Reinnervation of the rat musculocutaneous nerve stump after its direct reconnection with the C5 spinal cord segment by the nerve graft following avulsion of the ventral spinal roots: a comparison of intrathecal administration of brain-derived neurotrophic factor and Cerebrolysin

Haninec, Pavel; Dubový, Petr; Šámal, Filip; Houšťava, Ladislav; Stejskal, L

doi:10.1007/s00221-004-1969-z

Cited by 25 publications

(17 citation statements)

References 37 publications

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“…Western blot analysis of total H3 histone levels (Figure 9b) revealed no differences between wild type and vehicle- or CBL-treated Mecp2 308/Y mutant mice. These results indicate that the beneficial effects of CBL seen in this study are independent of the known transcription-regulating effects of Mecp2 and are suggest that they likely to be related to the previously reported neurotrophic action of CBL [14, 21, 23, 26, 55]. …”

Section: Resultssupporting

confidence: 78%

“…Consistent with this hypothesis, CBL has been reported to have neurotrophic effects in vitro on cultured neurons from chicken embryos [40] and synaptotrophic effects on neuronal cells [34]. Consistent with in vitro data, in vivo demonstration of the neurotrophic effects of CBL were observed in studies examining cell death in rat spinal motoneurons following avulsion of the ventral spinal roots [21, 22]. Though the molecular mediators of the neurotrophic effect of CBL remain to be definitively determined, CBL had been reported to reduce levels of CDK5 and GSK3beta [53], and this may be related to the beneficial effects of CBL on neuronal survival and its anti-apoptotic effects [24].…”

Section: Discussionmentioning

confidence: 54%

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Neurotrophic effects of Cerebrolysin in the Mecp2308/Y transgenic model of Rett syndrome

et al. 2008

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Rett syndrome is a childhood neurodevelopmental disorder caused by mutations in the gene encoding for methyl CpG binding protein (MeCP2). Neuropathological studies in patients with Rett syndrome and in MeCP2 mutant models have shown reduced dendritic arborization and abnormal neuronal packing. We have previously shown that Cerebrolysin (CBL), a neurotrophic peptide mixture, ameliorates the synaptic and dendritic pathology in models of aging and neurodegeneration. This study aimed to determine whether CBL was capable of reducing behavioral and neuronal alterations in Mecp2 308/Y mutant mice. Two sets of experiments were performed, the first with 4 month old male Mecp2 308/Y mutant mice treated with CBL or vehicle for 3 months (Group A) and the second with 1 month old mice treated for 6 months (Group B). Behavioral analysis showed improved motor performance with CBL in Group A and a trend toward improvement in Group B. Consistent with behavioral findings, neuropathological analysis of the basal ganglia showed amelioration of dendritic simplification in CBL-treated Mecp2 308/Y mutant mice. CBL treatment also ameliorated dendritic pathology and neuronal loss in the hippocampus and neocortex in Mecp2 308/Y mutant mice. In conclusion, this study demonstrates that CBL promotes recovery of dendritic and neuronal damage and behavioral improvements in young adult Mecp2 308/Y mutant mice and suggests that CBL may have neurotrophic effects in this model. These findings support the possibility that CBL may have beneficial effects in the management of Rett syndrome.

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Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 54%

Neurotrophic effects of Cerebrolysin in the Mecp2308/Y transgenic model of Rett syndrome

et al. 2008

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“…A miniosmotic pump (Alzet 2002), Cupertino, CA) was securely implanted subcutaneously in the mid back in order to deliver intrathecal agents for up to 14 days (12 µl/day). BDNF was delivered at 180 ng/day (R&D Systems, Inc., Minneapolis, MN), in agreement with previous studies (Groth and Aanonsen, 2002, Haninec, et al, 2004, Kishino, et al, 1997, Kishino, et al, 2001, Novikova, et al, 2000, Novikova, et al, 2002, Sayer, et al, 2002). The fusion protein TrkB-Fc was delivered at 1.5 µg/day (R&D Systems, Inc.) in order to quench available BDNF (Binder, et al, 1999, Yajima, et al, 2005).…”

Section: Methodsmentioning

confidence: 72%

Motoneuron BDNF/TrkB signaling enhances functional recovery after cervical spinal cord injury

