Antiepileptic effects of CNK-602A, a novel thyrotropin-releasing hormone analog, on absence-like and tonic seizures of spontaneously epileptic rats.

The effects of CNK-602A (N-[(6-methyl-5-oxo-3-thiomorpholinyl) carbonyl]-L-histidyl-L-prolinamide), a novel thyrotropin-releasing hormone related analog, were investigated on absence-like seizure and tonic convulsion in the spontaneously epileptic rat (SER), which is a genetically defined double-mutant. When CNK-602A of 0.2-1 mg/kg was given intravenously to the animal, there were no changes in the background EEG except for an increase in low-voltage fast waves concomitant with behavioral alertness. However, CNK-602A suppressed absence-like seizure and tonic convulsion in a dose-dependent manner for over 1 h. These antiepileptic effects of CNK-602A on both seizures were antagonized by pretreatment with haloperidol (1 mg/kg, i.p.). It was found, using a brain in vivo microdialysis method, that CNK-602A at a dose of 1 mg/kg, which inhibits the seizures, increased the release of dopamine in the caudate nucleus. These results suggest that CNK-602A inhibits the seizures of SER in a similar manner to thyrotropin-releasing hormone (TRH), probably by increasing the release of dopamine in the central nervous system. In addition, the antiepileptic effects of CNK-602A were more potent and lasted longer than those of TRH.     

Adenocarcinoma arising from respiratory ciliated epithelium in benign cystic teratoma of the ovary: a case report with analyzes of the CT, MRI, and pathological findings

The malignant transformation of mature cystic teratoma is rare, thus occurring in only 1-2% of all cases. The most common malignancy arising in mature cystic teratoma is squamous cell carcinoma. Adenocarcinoma occurs with less frequency. We herein present a patient with an ovarian mature cystic teratoma who demonstrated a malignant transformation to well-differentiated adenocarcinoma. Malignant transformation was diagnosed preoperatively by contrast enhanced computed tomography (CT) and magnetic resonance imaging (MRI). Microscopically and immunohistochemically, the adenocarcinoma was considered to have arisen from the ciliated respiratory epithelium. After a 28-month of follow-up period, she remains free of the disease. This is the third reported case of adenocarcinoma arising in the respiratory epithelium of an ovarian mature cystic teratoma. Contrast enhanced CT and MRI are useful for making a preoperative diagnosis and an immunohistochemical study is helpful for defining its origin.     

Increased Ca2+ channel currents in cerebellar Purkinje cells of the ataxic groggy rat

The ataxic groggy rat (strain name; GRY) is an autosomal recessive neurological mutant found in a closed colony of Slc:Wistar rats. Recent genetic analysis has identified the missense (M251K) mutation in the alpha(1) subunit of the Ca(V)2.1 (P/Q-type) voltage-dependent Ca(2+) channel gene (Cacna1a) of GRY rat. In this study, we found that high-voltage-activated (HVA) Ca(2+) channel currents in acutely dissociated Purkinje cells of GRY rats showed increased (not decreased) current density and depolarizing shift of the activation and inactivation curves compared with those of normal Wistar rats. In contrast low-voltage-activated (LVA) Ca(2+) channel currents of GRY rats showed no significant changes. These results suggest that functional alteration of Ca(2+) channel currents in cerebellar Purkinje cells of GRY rats is attributed to the change of HVA Ca(2+) channel currents, and that increased HVA Ca(2+) channel function underlies the cerebellar dysfunction and ataxic phenotype of GRY rats.     

Prenatal molecular diagnosis of X‐linked hydrocephalus via a silent C924T mutation in the L1CAM gene

We present a case of a patient whose L1CAM gene in X‐chromosome has a C924T transition. Her first son's ventriculomegaly was prenatally detected. A mature infant was born, his head circumference was large, and thumbs were bilaterally adducted. X‐linked hydrocephalus (XLH) was suspected. The DNA examination revealed that both her and boy's LICAM gene had a C924T transition. She became pregnant 5 years later and amniocentesis was performed. The results of cytogenetic analysis revealed that the fetus was female. She continued her pregnancy and delivered a healthy girl. She again became pregnant 3 years later. The chromosomal analysis revealed that the fetus was male. Fetal DNA analysis determined that the fetus had the inherited mutation. She chose to terminate the pregnancy. A C924T mutation can be disease causing for XLH, and the detection of this mutation would aid in genetic counseling for the prenatal diagnosis of XLH.     

