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Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.

It is known that the thalamus plays an important role in pathological brain conditions involved in demyelinating, inflammatory and neurodegenerative diseases such as Multiple Sclerosis (MS). Beside immune cells and cytokines, ion channels were found to be key players in neuroinflammation. MS is a prototypical example of an autoimmune disease of the central nervous system that is classified as a channelopathy where abnormal ion channel function leads to symptoms and clinical signs. Here we review the influence of the cytokine-ion channel interaction in the thalamocortical system in demyelination and inflammation., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

Background: Seizures and epilepsy may substantially add to the burden of disease in multiple sclerosis (MS), whereas the exact prevalence and prognosis of seizures and epilepsy in patients with MS remains largely unknown., Objectives: We aimed to investigate the epidemiology and prognosis of seizures and epilepsy in MS., Methods: We retrospectively analyzed a cohort of 4078 MS patients from a single tertiary referral clinic., Results: After excluding 37 patients with unconfirmed MS and alternative seizure etiologies, we found seizures attributable to MS in 1.5% and epilepsy in 0.9% of patients. 40.4% of patients with a follow-up of at least twelve months experienced only a single seizure and 59.6% had recurring seizures. 39% of patients with recurrent seizures were considered drug-resistant, with 9.7% experiencing status epilepticus. Seizure recurrence after a first seizure depended significantly on the MS subtype and was seen more often if the first seizure occurred simultaneously with a MS relapse than in the absence of a relapse., Conclusion: Our study shows a lower number of seizures and epilepsy in MS than previously reported. While a single seizure in MS usually has a good prognosis, relapse-associated seizures and established epilepsy in MS may not be as benign as previously assumed.

Alterations in cortical cellular organization, network functionality, as well as cognitive and locomotor deficits were recently suggested to be pathological hallmarks in multiple sclerosis and corresponding animal models as they might occur following demyelination. To investigate functional changes following demyelination in a well-defined, topographically organized neuronal network, in vitro and in vivo, we focused on the primary auditory cortex (A1) of mice in the cuprizone model of general de- and remyelination. Following myelin loss in this model system, the spatiotemporal propagation of incoming stimuli in A1 was altered and the hierarchical activation of supra- and infragranular cortical layers was lost suggesting a profound effect exerted on neuronal network level. In addition, the response latency in field potential recordings and voltage-sensitive dye imaging was increased following demyelination. These alterations were accompanied by a loss of auditory discrimination abilities in freely behaving animals, a reduction of the nuclear factor-erythroid 2-related factor-2 (Nrf-2) protein in the nucleus in histological staining and persisted during remyelination. To find new strategies to restore demyelination-induced network alteration in addition to the ongoing remyelination, we tested the cytoprotective potential of dimethyl fumarate (DMF). Therapeutic treatment with DMF during remyelination significantly modified spatiotemporal stimulus propagation in the cortex, reduced the cognitive impairment, and prevented the demyelination-induced decrease in nuclear Nrf-2. These results indicate the involvement of anti-oxidative mechanisms in regulating spatiotemporal cortical response pattern following changes in myelination and point to DMF as therapeutic compound for intervention.

Members of the two-pore domain K(+) channel (K2P) family are increasingly recognized as being potential targets for therapeutic drugs and could play a role in the diagnosis and treatment of neurologic disorders. Their broad and diverse expression pattern in pleiotropic cell types, importance in cellular function, unique biophysical properties, and sensitivity toward pathophysiologic parameters represent the basis for their involvement in disorders of the central nervous system (CNS). This review will focus on multiple sclerosis (MS) and stroke, as there is growing evidence for the involvement of K2P channels in these two major CNS disorders. In MS, TASK1-3 channels are expressed on T lymphocytes and are part of a signaling network regulating Ca(2+)- dependent pathways that are mandatory for T cell activation, differentiation, and effector functions. In addition, TASK1 channels are involved in neurodegeneration, resulting in autoimmune attack of CNS cells. On the blood-brain barrier, TREK1 channels regulate immune cell trafficking under autoinflammatory conditions. Cerebral ischemia shares some pathophysiologic similarities with MS, including hypoxia and extracellular acidosis. On a cellular level, K2P channels can have both proapoptotic and antiapoptotic effects, either promoting neurodegeneration or protecting neurons from ischemic cell death. TASK1 and TREK1 channels have a neuroprotective effect on stroke development, whereas TASK2 channels have a detrimental effect on neuronal survival under ischemic conditions. Future research in preclinical models is needed to provide a more detailed understanding of the contribution of K2P channel family members to neurologic disorders, before translation to the clinic is an option.

