Ethosuximide modifies network excitability in the rat entorhinal cortex via an increase in GABA release

Ethosuximide is the drug of choice for treating generalized absence seizures, but its mechanism of action is still a matter of debate. It has long been thought to act by disrupting a thalamic focus via blockade of T-type channels and, thus, generation of spike-wave activity in thalamocortical pathways. However, there is now good evidence that generalized absence seizures may be initiated at a cortical focus and that ethosuximide may target this focus. In the present study we have looked at the effect ethosuximide on glutamate and GABA release at synapses in the rat entorhinal cortex in vitro, using two experimental approaches. Whole-cell patch-clamp studies revealed an increase in spontaneous GABA release by ethosuximide concurrent with no change in glutamate release. This was reflected in studies that estimated global background inhibition and excitation from intracellularly recorded membrane potential fluctuations, where there was a substantial rise in the ratio of network inhibition to excitation, and a concurrent decrease in excitability of neurones embedded in this network. These studies suggest that, in addition to well-characterised effects on ion channels, ethosuximide may directly elevate synaptic inhibition in the cortex and that this could contribute to its anti-absence effects. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'

Effects of rapamycin and curcumin on inflammation and oxidative stress in vitro and in vivo - in search of potential anti-epileptogenic strategies for temporal lobe epilepsy

Background: Previous studies in various rodent epilepsy models have suggested that mammalian target of rapamycin (mTOR) inhibition with rapamycin has anti-epileptogenic potential. Since treatment with rapamycin produces unwanted side effects, there is growing interest to study alternatives to rapamycin as anti-epileptogenic drugs. Therefore, we investigated curcumin, the main component of the natural spice turmeric. Curcumin is known to have anti-inflammatory and anti-oxidant effects and has been reported to inhibit the mTOR pathway. These properties make it a potential anti-epileptogenic compound and an alternative for rapamycin.Methods: To study the anti-epileptogenic potential of curcumin compared to rapamycin, we first studied the effects of both compounds on mTOR activation, inflammation, and oxidative stress in vitro, using cell cultures of human fetal astrocytes and the neuronal cell line SH-SY5Y. Next, we investigated the effects of rapamycin and intracerebrally applied curcumin on status epilepticus (SE)—induced inflammation and oxidative stress in hippocampal tissue, during early stages of epileptogenesis in the post-electrical SE rat model for temporal lobe epilepsy (TLE).Results: Rapamycin, but not curcumin, suppressed mTOR activation in cultured astrocytes. Instead, curcumin suppressed the mitogen-activated protein kinase (MAPK) pathway. Quantitative real-time PCR analysis revealed that curcumin, but not rapamycin, reduced the levels of inflammatory markers IL-6 and COX-2 in cultured astrocytes that were challenged with IL-1β. In SH-SY5Y cells, curcumin reduced reactive oxygen species (ROS) levels, suggesting anti-oxidant effects. In the post-SE rat model, however, treatment with rapamycin or curcumin did not suppress the expression of inflammatory and oxidative stress markers 1 week after SE.Conclusions: These results indicate anti-inflammatory and anti-oxidant properties of curcumin, but not rapamycin, in vitro. Intracerebrally applied curcumin modified the MAPK pathway in vivo at 1 week after SE but failed to produce anti-inflammatory or anti-oxidant effects. Future studies should be directed to increasing the bioavailability of curcumin (or related compounds) in the brain to assess its anti-epileptogenic potential in vivo

Progress in gene therapy for neurological disorders

Diseases of the nervous system have devastating effects and are widely distributed among the population, being especially prevalent in the elderly. These diseases are often caused by inherited genetic mutations that result in abnormal nervous system development, neurodegeneration, or impaired neuronal function. Other causes of neurological diseases include genetic and epigenetic changes induced by environmental insults, injury, disease-related events or inflammatory processes. Standard medical and surgical practice has not proved effective in curing or treating these diseases, and appropriate pharmaceuticals do not exist or are insufficient to slow disease progression. Gene therapy is emerging as a powerful approach with potential to treat and even cure some of the most common diseases of the nervous system. Gene therapy for neurological diseases has been made possible through progress in understanding the underlying disease mechanisms, particularly those involving sensory neurons, and also by improvement of gene vector design, therapeutic gene selection, and methods of delivery. Progress in the field has renewed our optimism for gene therapy as a treatment modality that can be used by neurologists, ophthalmologists and neurosurgeons. In this Review, we describe the promising gene therapy strategies that have the potential to treat patients with neurological diseases and discuss prospects for future development of gene therapy

Long-term effects of feral goats (Capra hircus) on Mediterranean island communities: results from whole island manipulations

Islands exhibit disproportionally high biodiversity, however high levels of endemism and simplified food webs make their communities susceptible to invasive species. Introduced goats (Capra hircus), a generalist herbivore, are among the most harmful invasive species on islands. Concern about goat impacts on island communities have resulted in eradication programs, which have been generally implemented without comprehensive evaluation and monitoring. Unintended consequences may follow eradication, as grazing can have complex effects on island food webs. Using whole island manipulations, we evaluate the long-term, community-wide effects of goat herbivory, as well as their subsequent removal, in a system of 16 islands in the Aegean Sea (Greece) located within the Mediterranean biodiversity hotspot. Goat grazing on these islands is a major conservation concern, as these support endemic plant communities that have evolved in low herbivory conditions and lack appropriate defenses. We show that goat introductions lead to significant decreases in vegetation height, percent cover, and biomass but not to immediate plant species loss, as native island endemics are replaced with widespread generalist taxa carried in by the livestock. Additionally, goats contribute to the desertification of islands by initiating a long-term soil loss cycle that continues even after goats are removed; however, remaining soil structure and chemistry are not affected. Island arthropod populations do not appear to be significantly impacted by goat introduction or removal, except for a distinct increase in the order Diptera with goat presence. This study also reaffirms the role of seabirds in providing important marine subsidies, rich in nitrogen and phosphorus, to island food webs. Plant species diversity declines following goat removal, and vegetation cover returns only partially, as further recovery is being prevented by the long-term loss of soil. This suggests that following goat removal, island communities may require additional restoration efforts, including seabird reestablishment and reintroduction of extirpated plant populations, to promote island recovery. © 2017, Springer International Publishing AG, part of Springer Nature

Mixed cryoglobulinemia in Greece: Primary disorders in 10 cases

Mixed cryoglobulinemia (MC) is a systemic disorder whose pathogenesis is based on the presence of serum cryoglobulins. The purpose of this study was to evaluate on a prospective basis patients presenting with MC with regard to the clinical manifestations and the underlying disorders. We present ten patients with MC, who were diagnosed and followed up during a one year period in the Division of autoimmune rheumatic diseases (Clinical Department of Pathophysiology). MC was associated with hepatitis C virus (HCV) infection in two cases, with hepatitis B virus (HBV) infection in six, one patient had both HCV and evidence of HBV infection, while the remaining three patients fulfilled European classification criteria for diagnosis of Sjogren's syndrome (SS). In all ten cases, the presence of an underlying factor was identified, being either vital or autoimmune. It is concluded therefore that all patients presenting with MC should be completely evaluated for a hepatitis virus infection or an autoimmune or lymphoproliferative disorder. Furthermore, since the initiation of the process of MC is triggered by many factors, research should be directed towards the identification of the underlying common denominator