Experimental neurology
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Experimental neurology · Aug 2008
Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats.
Spinal cord injury (SCI) impairs sensory systems causing chronic allodynia. Mechanisms underlying neuropathic pain have been more extensively studied following peripheral nerve injury (PNI) than after central trauma. Microglial activation, pro-inflammatory cytokine production and activation of p38 MAP kinase pathways may induce at-level allodynia following PNI. ⋯ These data suggest that remote microglial activation is pivotal in the development and maintenance of below-level allodynia after SCI. Fractalkine, a known activator of microglia, and astrocytes were not primary modulators of below-level pain. Although the mechanisms of remote microglial activation are unknown, this response may be a viable target for limiting or preventing neuropathic pain after SCI in humans.
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Experimental neurology · Aug 2008
Secondary pathology following contusion, dislocation, and distraction spinal cord injuries.
Preclinical studies for spinal cord injury (SCI) have utilized transection and contusion injury paradigms even though human SCIs occur by a spectrum of primary injury mechanisms such as spinal cord contusion from vertebral burst fracture, shearing from fracture-dislocation, and stretching from distraction injuries. We contrasted the neuropathology in animal models mimicking these clinically relevant injuries at an early 3-hour time-point in order to relate patterns of secondary pathology to the primary injury mechanism. Axolemma compromise, detected by the intracellular penetration of dextran-conjugated fluorophores, was localized to the contusion epicentre but extended rostrally following dislocation and distraction injuries. ⋯ Microglial activation was localized to the contusion epicentre, extended rostro-caudally following dislocation, but was similar to surgical controls after distraction injuries. Reactive astrocytes extended rostro-caudally only following dislocation injuries. Hence, the primary injury mechanism alters the pattern of secondary degeneration indicating that different neuroprotective strategies may ultimately be required for treating distinct clinically relevant SCIs.
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Experimental neurology · Aug 2008
Transient cerebral ischemia increases CA1 pyramidal neuron excitability.
In human and experimental animals, the hippocampal CA1 region is one of the most vulnerable areas of the brain to ischemia. Pyramidal neurons in this region die 2-3 days after transient cerebral ischemia whereas other neurons in the same region remain intact. The mechanisms underlying the selective and delayed neuronal death are unclear. ⋯ Finally, when lamotrigine, an enhancer of dendritic I(h), was applied immediately after ischemia, there was a significant attenuation of CA1 cell loss. These data suggest that an increase in CA1 pyramidal neuron excitability after ischemia may exacerbate cell loss. Moreover, this dendritic channelopathy may be amenable to treatment.
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Experimental neurology · Jul 2008
Neuroprotective effect of the new thiadiazolidinone NP00111 against oxygen-glucose deprivation in rat hippocampal slices: implication of ERK1/2 and PPARgamma receptors.
Thiadiazolidinones (TDZDs) are small molecules that inhibit glycogen synthase kinase 3-beta (GSK3-beta) activity in a non competitive manner to ATP. NP00111, a new TDZD, besides causing inhibition of GSK-3beta, has also shown to be an agonist of PPARgamma. Since phosphorylation and consequent inhibition of GSK-3beta by PI-3K/Akt and agonism of PPARgamma have shown to afford neuroprotection in several in vitro and in vivo models, we have studied the potential neuroprotective effect of NP00111 in an "in vitro" model of ischemia-reperfusion. ⋯ Protection afforded by NP00111 and rosiglitazone were prevented by the PPARgamma antagonist GW9662, suggesting that both NP00111 and rosiglitazone were preventing cell death caused by oxygen-glucose deprivation via activation of PPARgamma. NP00111 increased by two fold phosphorylation of ERK1/2 and its protective effects were lost when the hippocampal slices were co-incubated with the mitogen-activated protein kinase (MAPK) inhibitor PD98059. In conclusion, the novel TDZD NP00111 was protective against OGD in rat hippocampal slices by a mechanism related to phosphorylation of ERK1/2 via activation of PPARgamma.
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Experimental neurology · Jul 2008
A novel transgenic mouse expressing double mutant tau driven by its natural promoter exhibits tauopathy characteristics.
The neurofibrillary-tangles (NTFs), characteristic of tauopathies including Alzheimer's-disease (AD), are the pathological features which correlate best with dementia. The objective of our study was to generate an authentic transgenic (tg) animal model for NFT pathology in tauopathy/AD. Previous NFT-tg mice were driven by non-related/non-homologous promoters. ⋯ This is a unique mutant-htau-tg model which presents a wide spectrum of features characteristic of tauopathy/AD, which does not show unrelated motor deficits described in other models of tauopathy. In addition, expressing the DM-htau in a neuronal cell model resulted in tau-aggregation, as well as impaired microtubule arrangement. Both animal and cell models, which were regulated under the natural tau promoter (of rat origin), provide authentic and reliable models for tauopathy, and offer valuable tools for understanding the molecular events underlying tauopathies including AD.