Temporal lobe epilepsy (TLE) is frequently associated with hippocampal sclerosis, possibly caused by a primary brain injury that occurred a long time before the appearance of neurological symptoms. This type of epilepsy is characterized by refractoriness to drug treatment, so to require surgical resection of mesial temporal regions involved in seizure onset. Even this last therapeutic approach may fail in giving relief to patients. Although prevention of hippocampal damage and epileptogenesis after a primary event could be a key innovative approach to TLE, the lack of clear data on the pathophysiological mechanisms leading to TLE does not allow any rational therapy. Here we address the current knowledge on mechanisms supposed to be involved in epileptogenesis, as well as on the possible innovative treatments that may lead to a preventive approach. Besides loss of principal neurons and of specific interneurons, network rearrangement caused by axonal sprouting and neurogenesis are well known phenomena that are integrated by changes in receptor and channel functioning and modifications in other cellular components. In particular, a growing body of evidence from the study of animal models suggests that disruption of vascular and astrocytic components of the blood-brain barrier takes place in injured brain regions such as the hippocampus and piriform cortex. These events may be counteracted by drugs able to prevent damage to the vascular component, as in the case of the growth hormone secretagogue ghrelin and its analogues. A thoroughly investigation on these new pharmacological tools may lead to design effective preventive therapies.

Interleukin-1β (IL-1β) is a crucial mediator in the pathogenesis of inflammatory diseases at the periphery and in the central nervous system (CNS). Produced as an unprocessed and inactive pro-form which accumulates intracellularly, release of the processed cytokine is strongly promoted by ATP acting at the purinergic P2X7 receptor (P2X7R) in cells primed with lipopolysaccharide (LPS), a Toll-like receptor (TLR) 4 ligand. Microglia are central to the inflammatory process and a major source of IL-1β when activated. Here we show that purified (>99%) microglia cultured from rat cortex, spinal cord and cerebellum respond robustly to ATP-dependent IL-1β release, upon priming with a number of TLR isoform ligands (zymosan and Pam3CSK4 for TLR2, poly(I:C) for TLR3). Cytokine release was prevented by a P2X7R antagonist and inhibitors of stress-activated protein kinases. Enriched astrocytes (≤5% microglia) from these CNS regions displayed responses qualitatively similar to microglia but became unresponsive upon eradication of residual microglia with the lysosomotropic agent Leu-Leu-OMe. Activation of multiple TLR isoforms in nervous system pathology, coupled with elevated extracellular ATP levels and subsequent P2X7R activation may represent an important route for microglia-derived IL-1β. This phenomenon may have important consequences for neuroinflammation and its position to the common pathology of CNS diseases.

We prove existence, uniqueness and Lipschitz dependence on the initial datum for mild solutions of stochastic partial differential equations with Lipschitz coefficients driven by Wiener and Poisson noise. Under additional assumptions, we prove Gâteaux and Fréchet differentiability of solutions with respect to the initial datum. As an application, we obtain gradient estimates for the resolvent associated to the mild solution. Finally, we prove the strong Feller property of the associated semigroup.

We consider a class of optimal control problems of stochastic delay differential equations (SDDE) that arise in connection with optimal advertising under uncertainty for the introduction of a new product to the market, generalizing classical work of Nerlove and Arrow [30]. In particular, we deal with controlled SDDE where the delay enters both the state and the control. Following ideas of Vinter and Kwong [34] (which however hold only in the deterministic case), we reformulate the problem as an infinite dimensional stochastic control problem to which we associate, through the dynamic programming principle, a second order Hamilton-Jacobi-Bellman equation. We show a verification theorem and we exhibit some simple cases where such equation admits an explicit smooth solution, allowing us to construct optimal feedback controls.

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Glial cells not only serve supportive and nutritive roles for neurons, but also respond to protracted stress and insults by up-regulating inflammatory processes. The complexity of studying glial activation in vivo has led to the widespread adoption of in vitro approaches, for example the use of the bacterial toxin lipopolysaccharide (LPS, a ligand for toll-like receptor 4 (TLR4)) as an experimental model of glial activation. Astrocyte cultures frequently contain minor numbers of microglia, which can complicate interpretation of responses. In the present study, enriched (≤5% microglia) astrocytes cultured from neonatal rat cortex and spinal cord were treated with the lysosomotropic agent L-leucyl-L-leucine methyl ester to eliminate residual microglia, as confirmed by loss of microglia-specific marker genes. L-Leucyl-L-leucine methyl ester treatment led to a loss of LPS responsiveness, in terms of nitric oxide and cytokine gene up-regulation and mediator (pro-inflammatory cytokines, nitric oxide) output into the culture medium. Surprisingly, when astrocyte/microglia co-cultures were then reconstituted by adding defined numbers of purified microglia to microglia-depleted astrocytes, the LPS-induced up-regulation of pro-inflammatory gene and mediator output far exceeded that observed from cultures containing the same numbers of microglia only. Similar behaviors were found when examining interleukin-1β release caused by activation of the purinergic P2X7 receptor. Given that astrocytes greatly outnumber microglia in the central nervous system, these data suggest that a similar interaction between microglia and astrocytes in vivo may be an important element in the evolution of an inflammatory pathology.

