Actions of CNTF and neurotrophins on degenerating motoneurons: Preclinical studies and clinical implications

doi:10.1016/0022-510X(94)90187-2

Journal of the Neurological Sciences

Volume 124, Supplement, July 1994, Pages 77-83

https://doi.org/10.1016/0022-510X(94)90187-2 Get rights and content

Abstract

Spinal motoneurons innervating skeletal muscle were amongst the first neurons shown to require the presence of their target cells to develop appropriately. Isolated embryonic chick and rat motoneurons have been used to identify neurotrophic factors and cytokines capable of supporting the survival of developing motoneurons. Such factors include ciliary neurotrophic factor (CNTF), which is present physiologically in high amounts in myelinating Schwann cells of peripheral nerves, and brain-derived neurotrophic factor (BDNF) which is synthesized in skeletal muscle and, after peripheral nerve lesion, in Schwann cells. These factors have been further analyzed for their physiological significance in maintaining motoneuron function in vivo, and for their potential therapeutic usefulness in degenerative motoneuron disease. Both CNTF and BDNF are capable of rescuing injured facial motoneurons in newborn rats. Furthermore, CNTF prolongs survival and improves motor function of pmn mice, an animal model for degenerative motoneuron disease, by preventing degeneration of motoneuron axons and somata. Thus treatment of human motoneuron disease with neurotrophic factors should be possible, provided that rational means for application of these factors can be established considering also the appearance of potential side effects.

