Traumatic spinal cord injury (SCI) causes tissue loss and associated neurological dysfunction through mechanical damage and secondary biochemical and physiological responses. We have previously described the pathobiological role of cell cycle pathways following rat contusion SCI by examining the effects of early intrathecal cell cycle inhibitor treatment initiation or gene knockout on secondary injury. Here, we delineate changes in cell cycle pathway activation following SCI and examine the effects of delayed (24 h) systemic administration of flavopiridol, an inhibitor of major cyclin-dependent kinases (CDKs), on functional recovery and histopathology in a rat SCI contusion model. Immunoblot analysis demonstrated a marked upregulation of cell cycle-related proteins, including pRb, cyclin D1, CDK4, E2F1 and PCNA, at various time points following SCI, along with downregulation of the endogenous CDK inhibitor p27. Treatment with flavopiridol reduced induction of cell cycle proteins and increased p27 expression in the injured spinal cord. Functional recovery was significantly improved after SCI from day 7 through day 28. Treatment significantly reduced lesion volume and the number of Iba-1+ microglia in the preserved tissue and increased the myelinated area of spared white matter as well as the number of CC1+ oligodendrocytes. Furthermore, flavopiridol attenuated expression of Iba-1 and glactin-3, associated with microglial activation and astrocytic reactivity by reduction of GFAP, NG2, and CHL1 expression. Our current study supports the role of cell cycle activation in the pathophysiology of SCI and by using a clinically relevant treatment model, provides further support for the therapeutic potential of cell cycle inhibitors in the treatment of human SCI. 相似文献
The amyloid precursor protein (APP) is a transmembrane protein mostly recognized for its association with Alzheimer's disease. The physiological function of APP is still not completely understood much because of the redundancy between genes in the APP family. In this study we have used zebrafish to study the physiological function of the zebrafish APP homologue, appb, during development. We show that appb is expressed in post-mitotic neurons in the spinal cord. Knockdown of appb by 50–60% results in a behavioral phenotype with increased spontaneous coiling and prolonged touch-induced activity. The spinal cord motor neurons in these embryos show defective formation and axonal outgrowth patterning. Reduction in Appb also results in patterning defects and changed density of pre- and post-synapses in the neuromuscular junctions. Together, our data show that development of functional locomotion in zebrafish depends on a critical role of Appb in the patterning of motor neurons and neuromuscular junctions. 相似文献
Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem, and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. AR‐associated coregulator 70 (ARA70) was the first coregulator of AR to be identified, and it has been shown to interact with AR and increase its protein stability. Here, we report that genistein, an isoflavone found in soy, disrupts the interaction between AR and ARA70 and promotes the degradation of mutant AR in neuronal cells and transgenic mouse models of SBMA. We also demonstrate that dietary genistein ameliorates behavioral abnormalities, improves spinal cord and muscle pathology, and decreases the amounts of monomeric AR and high‐molecular‐weight mutant AR protein aggregates in SBMA transgenic mice. Thus, genistein treatment may be a potential therapeutic approach for alleviating the symptoms of SBMA by disrupting the interactions between AR and ARA70. 相似文献
Growth factors and nutrients, such as amino acids and glucose, regulate mammalian target of rapamycin complex 1 (mTORC1) signaling and subsequent translational control in a coordinated manner. Brain‐derived neurotrophic factor (BDNF), the most prominent neurotrophic factor in the brain, activates mTORC1 and induces phosphorylation of its target, p70S6 kinase (p70S6K), at Thr389 in neurons. BDNF also increases mammalian target of rapamycin‐dependent novel protein synthesis in neurons. Here, we report that BDNF‐induced p70S6K activation is dependent on glucose, but not amino acids, sufficiency in cultured cortical neurons. AMP‐activated protein kinase (AMPK) is the molecular background to this specific nutrient dependency. Activation of AMPK, which is induced by glucose deprivation, treatment with pharmacological agents such as 2‐Deoxy‐d ‐glucose, metformin, and 5‐aminoimidazole‐4‐carboxamide ribonucleoside or forced expression of a constitutively active AMPKα subunit, counteracts BDNF‐induced phosphorylation of p70S6K and enhanced protein synthesis in cortical neurons. These results indicate that AMPK inhibits the effects of BDNF on mTORC1‐mediated translation in neurons.
Activity of inhibitory neuron with delayed feedback is considered in the framework of point stochastic processes. The neuron receives excitatory input impulses from a Poisson stream, and inhibitory impulses from the feedback line with a delay. We investigate here, how does the presence of inhibitory feedback affect the output firing statistics. Using binding neuron (BN) as a model, we derive analytically the exact expressions for the output interspike intervals (ISI) probability density, mean output ISI and coefficient of variation as functions of model's parameters for the case of threshold 2. Using the leaky integrate-and-fire (LIF) model, as well as the BN model with higher thresholds, these statistical quantities are found numerically. In contrast to the previously studied situation of no feedback, the ISI probability densities found here both for BN and LIF neuron become bimodal and have discontinuity of jump type. Nevertheless, the presence of inhibitory delayed feedback was not found to affect substantially the output ISI coefficient of variation. The ISI coefficient of variation found ranges between 0.5 and 1. It is concluded that introduction of delayed inhibitory feedback can radically change neuronal output firing statistics. This statistics is as well distinct from what was found previously (Vidybida and Kravchuk, 2009) by a similar method for excitatory neuron with delayed feedback. 相似文献
Malignant neuroblastomas mostly occur in children and are frequently associated with N-Myc amplification. Oncogene amplification, which is selective increase in copy number of the oncogene, provides survival advantages in solid tumors including malignant neuroblastoma. We have decreased expression of N-Myc oncogene using short hairpin RNA (shRNA) plasmid to increase anti-tumor efficacy of the isoflavonoid apigenin (APG) in human malignant neuroblastoma SK-N-DZ and SK-N-BE2 cell lines that harbor N-Myc amplification. N-Myc knockdown induced morphological and biochemical features of neuronal differentiation. Combination of N-Myc knockdown and APG most effectively induced morphological and biochemical features of apoptotic death. This combination therapy also prevented cell migration and decreased N-Myc driven survival, angiogenic, and invasive factors. Collectively, N-Myc knockdown and APG treatment is a promising strategy for controlling the growth of human malignant neuroblastoma cell lines that harbor N-Myc amplification. 相似文献
The aim of this study is to examine mastication-specific activity of orofacial neurons in the motor and masticatory cortices of the awake cat. We examine properties of mastication-related neurons (MRNs) in masticatory (MA, the rostral region of the orbital gyrus) and motor (area P, the lateral wall of the presylvian sulcus) cortical areas that are related to mastication of cats. MRNs in MA and area P had in common mechanoreceptive fields (RFs) in perioral, mandibular and lingual regions, and many MRNs had bilateral RFs in the tongue and mandibular regions. Facial RF size was the largest in area P. Eleven percent of MRN recording sites in MA, and 43% in area P evoked various motor effects with the use of intracortical microstimulation (ICMS). MRNs of the pre-movement type showing activities prior to mastication, or masticatory or lingual EMG, were 14% in MA and 45% in area P. Based on wheat germ agglutinin–horseradish peroxidase (WGA-HRP) injection into area P and MA, cortico-cortical connections were examined. After the unilateral area P injection, were reciprocal connections between the contralateral area P and bilateral MA were demonstrated. After the unilateral MA injection, there were reciprocal connections between the contralateral MA, bilateral area P and bilateral orofacial SI (the orofacial region of the first somatosensory area). These findings suggest that accurate masticatory movements may be executed by the cortical processing in MA and area P. 相似文献