Aberrant reduction of an inhibitory protein factor in a rat epileptic model

Certain forms of seizure involve excessive glutamate transmission. We have recently identified a protein, referred to as the inhibitory protein factor (IPF), which potently inhibits glutamate uptake into isolated synaptic vesicles. In an effort to understand the mechanism underlying excessive glutamate transmission associated with seizure, we have analyzed IPF content in various brain regions of the spontaneously epileptic rat, SER (tm/tm, zi/zi), the absence-seizure tremor rat, TM (tm/tm), and the seizure-free control rats zitter ZI (zi/zi) and Wistar tremor control, each at 13 weeks of age. IPF content was found to be markedly reduced in the hippocampus, but not in the other brain regions, of SER, compared to the control and TM rats. TM rats also exhibited reduced IPF content compared to seizure-free controls. These changes appear developmentally regulated; no such alteration was observed in 8-week-old rats, which rarely show seizure. These observations indicate that an aberrant decrease in IPF is associated with certain forms of seizure; this decrease could lead to an abnormal increase in the amount of exocytotically released glutamate through its excessive accumulation in synaptic vesicles.     

Effects of AAV-2-mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease

The tremor rat is a spontaneous epilepsy model with a seizure phenotype caused by a deletion in the aspartoacylase (ASPA) gene. The absence of ASPA expression in these animals results in undetectable levels of enzyme activity and the accumulation of the substrate N-acetyl-aspartate (NAA) in brain, leading to generalized myelin vacuolation and severe motor and cognitive impairment. In support of human gene therapy for CD, recombinant adeno-associated viral vector (AAV-2) expressing ASPA was stereotactically delivered to the tremor rat brain and effects on the mutant phenotype were measured. AAV-ASPA gene transfer resulted in elevated aspartoacylase bioactivity compared to untreated mutant animals and elicited a significant decrease in the pathologically elevated whole-brain NAA levels. Assessment of motor function via quantitative rotorod testing demonstrated that rats injected with AAV-ASPA significantly improved on tests of balance and coordinated locomotion compared to animals receiving control vectors. This study provides evidence that AAV-2-mediated aspartoacylase gene transfer to the brain improves biochemical and behavioral deficits in tremor rat mutants (tm/tm) and supports the rationale of human gene transfer for Canavan disease.     

Long-lasting antiepileptic effects of levetiracetam against epileptic seizures in the spontaneously epileptic rat (SER): differentiation of levetiracetam from conventional antiepileptic drugs

PURPOSE: Some evidence suggests that levetiracetam (LEV) possesses antiepileptogenic characteristics. The purpose of this study was to investigate the time course of seizure protection by LEV compared with that of phenytoin (PHT), phenobarbital (PB), valproate (VPA), and carbamazepine (CBZ) in the spontaneously epileptic rat (SER). The SER is a double mutant (tm/tm, zi/zi) showing both tonic convulsions and absence-like seizures. METHODS: The effect of single (40, 80, and 160 mg/kg, i.p.) and 5-day (80 mg/kg/day, i.p.) administration of LEV on tonic convulsions and absence-like seizures in SERs were studied. Tonic convulsions induced by blowing air onto the animal's head at 5-min intervals for 30 min and spontaneous absence-like seizures characterized by 5- to 7-Hz spike-wave-like complexes in the cortical and hippocampal EEG were recorded for 30 min. In the single-administration study, observations for seizure activity were performed once before and 3 times (45, 75, and 135 min) after drug administration. In the 5-day administration study, seizure observation was performed 4 times for 30 min (once before and 3 times after drug administration) during the 5-day drug-administration period, and continued once a day until 8 days after the final administration. The antiepileptic effects of 5-day administration of conventional AEDs (PHT, PB, VPA, and CBZ) were examined by using similar methods. RESULTS: Tonic convulsions and absence-like seizures were inhibited by a single administration of LEV at 80 and 160 mg/kg, i.p., but not significantly at 40 mg/kg, i.p. When LEV was repeatedly administered at 80 mg/kg/day, i.p., for 5 days to SERs, the inhibitory effects on seizures increased with administration time. The number of tonic convulsions and absence-like seizures were significantly reduced to 39.1% and 38.4% compared with previous values, respectively, after 5-day LEV administration. Furthermore, significant inhibition of tonic convulsions was detected 相似文献