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Others authors also found similar alterations (Brooker et al., 2000; Offen et al., 2001; Trejo et al., 2001; Ding et al., 2006; Netchine et al., 2009; Li et al., 2015; Ma et al., 2015; Ostrowski et al., 2016; Wrigley et al., 2017). What is more, CNTF has been described the most potent NTF involved in motor neuron protection, due to its capacity to stimulate survival and regeneration in these neurons (Arakawa et al., 1990; Sendtner et al., 1991, 1994; Masu et al., 1993; Siegel and Chauhan, 2000; Selvaraj and Sendtner, 2013), further sustaining the indirect but potent implication of IGF-1 in Parkinson's disease, its deficiency being associated with a significant downregulation of CNTF and a possible compensatory mechanism of over-expression of its receptor. In line with the above, some children with primary IGF-1 deficiency (Laron syndrome or growth hormone insensitivity), present short stature and psychomotor delay among other cranial and cerebral alterations (Kornreich et al., 2002; Castilla-Cortazar et al., 2018).
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It is well-known that, after nerve transection and surgical repair, misdirected regrowth of regenerating motor axons may occur in three ways. The first way is that the axons enter into endoneurial tubes that they did not previously occupy, regenerate through incorrect fascicles and reinnervate muscles that they did not formerly supply. Consequently the activation of these muscles results in inappropriate movements. The second way is that, in contrast with the precise target-directed pathfinding by elongating motor nerves during embryonic development, several axons rather than a single axon grow out from each transected nerve fiber. The third way of misdirection occurs by the intramuscular terminal branching (sprouting) of each regenerating axon to culminate in some polyinnervation of neuromuscular junctions, i.e. reinnervation of junctions by more than a single axon. Presently, “fascicular” or “topographic specificity” cannot be achieved and hence target-directed nerve regeneration is, as yet, unattainable. Nonetheless, motor and sensory reinnervation of appropriate endoneurial tubes does occur and can be promoted by brief nerve electrical stimulation.
This review considers the expression of neurotrophic factors in the neuromuscular system and how this expression can promote functional recovery, with emphasis on the whisking of vibrissae on the rat face in relationship to the expression of the factors. Evidence is reviewed for a role of neurotrophic factors as short-range diffusible sprouting stimuli in promoting complete functional recovery of vibrissal whisking in blind Sprague Dawley (SD)/RCS rats but not in SD rats with normal vision, after facial nerve transection and surgical repair. Briefly, a complicated time course of growth factor expression in the nerves and denervated muscles include (1) an early increase in FGF2 and IGF2, (2) reduced NGF between 2 and 14 days after nerve transection and surgical repair, (3) a late rise in BDNF and (4) reduced IGF1 protein in the denervated muscles at 28 days. These findings suggest that recovery of motor function after peripheral nerve injury is due, at least in part, to a complex regulation of nerve injury-associated neurotrophic factors and cytokines at the neuromuscular junctions of denervated muscles. In particular, the increase of FGF2 and concomittant decrease of NGF during the first week after facial nerve-nerve anastomosis in SD/RCS blind rats may prevent intramuscular axon sprouting and, in turn, reduce poly-innervation of the neuromuscular junction.
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To overcome the deficiency of rapid elimination from blood, the truncated human recombinant ciliary neurotrophic factor was formulated by site-specific attachment of different-sized PEG-maleimide or by cross-linking with human transferrin through a hetero-bi-functional PEG linker (NHS-PEG5k-MAL). The PEGylated CNTF was purified by a two-step chromatography procedure and the transferrin coupling CNTF conjugate was separated through an elegant protocol. The conjugation site on CNTF was identified by peptide mapping analysis and validated that the linkage of the conjugates was specifically happened to Cys17 residue. Although both PEGylated and transferrin coupling CNTF demonstrated decreased cell based residual activity, markedly enhanced pharmacokinetic behaviors in normal male Sprague-Dawley rats were observed, especially for the PEG40k-CNTF with approximately 58-times improvement compared with the unmodified counterpart. The evaluation of the in vivo potency of body weight-losing was performed with normal male C57BL6 mice and the results revealed that both PEGylation and transferrin coupling could achieve improved therapeutic benefits relative to that of CNTF. Besides, PEG20k/40k-CNTF demonstrated more effective than transferrin coupling CNTF (Tf-PEG5k-CNTF) despite that the later showed preferable pharmacokinetic profile and cell based residual activity compared with PEG20k-CNTF. Weekly subcutaneous administration of PEG40k-CNTF with 0.5 mg/kg and 1.0 mg/kg dose resulted in approximately 35% and 50% decrease in food intake during one interval period of injection, indicating that PEG40k-CNTF is the most potential anti-obese agent for therapeutics.
CNTF and retina
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Citation Excerpt :
Although inactivation of the CNTF gene results in no specific abnormalities in humans and animals (Masu et al., 1993; Takahashi et al., 1994), exogenous CNTF has been shown to affect the survival and differentiation of a variety of neurons in the nervous system (Sleeman et al., 2000). CNTF is also a myotrophic factor (Sendtner et al., 1992, 1994; Kuzis and Eckenstein, 1996). In addition, CNTF influences energy balance and is being considered as a potential therapy for obesity and related type 2 diabetes (Lambert et al., 2001; Ettinger et al., 2003; Matthews and Febbraio, 2008).
Ciliary neurotrophic factor (CNTF) is one of the most studied neurotrophic factors for neuroprotection of the retina. A large body of evidence demonstrates that CNTF promotes rod photoreceptor survival in almost all animal models. Recent studies indicate that CNTF also promotes cone photoreceptor survival and cone outer segment regeneration in the degenerating retina and improves cone function in dogs with congenital achromotopsia. In addition, CNTF is a neuroprotective factor and an axogenesis factor for retinal ganglion cells (RGCs). This review focuses on the effects of exogenous CNTF on photoreceptors and RGCs in the mammalian retina and the potential clinical application of CNTF for retinal degenerative diseases.
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The present study was performed to elucidate the hearing development in the progressive motor neuronopathy (pmn) mouse mutant. This mouse has been used as a model for human motoneuron disease. A missense mutation in the tubulin-specific chaperon E (Tbce) gene on mouse chromosome 13 was localized as the underlying genetic defect. The protein encoded by the Tbce gene is essential for the formation of primary tubulin complexes. Studies on motoneurons show disorganization in microtubules and disturbed axonal transport, followed by retrograde degeneration of the motoneurons. A similar pathomechanism is also possible for hearing disorders where disrupted microtubules could cause functional deficits in spiral ganglion neurons or in cochlear hair cells. Click auditory brainstem response (ABR) audiometry in homozygous pmn mutants showed a normal onset of hearing, but an increasing hearing threshold from postnatal day 26 (P26) on to death, compared to heterozygous mutants and wild-type mice. Histological sections of the cochlea at different ages showed a regular morphology. Additionally, spiral ganglion explants from mutant and wild-type mice were cultured. The neurite length from pmn mutants was shorter than in wild-type mice, and the neurite number/explant was significantly decreased in pmn mutants. We show that the pmn mouse mutant is a model for a progressive rapid hearing loss from P26 on, after initially normal hearing development. Heterozygous mice are not affected by this defect. With the knowledge of the well-known pathomechanism of this defect in motoneurons, a dysfunction of cellular mechanisms regulating tubulin assembling suggests that tubulin assembling plays an essential role in hearing function and maintenance.
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Erythropoietin (Epo) has neuroprotective activity in a variety of settings. Thus, we investigated whether Epo has a role in the functional recovery of rats after facial nerve injury. The right facial nerve of 24 Wistar rats (6 wks old) was crushed twice at the level of the stylomastoid foramen, for 30 s each time, using jeweler’s forceps held perpendicular to the nerve. The left facial nerve did not undergo the surgical lesion. The rats were randomly divided into 4 groups: (group 1) the control group (placebo, treated with saline); and groups treated with Epo at a dose of 1,000 U/kg body weight (group 2), 5,000 U/kg body weight (group 3), and 10,000 U/kg body weight (group 4). The Epo and saline were administered subcutaneously pre-operatively and treatment was repeated every 24 h for the first 2 weeks after the operation. Behavioral recovery from facial paralysis was measured daily, beginning 1 day after surgery, until full recovery of the eye blink reflex and whisker movements were observed. The average recovery times for the full blink reflex and whisker movements were significantly shorter (about 2–3 days) in rats treated with a high dose Epo (5,000, 10,000 U/kg body weight) compared to the placebo-treated rats (p < 0.05). There was no significant difference between low dose Epo-treated rats (1,000 U/kg body weight) and the placebo-treated rats. These results suggest that high dose Epo can promote the functional recovery of rats following facial nerve injury. Further studies are warranted to probe alternative treatment schedules (dose, mode of administration), underlying histological mechanisms and combination treatment with additional neuroprotective factors.

