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Medicamentos anticonvulsivos; Cenobamato; Eficiencia Medicaments anticonvulsius; Cenobamat; Eficiència Anti-seizure medications; Cenobamate; Efficiency Introduction Epilepsy is a serious neurological disease, ranking high in the top causes of disability. The main goal of its treatment is to achieve seizure freedom without intolerable adverse effects. However, approximately 40% of patients suffer from Drug-Resistant Epilepsy (DRE) despite the availability of the latest options called third-generation Anti-Seizure Medications(ASMs). Cenobamate is the first ASM approved in Spain for the adjunctive treatment of Focal-Onset Seizures (FOS) in adult patients with DRE. The introduction of a new drug increases the number of therapeutic options available, making it important to compare it with existing alternatives in terms of clinical benefit and efficiency. Purpose This study aimed to compare the clinical benefit, in terms of the Number Needed to Treat (NNT), and the efficiency, in terms of Cost per NNT (CNT), associated with cenobamate versus third-generation ASMs used in Spain for the adjunctive treatment of FOS in patients with DRE. Methods The Number Needed to Treat data was calculated based on the ≥50% responder rate and seizure freedom endpoints (defined as the percentage of patients achieving 50% and 100% reduction in seizure frequency, respectively), obtained from pivotal clinical trials performed with cenobamate, brivaracetam, perampanel, lacosamide, and eslicarbazepine acetate. The NNT was established as the inverse of the treatment responder rate minus the placebo responder rate and was calculated based on the minimum, mid-range Daily Defined Dose (DDD), and maximum doses studied in the pivotal clinical trials of each ASM. CNT was calculated by multiplying the annual treatment cost by NNT values for each treatment option. Results In terms of NNT, cenobamate was the ASM associated with the lowest values at all doses for both ≥50% responder rate and seizure freedom compared with the alternatives. In terms of CNT, for ≥50% responder rate, cenobamate was the ASM associated with the lowest CNT values at DDD and lacosamide and eslicarbazepine acetate at the minimum and maximum dose, respectively. For seizure freedom, cenobamate was associated with the lowest CNT value at DDD and the maximum dose and lacosamide at the minimum dose. Conclusions Cenobamate could represent the most effective ASM in all doses studied compared to the third-generation ASMs and the most efficient option at DDD for both ≥50% responder rate and seizure freedom. This study could represent an important contribution towards informed decision-making regarding the selection of the most appropriate therapy for FOS in adult patients with DRE from a clinical and economical perspective in Spain. This study was sponsored by Angelini Pharma España, S.L.U.

Insulin (IR) and insulin-like growth factor I (IGF-IR) receptors share structural homology and can form hybrid heterodimers. While different observations suggest that hybrid receptors are important in physiology and pathology, little is known about their function in the brain. To gain further insight into the role of IR/IGF-IR hybrids in this organ, we analyzed their cellular distribution in the mouse brain. We combined proximity ligation assays (PLA) for IR and IGF-IR, a technique that detects close protein-protein interactions, with immunocytochemistry for brain cell markers to identify IR/IGF-IR hybrids in the major types of brain cells. Intriguingly, while all the types of brain cells analyzed co-express both receptors, only neurons, astroglia, and microglia show readily detectable IR/IGF-IR hybrids. Hybrid PLA signal was negligible in brain endothelial cells and was absent in oligodendrocytes. Hybrids were comparatively more abundant in neurons and peaked after brain development was completed. Cell-specific expression and greater abundance in the adult brain suggests specialized actions of IR/IGF-IR hybrids in this organ, particularly in neurons., This work was funded by grants SAF2013-40710-R (MINECO,Spain), S2017/BMD-3700 (NEUROMETAB-CM) from Comunidad de Madrid co-financed with the Structural Funds of the European Union,and by Inter-CIBER (PIE14/00061).

