Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin () gene. We report the design of a series of pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of mRNA transcripts and protein levels.

Genotype and Injury Effect on the Expression of a Novel Hypothalamic Protein Sushi Repeat-Containing Protein X-Linked 2 (SRPX2).

Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel hypothalamic protein and a ligand of the urokinase-type plasminogen activator receptor (uPAR), which is essential for proteolysis of extracellular matrix and tissue remodeling after an insult to the brain. However, little is known about regulation of SRPX2. Our objective was to investigate if SRPX2 expression is altered by (i) the deficiency of uPAR or uPA (urokinase-type plasminogen activator), and (ii) traumatic brain injury (TBI).

Deficiency of urokinase-type plasminogen activator and its receptor affects social behavior and increases seizure susceptibility.

Extracellular proteolysis initiated by the binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) regulates the development of inhibitory neuronal circuits in the cerebral cortex and tissue remodeling after epileptogenic brain injury. To study the function of different components of the uPA-uPAR system on behavior and epileptogenesis, and to complement our previous studies on naïve and injured mice deficient in the uPA-encoding gene Plau or the uPAR-encoding gene Plaur, we analyzed the behavioral phenotype, seizure susceptibility, and perineuronal nets surrounding parvalbumin-positive inhibitory interneurons in Plau and Plaur (double knockout dKO) mice. In a climbing test, dKO mice showed reduced interest towards the environment as compared with Wt mice (p < 0.

Sushi repeat-containing protein X-linked 2: A novel phylogenetically conserved hypothalamo-pituitary protein.

Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel protein associated with language development, synaptic plasticity, tissue remodeling, and angiogenesis. We investigated the expression and spatial localization of SRPX2 in normal mouse, rat, monkey, and human brain using in situ hybridization and immunohistochemistry. Antibody specificity was determined using in vitro siRNA based silencing of SRPX2.

Epileptogenesis after traumatic brain injury in Plaur-deficient mice.

Binding of the extracellular matrix proteinase urokinase-type plasminogen activator (uPA) to its receptor, uPAR, regulates tissue remodeling during development and after injury in different organs, including the brain. Accordingly, mutations in the Plaur gene, which encodes uPAR, have been linked to language deficits, autism, and epilepsy, both in mouse and human. Whether uPAR deficiency modulates epileptogenesis and comorbidogenesis after brain injury, however, is unknown.

Epileptogenesis after traumatic brain injury in Plau-deficient mice.

Several components of the urokinase-type plasminogen activator receptor (uPAR)-interactome, including uPAR and its ligand sushi-repeat protein 2, X-linked (SRPX2), are linked to susceptibility to epileptogenesis in animal models and/or humans. Recent evidence indicates that urokinase-type plasminogen activator (uPA), a uPAR ligand with focal proteinase activity in the extracellular matrix, contributes to recovery-enhancing brain plasticity after various epileptogenic insults such as traumatic brain injury (TBI) and status epilepticus. Here, we examined whether deficiency of the uPA-encoding gene Plau augments epileptogenesis after TBI.

Diffusion tensor imaging detects chronic microstructural changes in white and gray matter after traumatic brain injury in rat.

Traumatic brain injury (TBI) is a major cause of disability and death in people of all ages worldwide. An initial brain injury caused by external mechanical forces triggers a cascade of tissue changes that lead to a wide spectrum of symptoms and disabilities, such as cognitive deficits, mood or anxiety disorders, motor impairments, chronic pain, and epilepsy. We investigated the detectability of secondary injury at a chronic time-point using ex vivo diffusion tensor imaging (DTI) in a rat model of TBI, lateral fluid percussion (LFP) injury.

Urokinase-type plasminogen activator deficiency has little effect on seizure susceptibility and acquired epilepsy phenotype but reduces spontaneous exploration in mice.

