Ciliary Neurotrophic Factor

Developing motoneurons require trophic support from their target, the skeletal muscle. Despite a large number of neurotrophic molecules with survival-promoting activity for isolated embryonic motoneurons, those factors that are required for motoneuron survival during development are still not known. Cytokines of the ciliary neurotrophic factor (CNTF)-leukemia inhibitory factor (LIF) family have been shown to play a role in motoneuron (MN) survival. Importantly, in mice lacking the LIFRbeta or the CNTFRalpha there is a significant loss of MNs during embryonic development. Because genetic deletion of either (or both) CNTF or LIF fails, by contrast, to perturb MN survival before birth, it was concluded that another ligand exists that is functionally inactivated in the receptor deleted mice, resulting in MN loss during development. One possible candidate for this ligand is the CNTF-LIF family member cardiotrophin-1 (CT-1). CT-1 is highly expressed in embryonic skeletal muscle, secreted ...

Injuries to the adult mammalian spinal cord often lead to severe damage to both ascending (sensory) pathways and descending (motor) nerve pathways without the perspective of complete functional recovery. Future spinal cord repair strategies should comprise a multi-factorial approach addressing several issues, including optimalization of survival and function of spared central nervous system neurons in partial lesions and the modulation of trophic and inhibitory influences to promote and guide axonal regrowth. Neurotrophins have emerged as promising molecules to augment neuroprotection and neuronal regeneration. Although intracerebroventricular, intrathecal and local protein delivery of neurotrophins to the injured spinal cord has resulted in enhanced survival and regeneration of injured neurons, there are a number of drawbacks to these methods. Viral vector-mediated transfer of neurotrophin genes to the injured spinal cord is emerging as a novel and effective strategy to express neu...

Mutations in cardiotrophin-like cytokine factor (CLCF1) and the related cytokine to which it binds,
cytokine receptor-like factor 1 (CRLF1), are associated with Crisponi/cold induced sweating syndromes,
and lead to early neonatal death in mice due to a suckling defect. These cytokines are members of the IL-6
superfamily, and form a range of composite cytokines that signal through gp130 bound either to the
ciliary neurotrophic factor receptor (CNTFR) or a complex that involves the IL-27 p28 subunit. This
review describes current knowledge of the signalling complexes formed by these cytokines, and explores
their described and suggested roles in the neural, haematopoietic, skeletal, renal, immune and
respiratory systems during development and adulthood, and in degenerative diseases and cancer.

Application of neurotrophic proteins including ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), members of the family of gp130-associated cytokines, can rescue CNS neurons from injury-induced degeneration. However, it is not clear so far if these effects reflect a physiological function of the endogenous cytokines. Using fimbria-fornix transection as a model, we examined whether responses of GABAergic and cholinergic septohippocampal neurons to axotomy are altered in mice lacking CNTF. In addition, we studied the cellular expression of CNTF, LIF and related cytokine receptor components in the septal complex following lesion. Degeneration of septohippocampal GABAergic neurons in the medial septum as indicated by the loss of parvalbumin-immunoreactive neurons was accelerated and permanently enhanced in CNTF(-/-) mice as compared to wild-type animals. Unexpectedly, the number of axotomized cholinergic MS neurons was significantly higher in CNTF-deficient mice during the first 2 weeks postlesion. Both in wild-type and in CNTF(-/-) mutants, expression of mRNA for the CNTF-specific alpha-subunit of the cytokine receptor complex was specifically upregulated in axotomized GABAergic septal neurons, whereas enhanced expression of the LIF-binding beta-subunit was specifically observed in axotomized cholinergic neurons. Following lesion, CNTF expression in wild-type mice was induced in activated astrocytes surrounding the axotomized neurons and at the lesion site. Expression of LIF mRNA was localized in the GABAergic and cholinergic septohippocampal neurons. These results strongly indicate that endogenous CNTF, supplied by reactive glia cells, acts as a neuroprotective factor for axotomized CNS neurons. In the septum, endogenous CNTF specifically supports lesioned GABAergic projection neurons, whereas LIF may play a similar role for the cholinergic counterparts.

