1 (characterized by a spike followed by a wave) or type 2 (characterized by a spike with no wave). We found that: (i) there was a switch in the distribution of both types of interictal spikes before and after the occurrence of the first seizure; during the latent phase both types of interictal spikes predominated in the EC whereas during the chronic phase both types of spikes predominated in CA3; (ii) type 2 spike duration decreased in both regions from the latent to the chronic phase; (iii) type 2 spikes associated to fast ripples occurred at higher rates in EC compared to CA3 during the latent phase while they occurred at similar rates in both regions in the chronic phase; and (iv) rates of fast ripples outside of spikes were higher in EC compared to CA3 during the latent phase. Our findings demonstrate that the transition from the latent to the chronic phase is paralleled by dynamic changes in interictal spike and HFO expression in EC and CA3. We propose that these changes may represent biomarkers of epileptogenicity in MTLE.
- Cortistatin-14 Mediates its Anticonvulsant Effects Via sst2 and sst3 but Not Ghrelin Receptors. [JOURNAL ARTICLE]
- CNS Neurosci Ther 2014 Mar 31.
Cortistatin (CST)-14, a neuropeptide that is structurally and functionally related to somatostatin-14 (SRIF) binds all five somatostatin receptor subtypes (sst1 -sst5 ). Using in vivo microdialysis and telemetry-based electroencephalographic recordings, we provide the first experimental evidence for anticonvulsive effects of CST-14 in a pilocarpine-induced seizure model in rats and mice and for the involvement of sst2 and sst3 receptors in these anticonvulsant actions of CST-14. Both receptor subtypes are required for the anticonvulsant effects of CST-14 given that co-perfusion of a selective sst2 antagonist (cyanamid15486) or a selective sst3 antagonist (SST3-ODN-8) reversed anticonvulsant effect of CST-14, and this, independently of each other. Next, as the ghrelin receptor has been proposed as a target for the biological effects of CST-14, we used ghrelin receptor knockout mice and their wild type littermates to study the involvement of this receptor in the anticonvulsive actions of CST-14. Our results show a significant decrease in seizure duration in both genotypes when CST-14 treated mice were compared with corresponding control animals receiving only pilocarpine. In addition, this CST-14-induced decrease was comparable in both genotypes. We here thus provide the first evidence that ghrelin receptors are not involved in mediating anticonvulsant actions of CST-14 in vivo.
- Melatonin protects testes against lithium-pilocarpine-induced temporal lobe epilepsy in rats: a time course study. [JOURNAL ARTICLE]
- Andrologia 2014 Mar 30.
Male dysfunction is common in patients with temporal lobe epilepsy (TLE). We evaluated whether melatonin, as a supplement, can play a positive role in reducing the epileptogenesis imposing abnormalities of spermatozoa and testes in epileptic rats. Status epilepticus was induced based on the TLE lithium-pilocarpine model. Two patterns of melatonin were administered to the epileptic animals along the mean durations of latent (14 days) and chronic (60 days) phases. Sperm parameters, different antioxidant enzyme levels, germ cell apoptosis, body and relative sex organ weights were evaluated in all groups 60 days following SE induction. Chronic TLE caused a significant reduction in sperm parameters. In the testis, the reduced level of antioxidant enzymes was accompanied by a significant increase in malondialdehyde concentration. The presence of oxidant condition in the testes of epileptic animals caused expanded apoptosis in the germ cell layer. Moreover, the amount of weight gain in epileptic animals was more prominent. Melatonin administration was able to improve sperm motility by increasing the total antioxidant level. There was also a significant reduction in the spermatogenic cell line apoptosis and the extra weight gain of melatonin-treated animals. Melatonin supplementation might be considered as an acceptable cotreatment in epileptic patients.
- NDEL1 was decreased in the CA3 region but increased in the hippocampal blood vessel network during the spontaneous seizure period after pilocarpine-induced status epilepticus. [JOURNAL ARTICLE]
- Neuroscience 2014 Mar 25.:276-283.
Nuclear distribution factor E homolog like 1 (NDEL1) plays an important role in mitosis, neuronal migration, and microtubule organization during brain development by binding to disrupted-in-schizophrenia-1 (DISC1) or lissencephaly (LIS1). Although some evidence has suggested that DISC1 expression is altered in epilepsy, few studies have reported the relationship between NDEL1 and the etiology of epilepsy. In present study, we first investigated the expression of NDEL1 and its binding protein DISC1 after pilocarpine-induced epilepsy in male C57BL/6 mice. Data revealed that the mRNA and protein expression of NDEL1 and DISC1 in the whole hippocampus increased during the spontaneous seizure period after status epilepticus (SE). Interestingly, however, the expression of NDEL1 was decreased in the cornu ammonis 3 (CA3) and dentate gyrus (DG) regions. Moreover, SE also increased the number of blood vessels that fed the CA3 and DG regions of the hippocampus and increased the incidence of abnormalities in capillary network formation where NDEL1 protein was expressed positively. Meanwhile, the expression of phosphorylated ERK (p-ERK) was also increased during the spontaneous seizure period, with a similar expression pattern as NDEL1 and DISC1. Based on these results, we hypothesize that NDEL1 might interact with DISC1 to activate ERK signaling and function as a potential protective factor during the spontaneous seizure period after pilocarpine-induced SE.