Objective: Activation of T cells critically depends on potassium channels. We here characterize the impact of K(2P)5.1 (KCNK5; TASK2), a member of the 2-pore domain family of potassium channels, on T-cell function and demonstrate its putative relevance in a T-cell-mediated autoimmune disorder, multiple sclerosis (MS)., Methods: Expression of K(2P)5.1 was investigated on RNA and protein level in different immune cells and in MS patients' biospecimens (peripheral blood mononuclear cells, cerebrospinal fluid cells, brain tissue specimen). Functional consequences of K(2P)5.1 expression were analyzed using pharmacological modulation, small interfering RNA (siRNA), overexpression, electrophysiological recordings, and computer modeling., Results: Human T cells constitutively express K(2P)5.1. After T-cell activation, a significant and time-dependent upregulation of K(2P)5.1 channel expression was observed. Pharmacological blockade of K(2P)5.1 or knockdown with siRNA resulted in reduced T-cell functions, whereas overexpression of K(2P)5.1 had the opposite effect. Electrophysiological recordings of T cells clearly dissected K(2P)5.1-mediated effects from other potassium channels. The pathophysiological relevance of these findings was demonstrated by a significant K(2P)5.1 upregulation in CD4(+) and CD8(+) T cells in relapsing/remitting MS (RRMS) patients during acute relapses as well as higher levels on CD8(+) T cells of clinically isolated syndrome, RRMS, and secondary progressive multiple sclerosis patients during clinically stable disease. T cells in the cerebrospinal fluid from MS patients exhibit significantly elevated K(2P)5.1 levels. Furthermore, K(2P)5.1-positive T cells can be found in inflammatory lesions in MS tissue specimens., Interpretation: Selective targeting of K(2P)5.1 may hold therapeutic promise for MS and putatively other T-cell-mediated disorders.

Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are characterized by T cell-mediated autoimmune inflammation of the central nervous system (CNS) leading to oligodendrocyte loss and demyelination accompanied by neuronal cell death. Neuronal TWIK-related acid-sensitive potassium (TASK) channels allow the regulated efflux of potassium ions. These channels might either protect neurons in the inflamed CNS by modulating electrical excitability or even contribute to inflammatory neurodegeneration mediating intracellular potassium depletion. Using a combination of in-situ-hybridisation and immunofluorescence staining, we found increased neuronal expression of TASK1 and TASK3 channels in the optic nerve and decreased expression in the spinal cord and thalamus of rats undergoing MOG-induced EAE. Inflammatory plaques of human MS patients displayed profoundly lowered expression of both TASK isoforms. Thus, regulated expression of TASK channels might contribute to a molecular switch between death and survival of neurons in autoimmune CNS inflammation.