Mantilla

Gransee

Zhan

et al. 2013

Experimental Neurology

133

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A C 2 cervical spinal cord hemisection (SH) interrupts descending inspiratory-related drive to phrenic motoneurons located between C 3 and C 5 in rats, paralyzing the ipsilateral hemidiaphragm muscle. There is gradual recovery of rhythmic diaphragm muscle activity ipsilateral to cervical spinal cord injury over time, consistent with neuroplasticity and strengthening of spared, contralateral descending premotor input to phrenic motoneurons. Brainderived neurotrophic factor (BDNF) signaling through the tropomyosin related kinase receptor subtype B (TrkB) plays an important role in neuroplasticity following spinal cord injury. We hypothesized that 1) increasing BDNF/TrkB signaling at the level of the phrenic motoneuron pool by intrathecal BDNF delivery enhances functional recovery of rhythmic diaphragm activity after SH, and 2) inhibiting BDNF/ TrkB signaling by quenching endogenous neurotrophins with the soluble fusion protein TrkB-Fc or by knocking down TrkB receptor expression in phrenic motoneurons using intrapleurallydelivered siRNA impair functional recovery after SH. Diaphragm EMG electrodes were implanted bilaterally to verify complete hemisection at the time of SH and 3 days post-SH. After SH surgery in adult rats, an intrathecal catheter was placed at C 4 to chronically infuse BDNF or TrkB-Fc using an implanted mini-osmotic pump. At 14 days post-SH, all intrathecal BDNF treated rats (n=9) displayed recovery of ipsilateral hemidiaphragm EMG activity, compared to 3 out of 8 untreated SH rats (p < 0.01). During eupnea, BDNF treated rats exhibited 76 ± 17% of pre-SH root mean squared EMG vs. only 5 ± 3% in untreated SH rats (p < 0.01). In contrast, quenching endogenous BDNF with intrathecal TrkB-Fc treatment completely prevented functional recovery up to 14 days post-SH (n=7). Immunoreactivity of the transcription factor cAMP response element-binding protein (CREB), a downstream effector of TrkB signaling, increased in phrenic motoneurons following BDNF treatment (n=6) compared to artificial cerebrospinal fluid treatment (n=6; p < 0.001). Intrapleural injections of non-sense or TrkB siRNA were administered after SH to specifically target phrenic motoneurons. At 14 days post-SH, none out of 9 TrkB siRNA treated rats displayed functional recovery compared to 5 out of 9 non-sense siRNA treated rats. These results indicate that BDNF/TrkB signaling in phrenic motoneuron pool plays a critical role in functional recovery after cervical spinal cord injury.

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“…These peripheral nerve grafts contain Schwann cells which produce neurotrophic factors after nerve injury and thereby contribute to the guidance of sprouting axons. Previous results of Haninec et al [38] have indicated that motor neuronal outgrowth and survival are stimulated if a peripheral nerve graft is offered immediately after root avulsion. Thus, we determined the effects of minocycline treatment on neuronal survival, neurite growth and astroglial activation.…”

Section: Introductionmentioning

confidence: 99%

Prolonged Minocycline Treatment Impairs Motor Neuronal Survival and Glial Function in Organotypic Rat Spinal Cord Cultures

et al. 2013

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BackgroundMinocycline, a second-generation tetracycline antibiotic, exhibits anti-inflammatory and neuroprotective effects in various experimental models of neurological diseases, such as stroke, Alzheimer’s disease, amyotrophic lateral sclerosis and spinal cord injury. However, conflicting results have prompted a debate regarding the beneficial effects of minocycline.MethodsIn this study, we analyzed minocycline treatment in organotypic spinal cord cultures of neonatal rats as a model of motor neuron survival and regeneration after injury. Minocycline was administered in 2 different concentrations (10 and 100 µM) at various time points in culture and fixed after 1 week.ResultsProlonged minocycline administration decreased the survival of motor neurons in the organotypic cultures. This effect was strongly enhanced with higher concentrations of minocycline. High concentrations of minocycline reduced the number of DAPI-positive cell nuclei in organotypic cultures and simultaneously inhibited microglial activation. Astrocytes, which covered the surface of the control organotypic cultures, revealed a peripheral distribution after early minocycline treatment. Thus, we further analyzed the effects of 100 µM minocycline on the viability and migration ability of dispersed primary glial cell cultures. We found that minocycline reduced cell viability, delayed wound closure in a scratch migration assay and increased connexin 43 protein levels in these cultures.ConclusionsThe administration of high doses of minocycline was deleterious for motor neuron survival. In addition, it inhibited microglial activation and impaired glial viability and migration. These data suggest that especially high doses of minocycline might have undesired affects in treatment of spinal cord injury. Further experiments are required to determine the conditions for the safe clinical administration of minocycline in spinal cord injured patients.

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Reinnervation of the rat musculocutaneous nerve stump after its direct reconnection with the C5 spinal cord segment by the nerve graft following avulsion of the ventral spinal roots: a comparison of intrathecal administration of brain-derived neurotrophic factor and Cerebrolysin

Cited by 25 publications

References 37 publications

Neurotrophic effects of Cerebrolysin in the Mecp2308/Y transgenic model of Rett syndrome

Neurotrophic effects of Cerebrolysin in the Mecp2308/Y transgenic model of Rett syndrome

Motoneuron BDNF/TrkB signaling enhances functional recovery after cervical spinal cord injury

Prolonged Minocycline Treatment Impairs Motor Neuronal Survival and Glial Function in Organotypic Rat Spinal Cord Cultures

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