Inhibition of caspases promotes long-term survival and reinnervation by axotomized spinal motoneurons of denervated muscle in newborn rats

Chan, Yuk Tai; Yick, Leung-Wah; Yip, Henry K.; So, Kwok-Fai; Oppenheim, Ronald W.; Wu, Wutian

doi:10.1016/s0014-4886(03)00023-2

Cited by 23 publications

(13 citation statements)

References 63 publications

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“…Associated, downstream cytoplasmic cell death signals play a key role in promoting neuronal cell death in neonatal and immature animals that are sensitive to axonal injury. Deletion of bax or inhibition of caspase 3 or the whole family of caspases has been shown to prevent cell death [78,79], but with an enhanced and more persistent effect for broad caspase inhibitors than caspase 3 alone [79]. In both cases, bax and caspases appear to act downstream of jun phosphorylation (jun‐P) and the decrease in neuronal metabolism, suggesting a sequence of events beginning with jun‐P, leading to atrophy, activation of bax and ending with the initiation of the caspase cascade.…”

Section: Cell Death Signalsmentioning

confidence: 99%

Molecular mechanisms in successful peripheral regeneration

2005

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Injury to neurons results in a sequence of molecular and cellular responses that are associated with, and that may play an important role, in the mounting of a successful regenerative response, and the ensuing recovery of function. In the injured neuron, the rapid arrival of signals that contribute to cellular injury and stress is followed by the induction of transcription factors, adhesion molecules, growth-associated proteins and structural components needed for axonal elongation. These changes are accompanied by immense shifts in cellular organization: the appearance of growth cones at the proximal tip of the lesioned axons, the swelling of the neuronal cell body associated with a strong increase in cellular metabolism and protein synthesis, and the increase and regional dispersion of areas of rough endoplasmic reticulum or Nissl shoals in neuronal cytoplasm.This neuronal response is also associated with the expression of growth factors, cytokines, neuropeptides and other secreted molecules involved in cell-to-cell communication, which may be involved in the activation of neighbouring non-neuronal cells around the cell body of the injured neuron and in the distal nerve fibre tracts. In the adult mammalian nervous system peripheral nerves show vigorous regeneration. Conversely, axons injured inside central nerve tracts, normally fail to regenerate, regardless of whether their cell bodies are located inside the CNS. Deciphering the molecular and cellular basis for this failure of central regeneration and Peripheral nerve injury is normally followed by a robust regenerative response. Here we describe the early changes associated with injury from the initial rise in intracellular calcium and the subsequent activation of transcription factors and cytokines leading to an inflammatory reaction, and the expression of growth factors, cytokines, neuropeptides, and other secreted molecules involved in cell-to-cell communication promoting regeneration and neurite outgrowth. The aim of this review is to summarize the molecular mechanisms that play a part in executing successful regeneration.Abbreviations CH1L, close homologue of L1; CNTF, ciliary neurotrophic factor; FGF, fibroblast growth factor; IL, interleukin; MAP, mitogen-associated protein; MAP1B, microtubule-associated protein 1b; MCSF, macrophage colony-stimulating factor; MEK, mitogen-associated protein kinase kinase; NGF, nerve growth factor; NLS, nuclear localization signal; NT3, neurotrophin-3; PI3K, phosphatidyl-inositol-3 kinase; STAT3, signal transducer and activator of transcription-3; TNFR, tumour necrosis factor receptor.

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Section: Cell Death Signalsmentioning

confidence: 99%

Molecular mechanisms in successful peripheral regeneration

2005

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“…For example, ischemia‐induced apoptosis of hippocampal neurons was significantly curtailed by overexpression of caspase‐3 inhibitory proteins such as neuronal apoptosis inhibitory protein (NAIP) and X chromosome‐linked inhibitor of apoptosis protein (XIAP) (9, 10). Axotomy‐induced apoptosis of various neuronal subtypes was effectively suppressed by NAIP and XIAP expression (11–13) or through the use of caspase‐specific peptide inhibitors (14). In addition, peptide inhibition of caspase activity has been shown to substantially reduce apoptosis while promoting an increase in the survival of donor dopaminergic neurons following neural tissue grafts/transplants (15), although a more recent study suggests that such an approach may require further evaluation in a clinical setting (16).…”

