30 research outputs found
Implications of antiinflammatory properties of the anticonvulsant drug levetiracetam in astrocytes
No full textThere is accumulating evidence that epileptic activity is accompanied by inflammatory processes. In the present study, we evaluated the effect of levetiracetam (Keppra), an anticonvulsant drug with decisive antiepileptic features, with regard to its putative antiinflammatory potential. We previously established an in vitro cell culture model to mimic inflammatory conditions: Primary astrocytic cultures of newborn rats were cocultured with 30% (M30) microglial cells. Alternatively, co-cultures containing 5% microglia (M5) were incubated with the proinflammatory mediator, the cytokine interleukin-1 beta (IL-1 beta), and lipopolysaccharide (LPS), a potent bacterial activator of the immune system. For the M30 cocultures, we observed reduced expression of connexin 43 (Cx43), the predominant gap junction protein. Impaired functional dye coupling and depolarized membrane resting potential (MRP) were monitored in M30 cocultures as well as in M5 cocultures treated with IL-1 beta and LPS. We could show that the Cx43 expression, the coupling property, and the membrane resting potential on which we focused our inflammatory coculture model were normalized to noninflammatory level under treatment with levetiracetam (Keppra). Cumulatively, our results provide evidence for antiinflammatory properties of levetiracetam in seizure treatment. (c) 2008 Wiley-Liss, Inc
Optimal ecosystem management with structural dynamics
No full textWe address the problem of optimal management of a self organizing ecosystem along ecological succession. A dynamic carrying capacity is interpreted as depicting the dynamics of habitat creation and occupation along ecological succession. The ecosystem may have three growth modes: pure compensation (concave ecosystem regeneration function), depensation (convex-concave regeneration function) and critical depensation (additionally having negative growth rates for low biomass). We analyse the optimal policies for the management of the ecosystem for the three growth modes. Accordingly, we prove the existence of a Skiba points for certain types of ecosystems. Further, we compare usual golden rule paths with the derived optimal policies near the Skiba points.Ecosystem management; habitat creation; optimal policies; Skiba point
The potential role of astroglial GABAA receptors in autoimmune encephalitis associated with GABAA receptor antibodies and seizures
No full textAbstract The γ‐aminobutyric acid (GABA) is the main inhibitory transmitter in the central nervous system and GABA receptors mediate the inhibitory synaptic transmission. GABA binding to neuronal GABAAR leads to a rapid hyperpolarization and a higher excitation threshold due to an increase in membrane Cl− permeability. The synaptic GABAAR is mostly composed of two α(1–3), two β, and one γ subunit with the most abundant configuration α1β2γ2. Recently, antibodies (Abs) against α1, β3, and γ2 subunits of GABAAR were detected in a severe form of autoimmune encephalitis with refractory seizures, status epilepticus, and multifocal brain lesions, affecting gray and white matter. Experimental studies confirmed multiple mechanisms and direct functional effects of GABAAR Abs on neurons with decreased GABAergic synaptic transmission and increased neuronal excitability. The expression of GABAAR on astrocytes is well established. However, extensive studies about the effects of autoimmune GABAAR Abs on astrocytic GABAAR are missing. We hypothesize that GABAAR Abs may lead additionally to blocking astrocytic GABAARs with impaired Ca2+ homeostasis/spreading, astrocytic Cl− imbalance, dysfunction of astrocyte‐mediated gliotransmission (e.g., decreased adenosine levels) and accumulation of excitatory neurotransmission, all this contributing to seizures, variable clinical/MRI presentations, and severity. The most abundant expressed GABAAR subunits in rodent astrocytes are α1, α2, β1, β3, and γ1 localized in both white and gray matter. Data about GABAAR subunits in human astrocytes are even more limited, comprising α2, β1, and γ1. Overlapping binding of GABAAR Abs to neuronal and astroglial receptors is still possible. In vitro and in vivo animal models can be helpful to test the effects of GABAAR Abs on glia. This is from an epileptological point of view relevant because of the increasing evidence, confirming the glial involvement in the pathogenesis of epilepsy. Taken together, autoimmune disorders are complex and multiple mechanisms including glia could contribute to the pathogenesis of GABAAR encephalitis with seizures
Experimental investigations of antiepileptic drugs in astrocytes‐microglia co‐cultures suggest possible protective effects on astrocytes during early epileptogenesis
No full text
Inhibition of Microglial Activation by Amitriptyline and Doxepin in Interferon-β Pre-Treated Astrocyte–Microglia Co-Culture Model of Inflammation
No full textDepression may occur in patients with multiple sclerosis, especially during interferon-β (IFN-β) treatment, and therapy with antidepressants may be necessary. Interactions of IFN-β with antidepressants concerning glia-mediated inflammation have not yet been studied. Primary rat co-cultures of astrocytes containing 5% (M5, consistent with “physiological” conditions) or 30% (M30, consistent with “pathological, inflammatory” conditions) of microglia were incubated with 10 ng/mL amitriptyline or doxepin for 2 h, or with 2000 U/mL IFN-β for 22 h. To investigate the effects of antidepressants on IFN-β treatment, amitriptyline or doxepin was added to IFN-β pre-treated co-cultures. An MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to measure the glial cell viability, immunocytochemistry was performed to evaluate the microglial activation state, and ELISA was performed to measure pro-inflammatory TNF-α and IL-6 cytokine concentrations. Incubation of inflammatory astrocyte–microglia co-cultures with amitriptyline, doxepin or IFN-β alone, or co-incubation of IFN-β pre-treated co-cultures with both antidepressants, significantly reduced the extent of inflammation, with the inhibition of microglial activation. TNF-α and IL-6 levels were not affected. Accordingly, the two antidepressants did not interfere with the anti-inflammatory effect of IFN-β on astrocytes and microglia. Furthermore, no cytotoxic effects on glial cells were observed. This is the first in vitro study offering novel perspectives in IFN-β treatment and accompanying depression regarding glia
Influence of antipsychotic drugs on microglia-mediated neuroinflammation in schizophrenia: perspectives in an astrocyte–microglia co-culture model
No full textSchizophrenia is a severe mental disorder with a strong lifetime impact on patients’ health and wellbeing. Usually, symptomatic treatment includes typical or atypical antipsychotics. Study findings show an involvement of low-grade inflammation (blood, brain parenchyma, and cerebrospinal fluid) in schizophrenia. Moreover, experimental and neuropathological evidence suggests that reactive microglia, which are the main resident immune cells of the central nervous system (CNS), have a negative impact on the differentiation and function of oligodendrocytes, glial progenitor cells, and astrocytes, which results in the disruption of neuronal networks and dysregulated synaptic transmission, contributing to the pathophysiology of schizophrenia. Here, the role of microglial cells related to neuroinflammation in schizophrenia was discussed to be essential. This review aims to summarize the evidence for the influence of antipsychotics on microglial inflammatory mechanisms in schizophrenia. Furthermore, we propose an established astrocyte–microglia co-culture model for testing regulatory mechanisms and examining the effects of antipsychotics on glia-mediated neuroinflammation. This could lead to a better understanding of how typical and atypical antipsychotics can be used to address positive and negative symptoms in schizophrenia and comorbidities like inflammatory diseases or the status of low-grade inflammation
