Patrick Küry

Fingolimod is a potential novel therapy for multiple sclerosis

Fingolimod (also known as FTY720) is an orally available sphingosine-1-phosphate (S1P) receptor modulator that has unique and potent immunoregulatory properties. Mechanistic studies indicate that on phosphorylation fingolimod can bind with high affinity to S1P1 receptors. Persistent modulation of lymphocyte S1P1 receptors by fingolimod and the subsequent internalization of these receptors inhibits lymphocyte egress from the lymph nodes, and prevents these cells from infiltrating inflammatory lesions in the CNS. Results of two phase III studies—FREEDOMS and TRANSFORMS—support previous phase II trial observations indicating that fingolimod exerts powerful anti-inflammatory effects in relapsing–remitting multiple sclerosis (MS). Fingolimod might, therefore, be one of the first orally active drug therapies available for the treatment of relapsing–remitting MS. Moreover, results from preclinical studies suggest that fingolimod might promote neural repair in vivo. In this article, we review the background to these findings, present the proposed immunological and neurobiological profile of fingolimod, discuss the data from the FREEDOMS and TRANSFORMS trials, and provide an expert opinion regarding the future of next-generation S1P receptor modulators for MS therapy.

The complex world of oligodendroglial differentiation inhibitors.

Myelination is a central nervous system (CNS) process wherein oligodendrocyte‐axon interactions lead to the establishment of myelin sheaths that stabilize, protect, and electrically insulate axons. In inflammatory demyelinating diseases such as multiple sclerosis (MS), the degeneration and eventual loss of functional myelin sheaths slows and blocks saltatory conduction in axons, which results in clinical impairment. However, remyelination can occur, and lesions can be partially repaired, resulting in clinical remission. The recruitment and activation of resident oligodendrocyte precursor cells (OPCs) play a critical role in the repair process because these cells have the capacity to differentiate into functional myelinating cells. Mature oligodendrocytes, however, are thought to have lost the capacity to develop new myelin sheaths and frequently undergo programmed cell death in MS. The endogenous capacity to generate new oligodendrocytes in MS is limited, and this is predominantly due to the presence of inhibitory components that block OPC differentiation and maturation. Here, we present an overview of recently identified negative regulators of oligodendroglial differentiation and their potential relevance for CNS repair in MS. Because currently available immunomodulatory drugs for MS mainly target inflammatory cascades outside the brain and fail to repair existing lesions, achieving more efficient lesion repair constitutes an important goal for future MS therapies. Ann Neurol 2011;69:602–618

CXCR7 is an active component of SDF-1 signalling in astrocytes and Schwann cells

The alternative SDF-1 (stromal cell derived factor-1) receptor, CXCR7, has been suggested to act as either a scavenger of extracellular SDF-1 or a modulator of the primary SDF-1 receptor, CXCR4. CXCR7, however, also directly affects the function of various tumor-cell types. Here, we demonstrate that CXCR7 is an active component of SDF-1 signalling in astrocytes and Schwann cells. Cultured cortical astrocytes and peripheral nerve Schwann cells exhibit comparable total and cell-surface levels of expression of both SDF-1 receptors. Stimulation of astrocytes with SDF-1 resulted in the temporary activation of Erk1/2, Akt and PKCζ/λ, but not p38 and PKCα/β. Schwann cells showed SDF-1-induced activation of Erk1/2, Akt and p38, but not PKCα/β and PKCζ/λ. The respective signalling pattern remained fully inducible in astrocytes from CXCR4-deficient mice, but was abrogated following depletion of astrocytic CXCR7 by RNAi. In Schwann cells, RNAi-mediated depletion of either CXCR4 or CXCR7 silenced SDF-1 signalling. The findings of the astrocytic receptor-depletion experiments were reproduced by CXCR7 antagonist CCX754, but not by CXCR4 antagonist AMD3100, both of which abolished astrocytic SDF-1 signalling. Further underlining the functional importance of CXCR7 signalling in glial cells, we show that the mitogenic effects of SDF-1 on both glial cell types are impaired upon depleting CXCR7.

Gene expression profiling reveals that peripheral nerve regeneration is a consequence of both novel injury-dependent and reactivated developmental processes

One of the most striking features of the injured mature peripheral nervous system is the ability to regenerate. The lesioned peripheral nervous system displays stereotypic histopathological reactions indicating the activation of a co‐ordinated lesion‐induced gene expression programme. Previous research has already identified molecular components of this axonal switch from a mature transmitting to a regenerative growth mode. The observed alterations in gene expression within the lesioned distal nerve stump were largely attributed to recapitulated developmental processes. However, to our knowledge, this hypothesis has not been proven systematically. Most of the stereotypic molecular and cellular reactions during nerve development and repair can be assigned to specific time windows. Consequently, we have compared gene expression profiles of both paradigms at six different time‐points each by means of cDNA array hybridization. Our data identified injury‐specific molecular reactions and revealed to what extent developmental mechanisms are reactivated in response to nerve lesion. Ninety‐one genes (47% of the regeneration‐associated genes) were found to be significantly regulated in both paradigms, suggesting that regeneration only partially recapitulates development and that approximately half of the regulated genes are part of a regeneration‐dependent programme. Interestingly, mainly genes encoding signal transducers or factors involved in processes such as cell death, immune response, transport and transcriptional regulation showed injury‐specific gene expression.

Unrestricted somatic stem cells from human umbilical cord blood can be differentiated into neurons with a dopaminergic phenotype.

