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

Indications for implant removal after fracture healing: a review of the literature

Introduction: The aim of this review was to collect and summarize published data on the indications for implant removal after fracture healing, since these are not well defined and guidelines hardly exist. Methods: A literature search was performed. Results: Though there are several presumed benefits of implant removal, such as functional improvement and pain relief, the surgical procedure can be very challenging and may lead to complications or even worsening of the complaints. Research has focused on the safety of metal implants (e.g., risk of corrosion, allergy, and carcinogenesis). For these reasons, implants have been removed routinely for decades. Along with the introduction of titanium alloy implants, the need for implant removal became a subject of debate in view of potential (dis)advantages since, in general, implants made of titanium alloys are more difficult to remove. Currently, the main indications for removal from both the upper and lower extremity are mostly 'relative' and patient-driven, such as pain, prominent material, or simply the request for removal. True medical indications like infection or intra-articular material are minor reasons. Conclusion: This review illustrates the great variety of view points in the literature, with large differences in opinions and practices about the indications for implant removal after fracture healing. Since some studies have described asymptomatic patients developing complaints after removal, the general advice nowadays is to remove implants after fracture healing only in symptomatic patients and after a proper informed consent. Well-designed prospective studies on this subject are urgently needed in order to form guidelines based on scientific evidence

Mapping the Spatio-Temporal Pattern of the Mammalian Target of Rapamycin (mTOR) Activation in Temporal Lobe Epilepsy

Growing evidence from rodent models of temporal lobe epilepsy (TLE) indicates that dysregulation of the mammalian target of rapamycin (mTOR) pathway is involved in seizures and epileptogenesis. However, the role of the mTOR pathway in the epileptogenic process remains poorly understood. Here, we used an animal model of TLE and sclerotic hippocampus from patients with refractory TLE to determine whether cell-type specific activation of mTOR signaling occurs during each stage of epileptogenesis. In the TLE mouse model, we found that hyperactivation of the mTOR pathway is present in distinct hippocampal subfields at three different stages after kainate-induced seizures, and occurs in neurons of the granular and pyramidal cell layers, in reactive astrocytes, and in dispersed granule cells, respectively. In agreement with the findings in TLE mice, upregulated mTOR was observed in the sclerotic hippocampus of TLE patients. All sclerotic hippocampus (n = 13) exhibited widespread reactive astrocytes with overactivated mTOR, some of which invaded the dispersed granular layer. Moreover, two sclerotic hippocampus exhibited mTOR activation in some of the granule cells, which was accompanied by cell body hypertrophy. Taken together, our results indicate that mTOR activation is most prominent in reactive astrocytes in both an animal model of TLE and the sclerotic hippocampus from patients with drug resistant TLE

The role of inflammation in epilepsy.

Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis

The Impact of Public Budgets on Overall Productivity Growth

To fulfil their tasks, governments rely on public expenditures and taxes. Both influence the incentives and shape the decisions and actions of private economic agents. As governments resort to both instruments simultaneously, their combined theoretical impact on economic performance is a priori indeterminate. Clarification can only come from empirical evaluations. This paper reviews the recent literature trying to quantify the impact of fiscal policies on productivity and growth. Unfortunately, this survey shows that the empirical literature too is inconclusive: although the growth and composition of public expenditures and taxes as well as the fiscal stance seem to have some effect in the short run, their long-run implications cannot easily be quantified because of, e.g., reverse causation and crowding-out effects. The empirical evidence on the growth effects of government size points at a non-linear relationship: For small governments additional public expenditures seem to have a positive impact on growth, while for large governments further additions tend to be growth-retarding. It is an open question, however, where the optimum is located

Pre-treatment with the NMDA receptor glycine-binding site antagonist L-701, 324 improves pharmacosensitivity in a mouse kindling model

The glycine co-agonist binding site of the N-methyl-d-aspartat (NMDA) receptor is discussed as an interesting target for different central nervous system diseases. Antagonism at this co-agonist site has been suggested as an alternative to the use of non-competitive or competitive NMDA receptor antagonists, which are associated with a pronounced adverse effect profile in chronic epilepsy models and epilepsy patients. In the present study, we addressed the hypothesis that sub-chronic administration of the glycine-binding site antagonist L-701,324 might exert disease-modifying effects in fully kindled mice during a period with frequent seizure elicitation (massive kindling). Moreover, we analyzed whether L-701,324 exposure during this phase affects the subsequent response to an antiepileptic drug. L-701,324 treatment during the massive kindling phase did not affect ictogenesis. Mean seizure severity and cumulative seizure duration proved to be comparable between vehicle- and L-701,324-treated mice. Following withdrawal of L-701,324 seizure thresholds did not differ in a significant manner from those in animals that received vehicle injections. A low dosage of phenobarbital caused a significant increase of the generalized seizure threshold in the L-701,324 pre-treated group, whereas it did not exert a comparable effect in animals that received vehicle during the massive kindling phase. Analysis of P-glycoprotein in the hilus of the hippocampus revealed lower expression rates in L-701,324 pre-treated kindled mice. In conclusion, the data indicate that targeting of the NMDA receptor glycine-binding site does not result in anticonvulsant or disease-modifying effects. However, it might improve antiepileptic drug responses. The findings might be linked to an impact on P-glycoprotein expression. However, future studies are necessary to further evaluate the mechanisms and assess the potential of respective add-on approaches