Background/Aims: Multiple sclerosis (MS) is a prototypical autoimmune central nervous system (CNS) disease. Particularly progressive forms of MS (PMS) show significant neuroaxonal damage as consequence of demyelination and neuronal hyperexcitation. Immuno-modulatory treatment strategies are beneficial in relapsing MS (RMS), but mostly fail in PMS. Pregabalin (Lyrica®) is prescribed to MS patients to treat neuropathic pain. Mechanistically, it targets voltage-dependent Ca2+ channels and reduces harmful neuronal hyperexcitation in mouse epilepsy models. Studies suggest that GABA analogues like pregabalin exert neuroprotective effects in animal models of ischemia and trauma. Methods: We tested the impact of pregabalin in a mouse model of MS (experimental autoimmune encephalomyelitis, EAE) and performed histological and immunological evaluations as well as intravital two-photon-microscopy of brainstem EAE lesions. Results: Both prophylactic and therapeutic treatments ameliorated the clinical symptoms of EAE and reduced immune cell infiltration into the CNS. On neuronal level, pregabalin reduced long-term potentiation in hippocampal brain slices indicating an impact on mechanisms of learning and memory. In contrast, T cells, microglia and brain endothelial cells were unaffected by pregabalin. However, we found a direct impact of pregabalin on neurons during CNS inflammation as it reversed the pathological elevation of neuronal intracellular Ca2+ levels in EAE lesions. Conclusion: The presented data suggest that pregabalin primarily acts on neuronal Ca2+ channel trafficking thereby reducing Ca2+-mediated cytotoxicity and neuronal damage in an animal model of MS. Future clinical trials need to assess the benefit for neuronal survival by expanding the indication for pregabalin administration to MS patients in further disease phases. [ABSTRACT FROM AUTHOR]

K2P5.1 channels (also called TASK-2 or Kcnk5) have already been shown to be relevant in the pathophysiology of autoimmune disease because they are known to be upregulated on peripheral and central T lymphocytes of multiple sclerosis (MS) patients. Moreover, overexpression of K2P5.1 channels in vitro provokes enhanced T-cell effector functions. However, the molecular mechanisms regulating intracellular K2P5.1 channel trafficking are unknown so far. Thus, the aim of the study is to elucidate the trafficking of K2P5.1 channels on T lymphocytes. Using mass spectrometry analysis, we have identified 14-3-3 proteins as novel binding partners of K2P5.1 channels. We show that a non-classical 14-3-3 consensus motif (R-X-X-pT/S-x) at the channel's C-terminus allows the binding between K2P5.1 and 14-3-3. The mutant K2P5.1/S266A diminishes the protein-protein interaction and reduces the amplitude of membrane currents. Application of a non-peptidic 14-3-3 inhibitor (BV02) significantly reduces the number of wild-type channels in the plasma membrane, whereas the drug has no effect on the trafficking of the mutated channel. Furthermore, blocker application reduces T-cell effector functions. Taken together, we demonstrate that 14-3-3 interacts with K2P5.1 and plays an important role in channel trafficking. [ABSTRACT FROM AUTHOR]

Background: Demyelination and remyelination are common pathological processes in many neurological disorders, including multiple sclerosis (MS). Clinical evidence suggests extensive involvement of the thalamocortical (TC) system in patients suffering from MS.Methods: Using murine brain slices of the primary auditory cortex, we investigated the functional consequences of cuprizone-induced de- and remyelination on neuronal activity and auditory TC synaptic transmission in vitro.Results: Our results revealed an impact of myelin loss and restoration on intrinsic cellular firing patterns, synaptic transmission, and neuronal plasticity in layer 3 and 4 neurons of the auditory TC network. While there was a complex hyper- and depolarizing shift of the resting membrane potential, spontaneous and induced action potential firing was reduced during demyelination and early remyelination. In addition, excitatory postsynaptic potential amplitudes were decreased and induction of LTP was reduced during demyelination.Conclusions: These data indicate that demyelination-induced impairment of neurons and network activity within the TC system may underlie clinical symptoms observed in demyelinating diseases, corroborating human findings that disease progression is significantly correlated with microstructural tissue damage of the TC system. Further investigation into focal inflammation-induced demyelination models ex vivo and in vivo are needed to understand the functional implication of local and remote lesion formation on TC network activity in MS. [ABSTRACT FROM AUTHOR]

