Migraine preventive drugs differentially affect cortical spreading depression in rat

Cortical spreading depression (CSD) is the most likely cause of the migraine aura. Drugs with distinct pharmacological properties are effective in the preventive treatment of migraine. To test the hypothesis that their common denominator might be suppression of CSD we studied in rats the effect of three drugs used in migraine prevention: lamotrigine which is selectively effective on the aura but not on the headache, valproate and riboflavin which have a non-selective effect. Rats received for 4 weeks daily intraperitoneal injections of one of the three drugs. For valproate and riboflavin we used saline as control, for lamotrigine its vehicle dimethyl sulfoxide. After treatment, cortical spreading depressions were elicited for 2h by occipital KCl application. We measured CSD frequency, its propagation between a posterior (parieto-occipital) and an anterior (frontal) electrode, and number of Fos-immunoreactive nuclei in frontal cortex. Lamotrigine suppressed CSDs by 37% and 60% at posterior and anterior electrodes. Valproate had no effect on posterior CSDs, but reduced anterior ones by 32% and slowed propagation velocity. Riboflavin had no significant effect at neither recording site. Frontal Fos expression was decreased after lamotrigine and valproate, but not after riboflavin. Serum levels of administered drugs were within the range of those usually effective in patients. Our study shows that preventive anti-migraine drugs have differential effects on CSD. Lamotrigine has a marked suppressive effect which correlates with its rather selective action on the migraine aura. Valproate and riboflavin have no effect on the triggering of CSD, although they are effective in migraine without aura. Taken together, these results are compatible with a causal role of CSD in migraine with aura, but not in migraine without aura.     

Effects of tongue volume reduction on craniofacial growth: A longitudinal study on orofacial skeletons and dental arches

The interaction between tongue size/volume and craniofacial skeletal growth is essential for understanding the mechanism of specific types of malocclusion and objectively measuring outcomes of various surgical and/or orthodontic treatments. Currently available information on this interaction is limited. This study was designed to examine how tongue body volume reduction affects craniofacial skeleton and dental arch formation during the rapid growth period in five 12-week-old Yucatan minipig sibling pairs. One of each pair received a standardized reduction glossectomy to reduce tongue volume by 15-17% (reduction group), and the other had the reduction glossectomy incisions without tissue removal (sham group). Before surgery, five stainless steel screws were implanted into standardized craniofacial skeletal locations. A series of cephalograms, lateral and axial, were obtained longitudinally at 1 week preoperative, and 2 and 4 weeks postoperative. These images were traced using superimposition, and linear and angular variables were measured digitally. Upon euthanasia, direct osteometric measurements were obtained from harvested skulls. Five en-bloc bone pieces were further cut for bone mineral examination by dual photon/energy X-ray absorptiometry (DEXA). The results indicate that: (1) while daily food consumption and weekly body weight were not significantly affected, tongue volume reduction showed an overall negative effect on the linear expansion of craniofacial skeletons; (2) premaxilla and mandibular symphysis lengths, and anterior dental arch width were significantly less in reduction than sham animals at 2 and/or 4 weeks after the surgery; (3) both premaxilla/maxilla and mandible bone mineral density and content were lower in reduction than sham animals, significantly lower in anterior mandible; (4) craniofacial skeletal and dental arch size were significantly smaller in reduction than sham animals, being most significant in the mandibular anterior length and ramus height, the anterior dental arch and midface width. These results suggest that reducing tongue body volume in young animals slows craniofacial skeletal growth and anterior dental arch expansion during rapid growth. The mandible, in particular its symphysis portion, and the anterior dental arch width are most affected. These effects may in part contribute to the decrease of functional loads in the anterior mouth by a volume-reduced tongue.     

Genes of tumor necrosis factors and their receptors and the primary open angle glaucoma in the population of Central Russia

AIM: To examine the association of genetic polymorphisms (-308)G/A TNFα, (+250)A/G Ltα, (+36)A/G TNFR1, (+1663)A/G TNFR2 with the development of primary open angle glaucoma (POAG) among people in Central Russia. METHODS: The study sample included 443 individuals, of which 252 patients with POAG and 191 individuals in the control group. Genotyping of (-308)G/A TNFα, (+250)A/G Ltα, (+36)A/G TNFR1, (+1663)A/G TNFR2 was performed using polymerase chain reaction. The distribution of alleles and genotypes of the studied DNA markers in the groups was examined by 2×2 contingency tables and χ2 with the Yates’s correction for continuity and odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Allele (-308)G TNFα (Р=0.01, OR=1.78, 95%CI 1.12-2.85) was identified as a risk factor for POAG. Homozygotes (-308) AA TNFα are at a lowest risk for development of the disease (Р=0.01, OR=0.0005). The following combination of genetic variants of cytokines were associated with a reduced risk of POAG: (+1663)A TNFR2 and (+250)G Ltα (OR=0.34) CONCLUSION: Genetic polymorphisms (-308)G/A TNFα, (+250)A/G Ltα, (+1663)A/G TNFR2 associated with the development of POAG in the population of Central Russia.     