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confidence: 99%

“…inhibitors (14). In addition, peptide inhibition of caspase activity has been shown to substantially reduce apoptosis while promoting an increase in the survival of donor dopaminergic neurons following neural tissue grafts/transplants (15), although a more recent study suggests that such an approach may require further evaluation in a clinical setting (16).…”

mentioning

confidence: 99%

Neural stem cell differentiation is dependent upon endogenous caspase‐3 activity

Fernando¹,

Brunette²,

2005

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Caspase proteases have become the focal point for the development and application of anti-apoptotic therapies in a variety of central nervous system diseases. However, this approach is based on the premise that caspase function is limited to invoking cell death signals. Here, we show that caspase-3 activity is elevated in nonapoptotic differentiating neuronal cell populations. Moreover, peptide inhibition of protease activity effectively inhibits the differentiation process in a cultured neurosphere model. These results implicate caspase-3 activation as a conserved feature of neuronal differentiation and suggest that targeted inhibition of this protease in neural cell populations may have unintended consequences.

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“…N‐acetyl‐cysteine promotes motoneuron survival for a period of 4 weeks (Zhang et al ., ). In contrast, a general caspase inhibitor (Boc‐D‐FMK) and a specific caspase‐3 inhibitor (Ac‐DEVD‐CHO) improved motoneuron survival in neonatal but not adult rats up to 2 weeks (Chan et al ., , ).…”

Section: Fundamental Researchmentioning

confidence: 97%

“…Pharmacotherapeutic interventions following ventral root avulsion have primarily targeted the motoneurons in the ventral horn using neuroprotective or immune-modulatory agents ( Table 2). Neuroprotective approaches aimed at reducing glutamate excitotoxicity (Nogradi & Vrbova, 2001;Nagano et al, 2003;Bergerot et al, 2004;Nogradi et al, 2007;Pinter et al, 2010;Penas et al, 2011;Wu et al, 2013;Chew et al, 2014;Fu et al, 2014), preventing apoptosis by inhibition of the caspase pathway (Chan et al, 2001(Chan et al, , 2003Zhang et al, 2005) or the inhibition of NOS (Wu & Li, 1993;Zhou & Wu, 2006a).…”

Section: Pharmacological Interventionsmentioning

confidence: 99%

Clinical and neurobiological advances in promoting regeneration of the ventral root avulsion lesion

Eggers

Tannemaat

Winter

et al. 2015

Eur J of Neuroscience

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Root avulsions due to traction to the brachial plexus causes complete and permanent loss of function. Until fairly recent, such lesions were considered impossible to repair. Here we review clinical repair strategies and current progress in experimental ventral root avulsion lesions. The current gold standard in patients with a root avulsion is nerve transfer, whereas reimplantation of the avulsed root into the spinal cord has been performed in a limited number of cases. These neurosurgical repair strategies have significant benefit for the patient but functional recovery remains incomplete. Developing new ways to improve the functional outcome of neurosurgical repair is therefore essential. In the laboratory, the molecular and cellular changes following ventral root avulsion and the efficacy of intervention strategies have been studied at the level of spinal motoneurons, the ventral spinal root and peripheral nerve, and the skeletal muscle. We present an overview of cell-based pharmacological and neurotrophic factor treatment approaches that have been applied in combination with surgical reimplantation. These interventions all demonstrate neuroprotective effects on avulsed motoneurons, often accompanied with various degrees of axonal regeneration. However, effects on survival are usually transient and robust axon regeneration over long distances has as yet not been achieved. Key future areas of research include finding ways to further extend the post-lesion survival period of motoneurons, the identification of neuron-intrinsic factors which can promote persistent and long-distance axon regeneration, and finally prolonging the pro-regenerative state of Schwann cells in the distal nerve.

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Inhibition of caspases promotes long-term survival and reinnervation by axotomized spinal motoneurons of denervated muscle in newborn rats

Cited by 23 publications

References 63 publications

Molecular mechanisms in successful peripheral regeneration

Molecular mechanisms in successful peripheral regeneration

Neural stem cell differentiation is dependent upon endogenous caspase‐3 activity

Clinical and neurobiological advances in promoting regeneration of the ventral root avulsion lesion

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