Members of the two-pore domain K channel (K) family are increasingly recognized as being potential targets for therapeutic drugs and could play a role in the diagnosis and treatment of neurologic disorders. Their broad and diverse expression pattern in pleiotropic cell types, importance in cellular function, unique biophysical properties, and sensitivity toward pathophysiologic parameters represent the basis for their involvement in disorders of the central nervous system (CNS). This review will focus on multiple sclerosis (MS) and stroke, as there is growing evidence for the involvement of K channels in these two major CNS disorders. In MS, TASK1-3 channels are expressed on T lymphocytes and are part of a signaling network regulating Ca- dependent pathways that are mandatory for T cell activation, differentiation, and effector functions. In addition, TASK1 channels are involved in neurodegeneration, resulting in autoimmune attack of CNS cells. On the blood-brain barrier, TREK1 channels regulate immune cell trafficking under autoinflammatory conditions. Cerebral ischemia shares some pathophysiologic similarities with MS, including hypoxia and extracellular acidosis. On a cellular level, K channels can have both proapoptotic and antiapoptotic effects, either promoting neurodegeneration or protecting neurons from ischemic cell death. TASK1 and TREK1 channels have a neuroprotective effect on stroke development, whereas TASK2 channels have a detrimental effect on neuronal survival under ischemic conditions. Future research in preclinical models is needed to provide a more detailed understanding of the contribution of K channel family members to neurologic disorders, before translation to the clinic is an option. [ABSTRACT FROM AUTHOR]

Abstract: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by widespread inflammation, focal demyelination and a variable degree of axonal and neuronal loss. Ionic conductances regulate T cell activation as well as neuronal function and thus have been found to play a crucial role in MS pathogenesis. Since present therapeutical approaches are only partially effective so far, ion channel modulation as a future strategy was brought into focus. Here, we review the status quo concerning recent findings from ion channel research in MS and its animal model, experimental autoimmune encephalomyelitis. [Copyright &y& Elsevier]

We provide evidence that TWIK-related acid-sensitive potassium channel 1 (TASK1), a member of the family of two-pore domain potassium channels relevant for setting the resting membrane potential and balancing neuronal excitability that is expressed on T cells and neurons, is a key modulator of T cell immunity and neurodegeneration in autoimmune central nervous system inflammation. After induction of experimental autoimmune encephalomyelitis, an experimental model mimicking multiple sclerosis, TASK1−/− mice showed a significantly reduced clinical severity and markedly reduced axonal degeneration compared with wild-type controls. T cells from TASK1−/− mice displayed impaired T cell proliferation and cytokine production, while the immune repertoire is otherwise normal. In addition to these effects on systemic T cell responses, TASK1 exhibits an independent neuroprotective effect which was demonstrated using both a model of acutely prepared brain slices cocultured with activated T cells as well as in vitro cultivation experiments with isolated optic nerves. Anandamide, an endogenous cannabinoid and inhibitor of TASK channels, reduced outward currents and inhibited effector functions of T cells (IFN-γ production and proliferation); an effect completely abrogated in TASK1−/− mice. Accordingly, preventive blockade of TASK1 significantly ameliorated experimental autoimmune encephalomyelitis after immunization. Therapeutic application of anandamide significantly reduced disease severity and was capable of lowering progressive loss of brain parenchymal volume as assessed by magnetic resonance imaging. These data support the identification and characterization of TASK1 as potential molecular target for the therapy of inflammatory and degenerative central nervous system disorders. [ABSTRACT FROM PUBLISHER]