- Chronic intermittent hypoxic preconditioning suppresses pilocarpine-induced seizures and associated hippocampal neurodegeneration. [JOURNAL ARTICLE]
- Brain Res 2014 Mar 27.
Mild brief hypoxia can protect against neuronal damage induced by epileptic seizures, at least in part by inhibiting apoptosis. Further elucidation of the antiepileptic mechanisms and optimization of the conditioning protocols are required before this strategy can be considered for clinical intervention. In this study, we compared the effects of different hypoxic preconditioning protocols on spontaneous recurrent seizures (SRS), intracellular free calcium concentration ([Ca(2+)]i), and apoptosis rate following pilocarpine-induced status epilepticus (SE). Male Sprague Dawley rats were subjected to either chronic intermittent hypobaric hypoxia (CIHH) or chronic intermittent normobaric hypoxia (CINH) (both for 6h/day×28 consecutive days) prior to pilocarpine-induced SE. The possible anticonvulsant and neuroprotective effects of CIHH and CINH were compared by video monitoring of behavioral seizure activity (frequency, delay), Nissl staining and Fluoro-Jade B (FJB) staining to examine changes in the morphology of hippocampal pyramidal neurons, and flow cytometry to detect the quantification of [Ca(2+)]i and cell apoptosis. Both hypoxic preconditioning protocols reduced the frequency and severity of SRS, suppressed post-ictal [Ca(2+)]i elevations, and inhibited neuronal apoptosis in the rat hippocampus compared to pilocarpine alone, but CIHH was more effective than CINH. Thus, mild hypoxic pretreatment, particularly when delivered as CIHH, may be a novel strategy for the clinical prevention and treatment of epilepsy.
- Status epilepticus during early development disrupts sexual behavior in adult female rats: Recovery with sexual experience. [JOURNAL ARTICLE]
- Epilepsy Behav 2014 Mar 24.:15-19.
Female sexual behavior is sensitive to stress and diseases. Some studies have shown that status epilepticus (SE) can affect sexual proceptivity and receptivity in female rats and also increases reject responses towards males. However, epidemiologic studies indicate that SE is more frequent in young individuals. Herein, we assessed the effects of SE in infant females on their sexual behavior during adulthood. Thirteen-day-old (P13) rat pups received intraperitoneal injections of lithium chloride (3mEq/kg). Twenty hours later, at P14, SE was induced by subcutaneous injection of pilocarpine hydrochloride (100mg/kg s.c.). Control animals were given an equal volume of saline subcutaneously. The animals were weaned at P21 and, later in adulthood, were ovariectomized and hormone-primed with estradiol+progesterone, and their sexual behavior assessed during 4 separate trials of 30min each with a stud male. Our results indicate that proceptive behaviors (solicitations and hops and darts) were impaired during the first trial, but no alterations were observed for receptivity and attractivity. By trial 3, all SE females displayed normal proceptivity. These results indicate that SE in infancy readily affects proceptivity in a reversible manner. We discuss the role of sexual experience in recovery.
- Clinical safety, tolerability and efficacy of combination tolterodine/pilocarpine in patients with overactive bladder. [JOURNAL ARTICLE]
- Int J Clin Pract 2014 Mar 25.
The purpose of this study was to assess the safety, tolerability and impact on overactive bladder (OAB) symptoms of a novel combination of tolterodine immediate-release (IR) 2 mg and delayed-release pilocarpine 9 mg in patients with OAB.Eligible patients with OAB were randomised to each of three treatments [tolterodine/pilocarpine (2/9 mg), tolterodine IR 2 mg or placebo] twice daily for 4 weeks in a double-blind, crossover fashion. At the end of the 12-week, double-blind treatment period, patients could enter an open-label extension during which they were re-randomised to either tolterodine/pilocarpine (3/13.5 mg) twice daily or tolterodine extended-release 4 mg once daily for 12 weeks.A total of 138 patients were randomised to double-blind medication. Both tolterodine/pilocarpine (2/9) and tolterodine IR 2 mg significantly reduced incontinence episodes and daily micturitions (p < 0.001 vs. placebo), with similar reductions in symptoms observed between active treatment groups. Tolterodine/pilocarpine (2/9) was associated with consistently lower Visual Analogue Scale (VAS) scores for all dry mouth parameters compared with tolterodine alone. Salivary flow over a 3 h period remained fairly constant after tolterodine/pilocarpine (2/9) administration, similar to placebo, but decreased markedly after administration of tolterodine alone. In the extension study, patients receiving tolterodine/pilocarpine (3/13.5) reported comparable dry mouth VAS scores to tolterodine extended-release alone without additional side effects or loss of efficacy. The combination was well tolerated, and the adverse effects observed were consistent with the known safety profiles of tolterodine and pilocarpine.A combination of tolterodine/pilocarpine (2/9) effectively reduced the incidence of dry mouth compared with tolterodine IR alone while maintaining treatment efficacy in OAB.