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Research articleActions of CNTF and neurotrophins on degenerating motoneurons: Preclinical studies and clinical implications

Abstract

Neuron

Apoptosis. Immunol. Today

Neurosci. Lett.

J. Neurol. Sci.

Cell

Trends Neurosci.

Genomics

Gene

Dev. Brain Res.

Neuron

Genomics

Biochem. Biophys. Res. Commun.

FEBS Lett.

Human gene therapy

Science

Survival effect of ciliary neurotrophic factor (CNTF) on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines

J. Neurosci.

Morphometric and biochemical studies of peripheral nerves in amyotrophic lateral sclerosis

Ann. Neurol.

Pathology-Light microscopy of Amyotrophic lateral sclerosis

Ciliary neurotrophic cancer: pharmacokinetics and acute phase response

Ann. Neurol.

Induction of motor neuron sprouting in vivo by ciliary neurotrophic factor and basic fibroblast growth factor

J. Neurosci.

Changes of nerve growth factor synthesis in non-neuronal cells in responses to sciatic nerve transection

J. Cell Biol.

Members of several gene families influence survival of rat motoneurons in vitro and in vivo

J. Neurosi. Res.

The gene for ciliary neurotrophic factor (CNTF) maps to murine chromosome 19 and its expression is not affected in the hereditary motoneuron disease ‘wobbler’ of the mouse

Eur. J. Neurosci.

Implantable pumps to deliver drugs directly into the CNS

Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy

Nature

Molecular cloning and expression of brain-derived neurotrophic factor

Nature

Research article
Actions of CNTF and neurotrophins on degenerating motoneurons: Preclinical studies and clinical implications