Inflammation and demyelination both contribute to the neurological deficits characteristic of multiple sclerosis. Neurological dysfunctions are attributable to inflammatory demyelination and, in addition, to soluble factors such as nitric oxide, cytokines and antibodies. QYNAD, an endogenous pentapeptide identified in the cerebrospinal fluid of patients with demyelinating disorders, has been proposed to promote axonal dysfunction by blocking sodium channels. The present study aimed at characterizing the properties of QYNAD in acutely isolated thalamic neurons in vitro. QYNAD, but not a scrambled peptide (NYDQA), blocked sodium channels in neurons by shifting the steady-state inactivation to more negative potentials. Blocking properties followed a dose–response curve with a maximum effect at 10 µ m. A fluorescently labelled QYNAD analogue with retained biological activity specifically stained thalamic neurons, positive for type II sodium channels, thus demonstrating the specificity of QYNAD binding. Our study confirms and extends previous observations describing QYNAD as a potent sodium channel-blocking agent. These data as well as our preliminary observations in in vivo experiments in an animal model of inflammatory CNS demyelination warrant further in vivo studies in order to clarify the exact pathogenetic role of QYNAD in inflammatory neurological diseases. [ABSTRACT FROM AUTHOR]

Cyclic GMP-AMP-synthase is a sensor of endogenous nucleic acids, which subsequently elicits a stimulator of interferon genes (STING)-dependent type I interferon (IFN) response defending us against viruses and other intracellular pathogens. This pathway can drive pathological inflammation, as documented for type I interferonopathies. In contrast, specific STING activation and subsequent IFN-β release have shown beneficial effects on experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Although less severe cases of relapse-remitting MS (RRMS) are treated with IFN-β, there is little information correlating aberrant type I IFN signaling and the pathologic conditions of MS. We hypothesized that there is a link between STING activation and the endogenous production of IFN-β during neuroinflammation. Gene expression analysis in EAE mice showed that Sting level decreased in the peripheral lymphoid tissue, while its level increased within the central nervous system over the course of the disease. Similar patterns could be verified in peripheral immune cells during the acute phases of RRMS in comparison to remitting phases and appropriately matched healthy controls. Our study is the first to provide evidence that the STING/IFN-β-axis is downregulated in RRMS patients, meriting further intensified research to understand its role in the pathophysiology of MS and potential translational applications. [ABSTRACT FROM AUTHOR]

Cuprizone (CPZ)-induced alterations in axonal myelination are associated with a period of neuronal hyperexcitability and increased activity of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels in the thalamocortical (TC) system. Substances used for the treatment of multiple sclerosis (MS) have been shown to normalize neuronal excitability in CPZ-treated mice. Therefore, we aimed to examine the effects of diroximel fumarate (DRF) and the sphingosine 1-phospate receptor (S1PR) modulator siponimod on action potential firing and the inward current (I h) carried by HCN ion channels in naive conditions and during different stages of de- and remyelination. Here, DRF application reduced I h current density in ex vivo patch clamp recordings from TC neurons of the ventrobasal thalamic complex (VB), thereby counteracting the increase of I h during early remyelination. Siponimod reduced I h in VB neurons under control conditions but had no effect in neurons of the auditory cortex (AU). Furthermore, siponimod increased and decreased AP firing properties of neurons in VB and AU, respectively. Computational modeling revealed that both DRF and siponimod influenced thalamic bursting during early remyelination by delaying the onset and decreasing the interburst frequency. Thus, substances used in MS treatment normalize excitability in the TC system by influencing AP firing and I h. • Axonal de- and remyelination influence neuronal excitability and Ih currents. • The cuprizone model is a powerful tool to study the myelination process in vitro. • Drugs used in MS therapy normalize hyperexcitability in distinct brain regions. • Diroximel fumarate (DRF) impacts thalamic bursting only during early remyelination. • Siponimod acts opposingly on thalamic and cortical neurons in all conditions. [ABSTRACT FROM AUTHOR]