BackgroundToll-like receptor (TLR) activation on microglia and astrocytes are key elements in neuroinflammation which accompanies a number of neurological disorders. While TLR activation on glia is well-established to up-regulate pro-inflammatory mediator expression, much less is known about how ligand engagement of one TLR may affect expression of other TLRs on microglia and astrocytes.MethodsIn the present study, we evaluated the effects of agonists for TLR2 (zymosan), TLR3 (polyinosinic-polycytidylic acid (poly(I:C)), a synthetic analogue of double-stranded RNA) and TLR4 (lipopolysaccaride (LPS)) in influencing expression of their cognate receptor as well as that of the other TLRs in cultures of rat cortical purified microglia (>99.5 %) and nominally microglia-free astrocytes. Elimination of residual microglia (a common contaminant of astrocyte cultures) was achieved by incubation with the lysosomotropic agent l-leucyl-l-leucine methyl ester (L-LME).ResultsFlow cytometric analysis confirmed the purity (essentially 100 %) of the obtained microglia, and up to 5 % microglia contamination of astrocytes. L-LME treatment effectively removed microglia from the latter (real-time polymerase chain reaction). The three TLR ligands robustly up-regulated gene expression for pro-inflammatory markers (interleukin-1 and interleukin-6, tumor necrosis factor) in microglia and enriched, but not purified, astrocytes, confirming cellular functionality. LPS, zymosan and poly(I:C) all down-regulated TLR4 messenger RNA (mRNA) and up-regulated TLR2 mRNA at 6 and 24 h. In spite of their inability to elaborate pro-inflammatory mediator output, the nominally microglia-free astrocytes (>99 % purity) also showed similar behaviours to those of microglia, as well as changes in TLR3 gene expression. LPS interaction with TLR4 activates downstream mitogen-activated protein kinase and nuclear factor-κB signalling pathways and subsequently causes inflammatory mediator production. The effects of LPS on TLR2 mRNA in both cell populations were antagonized by a nuclear factor-κB inhibitor.ConclusionsTLR2 and TLR4 activation in particular, in concert with microglia and astrocytes, comprise key elements in the initiation and maintenance of neuropathic pain. The finding that both homologous (zymosan) and heterologous (LPS, poly(I:C)) TLR ligands are capable of regulating TLR2 gene expression, in particular, may have important implications in understanding the relative contributions of different TLRs in neurological disorders associated with neuroinflammation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0458-6) contains supplementary material, which is available to authorized users.

Oligodendrogenesis and oligodendrocyte precursor maturation are essential processes during the course of central nervous system development, and lead to the myelination of axons. Cells of the oligodendrocyte lineage are generated in the germinal zone from migratory bipolar oligodendrocyte precursor cells (OPCs), and acquire cell surface markers as they mature and respond specifically to factors which regulate proliferation, migration, differentiation, and survival. Loss of myelin underlies a wide range of neurological disorders, some of an autoimmune nature—multiple sclerosis probably being the most prominent. Current therapies are based on the use of immunomodulatory agents which are likely to promote myelin repair (remyelination) indirectly by subverting the inflammatory response, aspects of which impair the differentiation of OPCs. Cells of the oligodendrocyte lineage express and are capable of responding to a diverse array of ligand-receptor pairs, including neurotransmitters and nuclear receptors such as γ-aminobutyric acid, glutamate, adenosine triphosphate, serotonin, acetylcholine, nitric oxide, opioids, prostaglandins, prolactin, and cannabinoids. The intent of this review is to provide the reader with a synopsis of our present state of knowledge concerning the pharmacological properties of the oligodendrocyte lineage, with particular attention to these receptor-ligand (i.e., neurotransmitters and nuclear receptor) interactions that can influence oligodendrocyte migration, proliferation, differentiation, and myelination, and an appraisal of their therapeutic potential. For example, many promising mediators work through Ca2+ signaling, and the balance between Ca2+ influx and efflux can determine the temporal and spatial properties of oligodendrocytes (OLs). Moreover, Ca2+ signaling in OPCs can influence not only differentiation and myelination, but also process extension and migration, as well as cell death in mature mouse OLs. There is also evidence that oligodendroglia exhibit Ca2+ transients in response to electrical activity of axons for activity-dependent myelination. Cholinergic antagonists, as well as endocannabinoid-related lipid-signaling molecules target OLs. An understanding of such pharmacological pathways may thus lay the foundation to allow its leverage for therapeutic benefit in diseases of demyelination.