Journal of neuropathology and experimental neurology
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J. Neuropathol. Exp. Neurol. · Dec 2011
Rescue of synaptic failure and alleviation of learning and memory impairments in a trisomic mouse model of down syndrome.
Down syndrome (DS) is caused by the triplication of ∼240 protein-coding genes on chromosome 21 and is the most prevalent form of developmental disability. This condition results in abnormalities in many organ systems, as well as in intellectual retardation. Many previous efforts to understand brain dysfunction in DS have indicated that cognitive deficits are coincident with reduced synaptic plasticity and decreased neuronal proliferation. ⋯ Here, we show that peripheral administration of Peptide 6, an 11-mer corresponding to an active region of ciliary neurotrophic factor, amino acid residues 146 to 156, can inhibit learning and memory impairments in Ts65Dn mice, a trisomic mouse model of DS. Long-term treatment with Peptide 6 enhanced the pool of neural progenitor cells in the hippocampus and increased levels of synaptic proteins crucial for synaptic plasticity. These findings suggest a therapeutic potential of Peptide 6 in promoting functional neural integration into networks, thereby strengthening biologic substrates of memory processing.
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J. Neuropathol. Exp. Neurol. · Nov 2011
Characteristics of an explosive blast-induced brain injury in an experimental model.
Mild traumatic brain injury resulting from exposure to an explosive blast is associated with significant neurobehavioral outcomes in soldiers. Little is known about the neuropathologic consequences of such an insult to the human brain. This study is an attempt to understand the effects of an explosive blast in a large animal gyrencephalic brain blast injury model. ⋯ The overall pathologic changes in all 3 blast scenarios were limited, with very little neuronal injury, fiber tract demyelination, or intracranial hemorrhage observed. However, there were 2 distinct neuropathologic changes observed: increased astrocyte activation and proliferation and periventricular axonal injury detected with β-amyloid precursor protein immunohistochemistry. We postulate that the increased astrogliosis observed may have a longer-term potential for the exacerbation of brain injury and that the pattern of periventricular axonal injury may be related to a potential for cognitive and mood disorders.
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J. Neuropathol. Exp. Neurol. · Sep 2011
Signaling of glial cell line-derived neurotrophic factor and its receptor GFRα1 induce Nurr1 and Pitx3 to promote survival of grafted midbrain-derived neural stem cells in a rat model of Parkinson disease.
Glial cell line-derived neurotrophic factor (GDNF) and its receptor GFRα1 have been implicated in the survival of ventral midbrain dopaminergic (DA) neurons, but the molecular mechanisms bywhich GDNF generates DA neurons in grafted midbrain-derived neural stem cells (mNSCs) are not understood. Midbrain-derived neural stem cells isolated from rat embryonic mesencephalon (embryonic day 12) were treated with GDNF or in combination with GFRα1 small interfering RNA. Reverse transcription-polymerase chain reaction, Western blot, and immunocytochemistry were used totest the expression of the orphan nuclear receptor Nurr1 and thetranscription factor Pitx3 and newborn tyrosine hydroxylase (TH)-positive cells. ⋯ Glialcell line-derived neurotrophic factor-treated mNSCs showed increased numbers of TH/Pitx3- and TH/Nurr1-postivie cells. The effect elicited by GDNF was inhibited by small interfering RNA-mediated knockdown of GFRα1. Our data demonstrate the contribution of GDNF to DA neuron development and may also elucidate pathogenetic mechanisms in Parkinson disease and contribute to the development of novel therapies for the disorder.
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J. Neuropathol. Exp. Neurol. · Aug 2011
Prominent microglial activation in the early proinflammatory immune response in naturally occurring canine spinal cord injury.
Better understanding of the pathogenesis of spinal cord injury (SCI) is needed for the development of new therapeutic strategies. Spinal cord injury has been investigated in various rodent models, but extrapolation to humans requires the use of a large animal model that more closely mimics human SCI. Dogs frequently develop spontaneous SCI with features that bear a striking resemblance to the human counterpart. ⋯ IL-10) remained unchanged, and transforming growth factor β upregulation was delayed. In organotypic spinal cord slices, there was similar activation of major histocompatibility complex class II-positive microglia and prolonged upregulation of inflammatory cytokines, indicating that resident rather than infiltrating cells play major roles in the postinjury immune response. Thus, canine SCI represents a bridge between rodent models and human SCI that may be relevant for clinical and preclinical treatment studies.
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J. Neuropathol. Exp. Neurol. · Jun 2011
Impairment of tight junctions and glucose transport in endothelial cells of human cerebral cavernous malformations.
Cerebral cavernous malformations (CCMs) often cause hemorrhages that can result in severe clinical manifestations, including hemiparesis and seizures. The underlying mechanisms of the aggressive behavior of CCMs are undetermined to date, but alterations of vascular matrix components may be involved. ⋯ Corresponding analysis using quantitative real-time reverse transcription polymerase chain reaction on 8 CCM and 8 control specimens revealed significant downregulation of mRNA expression of occludin, claudin-5, ZO-1, and GLUT-1. The altered expression and localization of the TJPs at interendothelial contact sites accompanied by a reduction of GLUT-1 expression in dilated CCM microvessels likely affect vascular matrix stability and may contribute to hemorrhages of CCMs.