- In Vivo Imaging of mGluR5 Changes during Epileptogenesis Using [11C]ABP688 PET in Pilocarpine-Induced Epilepsy Rat Model. [Journal Article]
- PLoS One 2014; 9(3):e92765.
Metabotropic glutamate receptor 5 (mGluR5) that regulates glutamatergic neurotransmission contributes to pathophysiology of epilepsy. In this study, we monitored the changes of mGluR5 in vivo using [11C]ABP688 PET during the epileptogenesis in a pilocarpine-induced epilepsy rat model.In vivo mGluR5 images were acquired using [11C]ABP688 microPET/CT in pilocarpine-induced chronic epilepsy rat models and controls. We also acquired microPET/CT at acute, subacute as well as chronic periods after status epilepticus. Non-displaceable binding potential (BPND) of [11C]ABP688 was calculated using simplified reference tissue model in a voxel-based manner. mGluR5 BPND of the rat brains of epilepsy models and controls were compared.Status epilepticus developed after pilocarpine administration and was followed by recurrent spontaneous seizures for more than 3 weeks. In chronic epilepsy rat model, BPND in hippocampus and amygdala was reduced on a voxel-based analysis. Temporal changes of mGluR5 BPND was also found. In acute period after status epilepticus, mGluR5 BPND was reduced in the whole brain. BPND of caudate-putamen was restored in subacute period, while BPND of the rest of the brain was still lower. In chronic period, global BPND was normalized except in hippocampus and amygdala.In vivo imaging of mGluR5 using [11C]ABP688 microPET/CT could successfully reveal the regional changes of mGluR5 binding potential of the rat brain in a pilocarpine-induced epilepsy model. The temporal and spatial changes in mGluR5 availability suggest [11C]ABP688 PET imaging in epilepsy provide abnormal glutamatergic network during epileptogenesis.
- Immunolocalization of AQP5 in resting and stimulated normal labial glands and in Sjögren's syndrome. [JOURNAL ARTICLE]
- Oral Dis 2014 Mar 24.
In our current work, in vivo examination of AQP5 distribution in labial salivary glands following stimulation of secretion has been carried out in normal individuals and in patients with Sjögren's syndrome.For this study, we selected five patients with primary Sjögren's syndrome (mean age 62.4 ± 10.6 s.d. years) diagnosed in accordance with the European Cooperative Community classification criteria. There were five patients (mean age 27 ± 2.5 s.d. years) in the control group. The subcellular distribution of AQP5 in human labial gland biopsies was determined with light and immunoelectron microscopy before and 30 min after administration of oral pilocarpine.In unstimulated control and Sjögren's labial glands, AQP5 is about 90% localized in the apical plasma membrane, with only rarely associated gold particles with intracellular membrane structures. We have found no evidence of pilocarpine-induced changes in localization of AQP5 in either healthy individuals or patients with Sjögren's syndrome.Our studies indicate that neither Sjögren's syndrome itself, nor muscarinic cholinergic stimulation in vivo caused any significant changes in the distribution of AQP5 in the labial salivary gland cells.
- Chemical functionalization of hyaluronic acid for drug delivery applications. [Journal Article]
- Mater Sci Eng C Mater Biol Appl 2014 May 1.:177-85.
Functionalized hyaluronic acid (HA) derivatives were obtained by ring opening mechanism of maleic anhydride (MA). FTIR and H(1) NMR spectroscopy were used to confirm the chemical linkage of MA on the hyaluronic acid chains. Thermal analysis (TG-DTG and DSC) and GPC data for the new products revealed the formation of new functional groups, without significant changes in molecular weight and thermal stability. New gels based on hyaluronic acid modified derivatives were obtained by acrylic acid copolymerization in the presence of a redox initiation system. The resulted circular and interconnected pores of the gels were visualized by SEM. The release profiles of an ophthalmic model drug, pilocarpine from tested gels were studied in simulated media. Evaluation of the cytotoxicity and cell proliferation properties indicates the potential of the new systems to be used in contact with biological media in drug delivery applications.