Inherited neurodegenerative diseases such as Friedreich's ataxia (FRDA), produced by deficiency of the mitochondrial chaperone frataxin (Fxn), shows specific neurological deficits involving different subset of neurons even though deficiency of Fxn is ubiquitous. Because astrocytes are involved in neurodegeneration, we analyzed whether they are also affected by frataxin deficiency and contribute to the disease. We also tested whether insulin-like growth factor I (IGF-I), that has proven effective in increasing frataxin levels both in neurons and in astrocytes, also exerts in vivo protective actions. Using the GFAP promoter expressed by multipotential stem cells during development and mostly by astrocytes in the adult, we ablated Fxn in a time-dependent manner in mice (FGKO mice) and found severe ataxia and early death when Fxn was eliminated during development, but not when deleted in the adult. Analysis of underlying mechanisms revealed that Fxn deficiency elicited growth and survival impairments in developing cerebellar astrocytes, whereas forebrain astrocytes grew normally. A similar time-dependent effect of frataxin deficiency in astrocytes was observed in a fly model. In addition, treatment of FGKO mice with IGF-I improved their motor performance, reduced cerebellar atrophy, and increased survival. These observations indicate that a greater vulnerability of developing cerebellar astrocytes to Fxn deficiency may contribute to cerebellar deficits in this inherited disease. Our data also confirm a therapeutic benefit of IGF-I in early FRDA deficiency., This work was supported by Spanish Ministry of Science (SAF2010–60051/SAF2013–40710-R), by CIBERNED, and by the Elitenetzwerk Bayern.

Brain activity requires a flux of glucose to active regions to sustain increased metabolic demands. Insulin, the main regulator of glucose handling in the body, has been traditionally considered not to intervene in this process. However, we now report that insulin modulates brain glucose metabolism by acting on astrocytes in concert with IGF-I. The cooperation of insulin and IGF-I is needed to recover neuronal activity after hypoglycemia. Analysis of underlying mechanisms show that the combined action of IGF-I and insulin synergistically stimulates a mitogen-activated protein kinase/protein kinase D pathway resulting in translocation of GLUT1 to the cell membrane through multiple protein-protein interactions involving the scaffolding protein GAIP-interacting protein C terminus and the GTPase RAC1. Our observations identify insulin-like peptides as physiological modulators of brain glucose handling, providing further support to consider the brain as a target organ in diabetes., This work was funded by MINECO (Spain) grants SAF2010-60051 and SAF2013-40710-R, and by CIBERNED. E.H.-G. was partially funded by a fellowship from ColFuturo and CIBERNED. T.I. is funded by MINECO (SAF2014-52737-P). T.I. and I.T.A. are funded by CIBERNED and Comunidad de Madrid, Spain (P2010/BMD-2331-Neurodegmodels).

The decision between cellular survival and death is governed by a balance between proapoptotic versus antiapoptotic signaling cascades. Growth factors are key actors, playing two main roles both at developmental and adult stages: a supporting antiapoptotic role through diverse actions converging in the mitochondria, and a promoter role of cell maturation and plasticity through dendritogenesis and synaptogenesis, especially relevant for the adult hippocampal neurogenesis, a case of development during adulthood. Here, both parallel roles mutually feed forward each other (the success in avoiding apoptosis lets the cell to grow and differentiate, which in turn lets the cell to reach new targets and form new synapses accessing new sources of growth factors to support cell survival) in a circular cause and consequence, or a >the chicken or the egg> dilemma. While identifying the first case of this dilemma makes no sense, one possible outcome might have biological relevance: the decision between survival and death in the adult hippocampal neurogenesis is mainly concentrated at a specific time window, and recent data suggest some divergences between the survival and the maturational promoter effect of growth factors. This review summarizes these evidences suggesting how growth factors might contribute to the live-or-die decision of adult-born immature granule neurons through influencing the maturation of the young neuron by means of its connectivity into a mature functional circuit. © 2013 Elsevier B.V.