Urokinase-type plasminogen activator (uPA), a serine protease, converts plasminogen to plasmin. Activation of plasmin leads to degradation of the extracellular matrix, which is critical for tissue recovery, angiogenesis, cell migration, and axonal and synaptic plasticity. We hypothesized that uPA deficiency would cause an abnormal neurophenotype and would lead to exacerbated epileptogenesis after brain injury.

Gender issues in antiepileptogenic treatments.

Disease modification of epilepsy refers to the alleviation of epileptogenesis or comorbidities after genetic or acquired epileptogenic brain insults. There are currently 30 proof-of-concept experimental pharmacologic studies that have demonstrated some beneficial disease-modifying effects. None of these studies, however, has yet passed from the laboratory to the clinic.

Posttraumatic epilepsy - disease or comorbidity?

Traumatic brain injury (TBI) can cause a myriad of sequelae depending on its type, severity, and location of injured structures. These can include mood disorders, posttraumatic stress disorder and other anxiety disorders, personality disorders, aggressive disorders, cognitive changes, chronic pain, sleep problems, motor or sensory impairments, endocrine dysfunction, gastrointestinal disturbances, increased risk of infections, pulmonary disturbances, parkinsonism, posttraumatic epilepsy, or their combinations. The progression of individual pathologies leading to a given phenotype is variable, and some progress for months.

The protective effect of myo-inositol on hippocamal cell loss and structural alterations in neurons and synapses triggered by kainic acid-induced status epilepticus.

It is known that myo-inositol pretreatment attenuates the seizure severity and several biochemical changes provoked by experimentally induced status epilepticus. However, it remains unidentified whether such properties of myo-inositol influence the structure of epileptic brain. In the present light and electron microscopic research we elucidate if pretreatment with myo-inositol has positive effect on hippocampal cell loss, and cell and synapses damage provoked by kainic acid-induced status epilepticus.

Development of post-traumatic epilepsy after controlled cortical impact and lateral fluid-percussion-induced brain injury in the mouse.

The present study investigated the development of hyperexcitability and epilepsy in mice with traumatic brain injury (TBI) induced by controlled cortical impact (CCI) or lateral fluid-percussion injury (FPI), which are the two most commonly used experimental models of human TBI in rodents. TBI was induced with CCI to 50 (14 controls) and with lateral FPI to 45 (15 controls) C57BL/6S adult male mice. The animals were followed-up for 9 months, including three 2-week periods of continuous video-electroencephalographic (EEG) monitoring, and a seizure susceptibility test with pentylenetetrazol (PTZ).

Anti-epileptogenesis in rodent post-traumatic epilepsy models.

Post-traumatic epilepsy (PTE) accounts for 10-20% of symptomatic epilepsies. The urgency to understand the process of post-traumatic epileptogenesis and search for antiepileptogenic treatments is emphasized by a recent increase in traumatic brain injury (TBI) related to military combat or accidents in the aging population. Recent developments in modeling of PTE in rodents have provided tools for identification of novel drug targets for antiepileptogenesis and biomarkers for predicting the risk of epileptogenesis and treatment efficacy after TBI.

Spontaneous epileptiform discharges in a mouse model of Alzheimer's disease are suppressed by antiepileptic drugs that block sodium channels.

Previous studies have demonstrated an increased risk of epilepsy in patients with Alzheimer's disease (AD). Also, in many mouse models of AD, animals have spontaneous seizures and frequent epileptiform discharges (EDs). Abnormal function of sodium channels has been proposed to contribute to hyperexcitability in a manner suggesting that drugs that block sodium channels might exacerbate the condition.

Effects of oxytocin on behaviour and memory in rats subjected to chronic restrained stress.

We studied whether 21 days of restraint chronic stress would affect the contextual fear conditioning, a memory task with hippocampal-dependent components and anxiety- like behavior in the open field, and to determine whether oxytocin treatment could prevent the chronic stress induced memory and emotional disturbances. Restraint-stressed rats were injected daily (21 days) with oxytocin (1 mg/kg) or saline then tested in open field (day 22) and contextual fear conditioning task (days 23-24). Our data demonstrate that chronic restraint stress induces some behavioural changes in both saline-treated and oxytocin-treated animals.