Abstract Multiple sclerosis is characterized by intermingled episodes of de- and remyelination and the occurrence of white- and grey-matter damage. To mimic the randomly distributed pathophysiological brain lesions observed in MS, we assessed the impact of focal white and grey matter demyelination on thalamic function by directing targeted lysolecithin-induced lesions to the capsula interna (CI), the auditory cortex (A1), or the ventral medial geniculate nucleus (vMGN) in mice. Pathophysiological consequences were compared with those of cuprizone treatment at different stages of demyelination and remyelination. Combining single unit recordings and auditory stimulation in freely behaving mice revealed changes in auditory response profile and electrical activity pattern in the thalamus, depending on the region of the initial insult and the state of remyelination. Cuprizone-induced general demyelination significantly diminished vMGN neuronal activity and frequency-specific responses. Targeted lysolecithin-induced lesions directed either to A1 or to vMGN revealed a permanent impairment of frequency-specific responses, an increase in latency of auditory responses and a reduction in occurrence of burst firing in vMGN neurons. These findings indicate that demyelination of grey matter areas in the thalamocortical system permanently affects vMGN frequency specificity and the prevalence of bursting in the auditory thalamus. Highlights • Demyelination impairs frequency-specific stimulus in vMGN neurons. • Myelin loss and gain alter thalamic burst activity. • Frequency-specific response is differently affected by white- and grey matter remyelination. [ABSTRACT FROM AUTHOR]

Myelin loss is a severe pathological hallmark common to a number of neurodegenerative diseases, including multiple sclerosis (MS). Demyelination in the central nervous system appears in the form of lesions affecting both white and gray matter structures. The functional consequences of demyelination on neuronal network and brain function are not well understood. Current therapeutic strategies for ameliorating the course of such diseases usually focus on promoting remyelination, but the effectiveness of these approaches strongly depends on the timing in relation to the disease state. In this study, we sought to characterize the time course of sensory and behavioral alterations induced by de- and remyelination to establish a rational for the use of remyelination strategies. By taking advantage of animal models of general and focal demyelination, we tested the consequences of myelin loss on the functionality of the auditory thalamocortical system: a well-studied neuronal network consisting of both white and gray matter regions. We found that general demyelination was associated with a permanent loss of the tonotopic cortical organization in vivo , and the inability to induce tone-frequency-dependent conditioned behaviors, a status persisting after remyelination. Targeted, focal lysolecithin-induced lesions in the white matter fiber tract, but not in the gray matter regions of cortex, were fully reversible at the morphological, functional and behavioral level. These findings indicate that remyelination of white and gray matter lesions have a different functional regeneration potential, with the white matter being able to regain full functionality while cortical gray matter lesions suffer from permanently altered network function. Therefore therapeutic interventions aiming for remyelination have to consider both region- and time-dependent strategies. [ABSTRACT FROM AUTHOR]

Abstract: Neuropathological changes following demyelination in multiple sclerosis (MS) lead to a reorganization of axolemmal channels that causes conduction changes including conduction failure. Pharmacological modulation of voltage-sensitive potassium channels (KV) has been found to improve conduction in experimentally induced demyelination and produces symptomatic improvement in MS patients. Here we used an animal model of autoimmune inflammatory neurodegeneration, namely experimental autoimmune encephalomyelitis (EAE), to test the influence of the KV-inhibitor 4-aminopyridine (4-AP) on various disease and immune parameters as well as mobility in MOG35–55 immunized C57Bl/6 mice. We challenged the hypothesis that 4-AP exerts relevant immunomodulatory or neuroprotective properties. Neither prophylactic nor therapeutic treatment with 4-AP altered disease incidence or disease course of EAE. Histopathological signs of demyelination and neuronal damage as well as MRI imaging of brain volume changes were unaltered. While application of 4-AP significantly reduced the standing outward current of stimulated CD4+ T cells compared to controls, it failed to impact intracellular calcium concentrations in these cells. Compatibly, KV channel inhibition neither influenced CD4+ T cell effector functions (proliferation, IL17 or IFNγ production). Importantly however, despite equal disease severity scores 4-AP treated animals showed improved mobility as assessed by 2 independent methods, 1) foot print and 2) rotarod analysis (0.332±0.03, n=7 versus 0.399±0.08, n=14, p<0.001, respectively). Our data suggest that 4-AP while having no apparent immunomodulatory or direct neuroprotective effects, significantly ameliorates conduction abnormalities thereby improving gait and coordination. Improvement of mobility in this experimental model supports trial data and clinical experience with 4-AP in the symptomatic treatment of MS. [Copyright &y& Elsevier]