Genetic and epigenetic changes in fibrosis‐associated hepatocarcinogenesis in mice

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and is rising in incidence worldwide. The molecular mechanisms leading to the development of HCC are complex and include both genetic and epigenetic events. To determine the relative contribution of these alterations in liver tumorigenesis, we evaluated epigenetic modifications at both global and gene specific levels, as well as the mutational profile of genes commonly altered in liver tumors. A mouse model of fibrosis‐associated liver cancer that was designed to emulate cirrhotic liver, a prevailing disease state observed in most humans with HCC, was used. Tumor and nontumor liver samples from B6C3F1 mice treated with N‐nitrosodiethylamine (DEN; a single ip injection of 1 mg/kg at 14 days of age) and carbon tetrachloride (CCl₄; 0.2 ml/kg, 2 times/week ip starting at 8 weeks of age for 14 weeks), as well as corresponding vehicle control animals, were analyzed for genetic and epigenetic alterations. H‐ras, Ctnnb1 and Hnf1α genes were not mutated in tumors in mice treated with DEN+CCl₄. In contrast, the increased tumor incidence in mice treated with DEN+CCl₄ was associated with marked epigenetic changes in liver tumors and nontumor liver tissue, including demethylation of genomic DNA and repetitive elements, a decrease in histone 3 lysine 9 trimethylation (H3K9me3) and promoter hypermethylation and functional downregulation of Riz1, a histone lysine methyltransferase tumor suppressor gene. Additionally, the reduction in H3K9me3 was accompanied by increased expression of long interspersed nucleotide elements 1 and short interspersed nucleotide elements B2, which is an indication of genomic instability. In summary, our results suggest that epigenetic events, rather than mutations in known cancer‐related genes, play a prominent role in increased incidence of liver tumors in this mouse model of fibrosis‐associated liver cancer.     

Transcriptomic responses provide a new mechanistic basis for the chemopreventive effects of folic acid and tributyrin in rat liver carcinogenesis

The steady increase in the incidence and mortality of hepatocellular carcinoma (HCC) signifies a crucial need to understand better its pathogenesis to improve clinical management and prevention of the disease. The aim of this study was to investigate molecular mechanisms for the chemopreventive effects of folic acid and tributyrin alone or in combination on rat hepatocarcinogenesis. Male Wistar rats were subjected to a classic “resistant hepatocyte” model of liver carcinogenesis and treated with folic acid and tributyrin alone or in combination for 5 weeks during promotion stage. Treatment with folic acid and tributyrin alone or in combination strongly inhibited the development of glutathione‐S‐transferase placental form (GSTP)‐positive foci. Microarray analysis showed significant changes in gene expression. A total of 498, 655 and 940 of differentially expressed genes, involved in cell cycle, p53‐signaling, angiogenesis and Wnt pathways, was identified in the livers of rats treated with folic acid, tributyrin or folic acid and tributyrin. A detailed analysis of these differentially expressed genes revealed that treatments inhibited angiogenesis in the preneoplastic livers. This was evidenced by the fact that 30 out of 77 differentially expressed genes common to all three treatments are involved in the regulation of the angiogenesis pathway. The inhibition of angiogenesis was confirmed by reduced levels of CD34 protein. In conclusion, the tumor‐suppressing activity of folic acid and tributyrin is associated with inhibition of angiogenesis at early stages of rat liver carcinogenesis. Importantly, the combination of folic acid and tributyrin has stronger chemopreventive effect than each of the compounds alone.     

Spinal cord injury with unilateral versus bilateral primary hemorrhage--effects of glibenclamide

In spinal cord injury (SCI), block of Sur1-regulated NC(Ca-ATP) channels by glibenclamide protects penumbral capillaries from delayed fragmentation, resulting in reduced secondary hemorrhage, smaller lesions and better neurological function. All published experiments demonstrating a beneficial effect of glibenclamide in rat models of SCI have used a cervical hemicord impact calibrated to produce primary hemorrhage located exclusively ipsilateral to the site of impact. Here, we tested the hypothesis that glibenclamide also would be protective in a model with more extensive, bilateral primary hemorrhage. We studied the effect of glibenclamide in 2 rat cervical hemicord contusion models with identical impact force (10 g, 25 mm), one with the impactor positioned laterally to yield unilateral primary hemorrhage (UPH), and the other with the impactor positioned more medially, yielding larger, bilateral primary hemorrhages (BPH) and 6-week lesion volumes that were 45% larger. Functional outcome measures included: modified (unilateral) Basso, Beattie, and Bresnahan scores, angled plane performance, and rearing times. In the UPH model, the effects of glibenclamide were similar to previous observations, including a functional benefit as early as 24h after injury and 6-week lesion volumes that were 57% smaller than controls. In the BPH model, glibenclamide exerted a significant benefit over controls, but the functional benefit was smaller than in the UPH model and 6-week lesion volumes were 33% smaller than controls. We conclude that glibenclamide is beneficial in different models of cervical SCI, with the magnitude of the benefit depending on the magnitude and extent of primary hemorrhage.     

Visual learning by cue-dependent and cue-invariant mechanisms

We examined learning at multiple levels of the visual system. Subjects were trained and tested on a same/different slant judgment task or a same/different curvature judgment task using simulated planar surfaces or curved surfaces defined by either stereo or monocular (texture and motion) cues. Taken as a whole, the results of four experiments are consistent with the hypothesis that learning takes place at both cue-dependent and cue-invariant levels, and that learning at these levels can have different generalization properties. If so, then cue-invariant mechanisms may mediate the transfer of learning from familiar cue conditions to novel cue conditions, thereby allowing perceptual learning to be robust and efficient. We claim that learning takes place at multiple levels of the visual system, and that a comprehensive understanding of visual perception requires a good understanding of learning at each of these levels.