[Quantitative analysis of gliocytes and macrogliocyte-neuronal ratio in the rat hippocampus after kindling].

Gliosis is one of the main morphological correlates of epilepsy. It is presented predominantly by proliferation and hypertrophy of astrocytes and activated microglia (macrophages) and is most characteristic to those areas of the epileptogenic zones, where the loss of neurons is significant. One of such structures is the hippocampus, the sclerosis of which develops already at the early stages of epileptogenesis.

[Indications to surgical treatment of patients with peptic ulcer disease].

The aim of this investigation is to study the influence of eradication of Helicobacter pylori (Hp) on the results of conservative treatment of patients with ulcer. The results of treatment of 216 patients with peptic ulcer disease (I gr.--152 patients with noncomplicated peptic ulcer disease and II gr.

Kindling-induced hippocampal cell death in rats.

Quantitative analysis of the main cells and interneurons in different layers and fields of Ammon's horn, the hilus, and dentate gyrus was performed two weeks and one month after kindling, i.e., specific electrical stimulation of the ventral hippocampus.

Effect of myo-inositol on convulsions induced by pentylenetetrazole and kainic acid in rats.

We studied the effect of myo-inositol on pentylenetetrazole and kainic acid-induced seizures in rats. Myo-inositol significantly reduced seizure activity.

[Hippocampal cell loss in rats as a result of kindling].

Quantitative analysis was performed to evaluate the numbers of principal cells cells and interneurons in differenet layers and areas of the horn of Ammonis, hilus and dentate gyrus 2 weeks and 1 month after kindling--specific electrical stimulation of ventral hippocampus. After both experimental time intervals, a significant cell loss was found in all the layers and areas studied, with the exception of stratum oriens of CA4. Thus, in this model of experimental epilepsy, both interneurons and principal cells were found to be involved in the process of epileptogenesis.

Effect of acoustic stimulation on cell composition of auditory brain structures in Krushinskii-Molodkina rats.

We studied the effect of acoustic stimulation on cell composition of auditory brain structures in Krushinskii-Molodkina rats. Significant structural changes in the inferior colliculi of rats with high seizure activity were revealed 1 month after acoustic stimulation. Therefore, this brain structure plays a role in the development of audiogenic epileptic activity.

Cellular composition of the piriform cortex of the rat brain in experimental epilepsy.

The cellular composition of all layers of the anterior, central, and posterior parts of the piriform cortex of the rat brain was studied two weeks and one month after specific electrical stimulation (kindling) of the ventral hippocampus. Stereomicroscopic analysis at both two weeks and one month after kindling showed significant decreases in the numbers of pyramidal cells and interneurons in all layers of all parts of the piriform cortex. At two weeks, the numbers of pyramidal cells and interneurons in the central part of the piriform cortex also decreased in rats in which electrodes were inserted into the ventral hippocampus but without stimulation.

Effect of kindling on GABAergic neurons of the hippocampus and pyriform cortex.

GABAergic neurons in different fields of the hippocampus and pyriform cortex were examined 2 weeks and 1 month after electric stimulation of the ventral hippocampus. The counts of GABAergic neurons in the studied structures decreased significantly. The most pronounced shifts in the pyriform cortex were found in the central compartment.

[Characteristics of structural organization of interneurons in CA 3 region and mossy fibers of hippocampus].

The paper reviews the current data on the structural peculiarities of the interneurons of hippocampal area CA 3. Special attention is paid to horizontal spiny interneurons located in the stratum lucidum and forming direct contacts with the system of mossy fibers. Their axons terminate at the proximal portions of dendrites and cell body of pyramidal neurons, occasionally they make contacts with the main cells of the hilus and other hippocampal interneurons.