Glycogen synthase kinase 3 (GSK-3) is a constitutively active kinase that has been implicated in the mechanism of action of mood stabilizers. According to the neurogenic hypothesis of depression, newborn neurons in the adult dentate gyrus are required for the antidepressant effects of certain agents. We demonstrate that administration of the GSK-3 inhibitor VP2.51 (2.5 mg/kg ip, for 3.5 weeks) increases cell proliferation (pH3+ cells), as well as the short- and long-term survival of newborn neurons (assessed by the 24 h survival of BrdU+ and DCX+ neurons), while significantly increasing the commitment of cells to the granule neuron lineage (Prox1 immunoreactivity). In parallel, VP2.51 induces a net antidepressant effect, as judged by the decrease in the immobility time in the forced swim test of naive mice (non-stressed mice), as well as a therapeutic effect on previously stressed mice (Porsolt-induced stress). Interestingly, the morphological changes were found prominently in the ventral region of the hippocampus. We found that these effects are neurogenesis dependent by combining the antimitotic temozolomide (50 mg/kg ip) with the drug. Importantly VP2.51 did not provoke changes in weight or in a battery of behavioral tests (learning/memory and activity tests). As the effects of VP2.51 were concomitant with the increase in β-catenin expression and a shift towards the inactive form of GSK-3, we suggest that VP2.51 has therapeutic benefits following stress, and it may be a preventive treatment in situations where a potential depressive state and/or loss of memory is associated with diminished neurogenesis, through selective GSK3-beta inhibition.

The influence of the learning process on the persistence of the newly acquired behavior is relevant both for our knowledge of the learning/memory mechanisms and for the educational policy. However, it is unclear whether during an operant conditioning process with a continuous reinforcement paradigm, individual differences in acquisition are also associated to differences in persistence of the acquired behavior. In parallel, adult neurogenesis has been implicated in spatial learning and memory, but the specific role of the immature neurons born in the adult brain is not well known for this process. We have addressed both questions by analyzing the relationship between water maze task acquisition scores, the persistence of the acquired behavior, and the size of the different subpopulations of immature neurons in the adult murine hippocampus. We have found that task acquisition and persistence rates were negatively correlated: the faster the animals find the water maze platform at the end of acquisition stage, the less they persist in searching for it at the learned position in a subsequent non-reinforced trial; accordingly, the correlation in the number of some new neurons' subpopulations and the acquisition rate is negative while with persistence in acquired behavior is positive. These findings reveal an unexpected relationship between the efficiency to learn a task and the persistence of the new behavior after a non-reinforcement paradigm, and suggest that the immature neurons might be involved in different roles in acquisition and persistence/extinction of a learning task. © 2016 Wiley Periodicals, Inc.

The influence of the learning process on the persistence of the newly acquired behavior is relevant both for our knowledge of the learning/memory mechanisms and for the educational policy. However, it is unclear whether during an operant conditioning process with a continuous reinforcement paradigm, individual differences in acquisition are also associated to differences in persistence of the acquired behavior. In parallel, adult neurogenesis has been implicated in spatial learning and memory, but the specific role of the immature neurons born in the adult brain is not well known for this process. We have addressed both questions by analyzing the relationship between water maze task acquisition scores, the persistence of the acquired behavior, and the size of the different subpopulations of immature neurons in the adult murine hippocampus. We have found that task acquisition and persistence rates were negatively correlated: the faster the animals find the water maze platform at the end of acquisition stage, the less they persist in searching for it at the learned position in a subsequent non-reinforced trial; accordingly, the correlation in the number of some new neurons' subpopulations and the acquisition rate is negative while with persistence in acquired behavior is positive. These findings reveal an unexpected relationship between the efficiency to learn a task and the persistence of the new behavior after a non-reinforcement paradigm, and suggest that the immature neurons might be involved in different roles in acquisition and persistence/extinction of a learning task. © 2016 Wiley Periodicals, Inc.