Abstract: The two-pore domain potassium channel TASK1 (KCNK3) has recently emerged as an important modulator in autoimmune CNS inflammation. Previously, it was shown that T lymphocytes obtained from TASK1−/− mice display impaired T cell effector functions and that TASK1−/− mice show a significantly reduced disease severity in myelin oligodendrocyte glycoprotein (MOG35–55) peptide induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We here evaluate a potent and specific TASK1 channel inhibitor, A293, which caused a dose-dependent reduction of T cell effector functions (cytokine production and proliferation). This effect was abolished in CD4+ T cells from TASK1−/− mice but not in cells from TASK3−/− mice. In electrophysiological measurements, A293 application induced a significant reduction of the outward current of wildtype T lymphocytes, while there was no effect in TASK1−/− cells. Preventive and therapeutic application of A293 significantly ameliorated the EAE disease course in wildtype mice while it had no significant effect in TASK1−/− mice and was still partly effective in TASK3−/− mice. In summary, our findings support the concept of TASK1 as an attractive drug target for autoimmune disorders. [Copyright &y& Elsevier]

Abstract: Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system (CNS) that shares clinical and pathophysiological feature with multiple sclerosis (MS) and is commonly used as an animal model for the human disease. Upon active immunization, different myelin proteins and other neuronal antigens are known to induce EAE in susceptible mouse strains. However, there are rodent strains reputed to be resistant to actively-induced EAE and the correct combination of animal strains and their respective autoantigen is absolutely critical as some antigens are encephalitogenic in one animal strain, but not in another. Here we describe actively-induced EAE in C3H/HeJ mice with different myelin peptides. Whereas no clinical signs could be found by immunization with myelin oligodendrocyte glycoprotein 35-55, significant weight loss as well as rapidly occurring severe ascending paralysis was found in animals immunized with proteolipid protein 190-209 (PLP190-209). Histologically, this form of EAE was characterized by predominant involvement of the spinal cord. As PLP is one of the major lipid antigens putatively involved in the pathogenesis of MS, this model may be useful for further studies of the disease. [Copyright &y& Elsevier]

Two major K+ channels are expressed in T cells, (i) the voltage- dependent K+1.3 channel and (ii) the Ca2+-activated K+ channel KCa3.1 (IKCa channel). Both critically influence T cell effector functions in vitro and animal models in vivo. Here we identify and characterize TWIK-related acid-sensitive potassium channel 1 (TASK1) and TASK3 as an important third K+ conductance on T lymphocytes. T lymphocytes constitutively express TASK1 and -3 protein. Application of semi-selective TASK blockers resulted in a significant reduction of cytokine production and cell proliferation. Interference with TASK channels on CD3+ T cells revealed a dose-dependent reduction (~40%) of an outward current in patch clamp recordings indicative of TASK channels, a finding confirmed by computational modeling. In vivo relevance of our findings was addressed in an experimental model of multiple sclerosis, adoptive transfer experimental autoimmune encephalomyelitis. Pre-treatment of myelin basic protein-specific encephalitogenic T lymphocytes with TASK modulators was associated with significant amelioration of the disease course in Lewis rats. These data introduce K2P channels as novel potassium conductance on T lymphocytes critically influencing T cell effector function and identify a possible molecular target for immunomodulation in T cell-mediated autoimmune disorders. [ABSTRACT FROM AUTHOR]