We examined the effect of FPF-1070 (Cerebrolysin®) on neurite outgrowth in explant cultures of dorsal root ganglia (DRG), sympathetic trunks (ST), and ciliary ganglia (CG) from 10- to 11-day chicken embryos. FPF-1070 significantly promoted neurite outgrowth in DRG and ST neurons at all concentrations examined, in comparison with phosphate buffered saline-treated negative controls; however, this effect on neurite outgrowth was not as significant as that observed for nerve growth factor-treated positive controls on DRG and ST neurons. Additionally, FPF-1070 exhibited an inverted U relationship between concentration and effectiveness in DRG and ST neurons. In contrast, FPF-1070 did not affect neurite outgrowth in CG neurons although ciliary neurotrophic factor-treated positive controls showed striking neurite outgrowth. Our results demonstrate that FPF-1070 has different neurotrophic effects depending on the subpopulation of neurons. This study clarifies a role for neurotrophic activity in the mechanism of action of FPF-1070.

Cytokines that are related to ciliary neurotrophic factor (CNTF) are physiologically important survival factors for motoneurons, but the mechanisms by which they prevent neuronal cell death remain unknown. Reg-2/PAP I (pancreatitis-associated protein I), referred to here as Reg-2, is a secreted protein whose expression in motoneurons during development is dependent on cytokines. Here we show that CNTF-related cytokines induce Reg-2 expression in cultured motoneurons. Purified Reg-2 can itself act as an autocrine/paracrine neurotrophic factor for a subpopulation of motoneurons, by stimulating a survival pathway involving phosphatidylinositol-3-kinase, Akt kinase and NF-kappaB. Blocking Reg-2 expression in motoneurons using Reg-2 antisense adenovirus specifically abrogates the survival effect of CNTF on cultured motoneurons, indicating that Reg-2 expression is a necessary step in the CNTF survival pathway. Reg-2 shows a unique pattern of expression in late embryonic spinal cord: it is progressively upregulated in individual motoneurons on a cell-by-cell basis, indicating that only a fraction of motoneurons in a given motor pool may be exposed to cytokines. Thus, Reg-2 is a neurotrophic factor for motoneurons, and is itself an obligatory intermediate in the survival signalling pathway of CNTF-related cytokines.

To correlate ellipsoid zone (EZ) defects on spectral-domain optical coherence tomography (SD-OCT) with retinal sensitivity loss on macular integrity assessment (MAIA) microperimetry in macular telangiectasia type 2 (MacTel). Macular SD-OCT volumes and microperimetry maps were obtained during the international, multicenter, randomized phase 2 trial of ciliary neurotrophic factor for type 2 MacTel on two visits within 5 days of one another. Software was developed to register SD-OCT to MAIA scanning laser ophthalmoscopy images and to overlay EZ defect areas on the microperimetry maps generated from microperimetry sensitivity values at specific points and from interpolated sensitivity values. A total of 134 eyes of 67 patients were investigated. The semiautomated registration algorithm was found to be accurate, both qualitatively by visual inspection of the nearly perfect overlap of the retinal vessels and quantitatively as assessed by interobserver reliability metrics performed in 98 e...