Recently, it has been shown that human unrestricted somatic stem cells (USSCs) from umbilical cord blood represent pluripotent, neonatal, nonhematopoietic stem cells with the potential to differentiate into the neural lineage. However, molecular and functional characterization of the neural phenotype and evaluation of the degree of maturity of the resulting cells are still lacking. In this study, we addressed the question of neuronal differentiation and maturation induced by a defined composition of growth and differentiation factors (XXL medium). We demonstrated the expression of different neuronal markers and their enrichment in USSC cultures during XXL medium incubation. Furthermore, we showed enrichment of USSCs expressing tyrosine hydroxylase (TH), an enzyme specific for dopaminergic neurons and other catecholamine-producing neurons, accompanied by induction of Nurr1, a factor regulating dopaminergic neurogenesis. The functionality of USSCs has been analyzed by patch-clamp recordings and high-performance liquid chromatography (HPLC). Voltage-gated sodium-channels could be identified in laminin-predifferentiated USSCs. In addition, HPLC analysis revealed synthesis and release of the neurotransmitter dopamine by USSC-derived cells, thus correlating well with the detection of TH transcripts and protein. This study provides novel insight into the potential of unrestricted somatic stem cells from human umbilical cord blood to acquire a neuronal phenotype and function.

Molecular mechanisms of cellular interactions in peripheral nerve regeneration.

The peripheral nervous system, as opposed to the central nervous system, has the intrinsic capacity to regenerate. It was recognized long ago that this can be achieved only after an extensive clean-up procedure, the so-called Wallerian degeneration, in which myelin debris is removed and a suitable environment for growing axons is generated. Wallerian degeneration and the regeneration process itself both depend on direct cellular interactions as well as on long-range signals between all participating cell types. Elucidating the nature and functional consequences of these signals is a main goal in understanding peripheral nerve repair.

Inflammatory gene expression in focal cortical brain ischemia: differences between rats and mice

The impact of species-specific factors on postischemic brain inflammation is largely unknown. In this study, we used quantitative real-time polymerase chain reaction in a highly standardized model of focal cortical brain ischemia for the comparison of cytokine and inducible nitric oxide synthase (iNOS) gene expression in rats and mice. In rats, we found rapid and strong induction of tumor necrosis factor-alpha (TNF-alpha) mRNA reaching its peak at 4 h after ischemia, followed by a slightly delayed peak of interleukin-1beta (IL-1beta) and iNOS mRNA at 16 h. Inflammatory gene induction in mice was overall weaker and considerably more protracted. Both TNF-alpha and IL-1beta transcripts reached their peak around 24 h. In addition, iNOS mRNA exhibited a rather variable, delayed increase between days 3 and 14. Accordingly, immunocytochemistry revealed strong iNOS immunoreactivity in the infarct borderzone at days 1 and 3 in rats whereas only a few iNOS-positive cells were detectable in mice. Taken together, our study demonstrates considerable species differences in inflammatory gene induction after focal brain ischemia.

Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation.

Differentiation of oligodendroglial precursor cells is crucial for central nervous system remyelination and is influenced by both extrinsic and intrinsic factors. Recent studies showed that human endogenous retrovirus type W (HERV‐W) contributes significantly to brain damage. In particular, its envelope protein ENV can mediate injury to specific cell types of the brain and immune system. Here, we investigated whether ENV protein affects oligodendroglial differentiation.

Transcriptional response to circumscribed cortical brain ischemia: spatiotemporal patterns in ischemic vs. remote non-ischemic cortex.

Focal brain infarcts are surrounded by extended perilesional zones that comprise the partially ischemic penumbra but also completely non‐ischemic cortex of the remote ipsilateral hemisphere. To delineate the impact of lesion‐associated vs. remote processes on transcriptional programming after focal ischemia, we used cDNA array analysis, quantitative real‐time polymerase chain reaction and immunohistochemistry in the photothrombosis model of circumscribed cortical ischemia in rats. At an early stage of 4 h after ischemia, gene induction occurred to a similar extent in the ischemic infarct and remote non‐ischemic cortex of the ipsilateral hemisphere. Among the genes induced in non‐ischemic cortex we found the NGF‐inducible genes PC3, VGF and Arc, the transcriptional regulators IκB‐α and Stat3, and the β‐chemokine MIP‐1α (CCL3). At 3 days, the spatial pattern of gene expression had changed dramatically with brain fatty acid‐binding protein as the only gene significantly induced in non‐ischemic ipsilateral cortex. In contrast, numerous genes were exclusively regulated at the lesion site, comprising genes involved in cell cycle regulation, proteolysis, apoptosis, lipid homeostasis and anti‐inflammatory counter‐regulation. Cortical spreading depression was identified as the main mechanism underlying gene induction in remote non‐ischemic cortex. Our data demonstrate a dynamic spatiotemporal pattern of gene induction, which may contribute to delayed progression of damage or, alternatively, mediate neuroprotection, tissue remodeling and functional compensation.

Activation of CXCR7 receptor promotes oligodendroglial cell maturation.

Differentiation of oligodendroglial precursor cells is crucial for central nervous system (re)myelination and is influenced by multiple extrinsic and intrinsic factors. Chemokines, a group of small proteins, are highly conserved among mammals and have been implicated in a variety of biological processes during development, tissue homeostasis, and repair. We investigated whether the chemokine CXCL12 influences oligodendrocytes and what cellular differentiation/maturation processes are controlled by this molecule.