Cytokines are a heterogenous group of polypeptide mediators that have been associated with activation of numerous functions, including the immune system and inflammatory responses. The cytokine families include, but are not limited to, interleukins (IL-Iα, IL-Iβ, ILIra and IL-2-IL-15), chemokines (IL-8/NAP-I, NAP-2, MIP-Iα and β, MCAF/MCP-I, MGSA and RANTES), tumor necrosis factors (TNF-α and TNF-β), interferons (INF-α, β and γ), colony stimulating factors (G-CSF, M-CSF, GM-CSF, IL-3 and some of the other ILs), growth factors (EGF, FGF, PDGF, TGFα, TGFβ and ECGF), neuropoietins (LIF, CNTF, OM and IL-6), and neurotrophins (BDNF, NGF, NT-3-NT-6 and GDNF). The neurotrophins represent a family of survival and differentiation factors that exert profound effects in the central and peripheral nervous system (PNS). The neurotrophins are currently under investigation as therapeutic agents for the treatment of neurodegenerative disorders and nerve injury either individually or in combination with other trophic factors such as ciliary neurotrophic factor (CNTF) or fibroblast growth factor (FGF).Responsiveness of neurons to a given neurotrophin is governed by the expression of two classes of cell surface receptor. For nerve growth factor (NGF), these are p75NTR (p75) and p140trk (referred to as trk or trkA), which binds both BDNF and neurotrophin (NT)-, and trkC receptor, which binds only NT-3. After binding ligand, the neurotrophin-receptor complex is internalized retrogradely transported in the axon to the soma. Both receptors undergo ligand-induced dimerization, which activates multiple signal transduction pathways. These include the ras-dependent pathway utilized by trk to mediate neurotrophin effects such as survival and differentiation. Indeed, cellular diversity in the nervous system evolves from the concerted processes of cell proliferation, differentiation, migration, survival, and synapse formation. Neural adhesion and extracellular matrix molecules have been shown to play crucial roles in axonal migration, guidance, and growth cone targeting.Proinflammatory cytokines, released by activated macrophages and monocytes during infection, can act on neural targets that control thermogenesis, behavior, and mood. In addition to induction of fever, cytokines induce other biological functions associated with the acute phase response, including hypophagia and sleep. Cytokine production has been detected within the central nervous system as a result of brain injury, following stab wound to the brain, during viral and bacterial infections (AIDS and meningitis), and in neurodegenerative processes (multiple sclerosis and Alzheimer's disease). Novel cytokine therapies, such as anticytokine antibodies or specific receptor antagonists acting on the cytokine network may provide an optimistic feature for treatment of multiple sclerosis and other diseases in which cytokines have been implicated. © 1997 Elsevier Science Ltd. All rights reserved

Recombinant lentiviral vectors (rLV) are powerful tools for gene transfer to the central nervous system (CNS) and hold great potential as a therapeutic gene therapy strategy for neurological disorders. Recent data indicate that rLVs are suitable for functional studies in the CNS by over expression or knock down of specific proteins. Based on a variety of lentiviruses species, different vector systems have been developed. However, the most commonly used rLV vector is based on the human immunodeficiency virus 1 (HIV-1). Here we describe the use of such vectors to achieve cell-specific transgene expression in the brain. In this setting, rLVs are versatile tools both due to their relatively large cloning capacity and their ability to transduce non-dividing cells. Furthermore, we discuss the preclinical development of gene therapy based on enzyme replacement and/or delivery of neurotrophic factors for neurodegenerative diseases and CNS manifestations of lysosomal storage diseases. Neuroprotective strategies that aim to deliver glial cell line-derived neurotrophic factor and ciliary neurotrophic factor for Parkinson's and Huntington's diseases in particular have been documented with success in appropriate animal models. More recently, rLVs were shown to be suitable to express small interfering RNA for treatment in models of Alzheimer's disease and amyotrophic lateral sclerosis. Finally, we present a review of the use of rLVs to model neurodegenerative diseases. rLVs have proven to be a very versatile tool to create genetic models of both Parkinson's and Huntington's diseases and thus provide possibilities to study complex genetic interactions in otherwise wild-type animals evading the necessity to create transgenic mice. Moreover, the potential of these vectors in the development of gene therapy to treat neurological disorders is considerable, which is supported by the fact that clinical trials using rLVs are underway.

Ciliary neurotrophic factor (CNTF) supports the survival of embryonic motor neurons in vitro and in vivo, and prevents lesion-mediated degeneration of rat motor neurons during early post-natal stages. Here we report that CNTF greatly reduces all the functional and morphological changes in pmn/pmn mice, an autosomal recessive mutant leading to progressive caudo-cranial motor neuron degeneration. The first manifestations of progressive motor neuronopathy in homozygous pmn/pmn mice become apparent in the hind limbs at the end of the third post-natal week, and all the mice die up to 6 or 7 weeks after birth from respiratory paralysis. Treatment with CNTF prolongs survival and greatly improves motor function of these mice. Moreover, morphological manifestations, such as loss of motor axons in the phrenic nerve and degeneration of facial motor neurons, were greatly reduced by CNTF, although the treatment did not start until the first symptoms of the disease had already become apparent and substantial degenerative changes were already present. The protective and restorative effects of CNTF in this mouse mutant give new perspectives for the treatment of human degenerative motor neuron diseases with CNTF.