Experimental neurology
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Experimental neurology · Feb 2012
Comparative StudyPosttraumatic hypothermia increases doublecortin expressing neurons in the dentate gyrus after traumatic brain injury in the rat.
Previous studies have demonstrated that moderate hypothermia reduces histopathological damage and improves behavioral outcome after experimental traumatic brain injury (TBI). Further investigations have clarified the mechanisms underlying the beneficial effects of hypothermia by showing that cooling reduces multiple cell injury cascades. The purpose of this study was to determine whether hypothermia could also enhance endogenous reparative processes following TBI such as neurogenesis and the replacement of lost neurons. ⋯ At 7 days after TBI, both normothermic and hypothermic TBI animals demonstrated a significant increase in the number of BrdU-immunoreactive cells in the DG as compared to sham-operated controls. At 7 days post-injury, hypothermia animals had a greater number of BrdU (ipsilateral cortex) and doublecortin (ipsilateral and contralateral cortex) immunoreactive cells in the DG as compared to normothermia animals. Because adult neurogenesis following injury may be associated with enhanced functional recovery, these data demonstrate that therapeutic hypothermia sustains the increase in neurogenesis induced by TBI and this may be one of the mechanisms by which hypothermia promotes reparative strategies in the injured nervous system.
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Experimental neurology · Feb 2012
Comparative StudySpinal cord injury with unilateral versus bilateral primary hemorrhage--effects of glibenclamide.
In spinal cord injury (SCI), block of Sur1-regulated NC(Ca-ATP) channels by glibenclamide protects penumbral capillaries from delayed fragmentation, resulting in reduced secondary hemorrhage, smaller lesions and better neurological function. All published experiments demonstrating a beneficial effect of glibenclamide in rat models of SCI have used a cervical hemicord impact calibrated to produce primary hemorrhage located exclusively ipsilateral to the site of impact. Here, we tested the hypothesis that glibenclamide also would be protective in a model with more extensive, bilateral primary hemorrhage. ⋯ In the UPH model, the effects of glibenclamide were similar to previous observations, including a functional benefit as early as 24h after injury and 6-week lesion volumes that were 57% smaller than controls. In the BPH model, glibenclamide exerted a significant benefit over controls, but the functional benefit was smaller than in the UPH model and 6-week lesion volumes were 33% smaller than controls. We conclude that glibenclamide is beneficial in different models of cervical SCI, with the magnitude of the benefit depending on the magnitude and extent of primary hemorrhage.
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Experimental neurology · Feb 2012
Comparative StudyIndependent evaluation of the effects of glibenclamide on reducing progressive hemorrhagic necrosis after cervical spinal cord injury.
These experiments were completed as part of an NIH-NINDS contract entitled "Facilities of Research Excellence - Spinal Cord Injury (FORE-SCI) - Replication". Our goal was to replicate pre-clinical data from Simard et al. (2007) showing that glibenclamide, an FDA approved anti-diabetic drug that targets sulfonylurea receptor 1 (SUR1)-regulated Ca(2+) activated, [ATP](i)-sensitive nonspecific cation channels, attenuates secondary intraspinal hemorrhage and secondary neurodegeneration caused by hemicontusion injury in rat cervical spinal cord. In an initial replication attempt, the Infinite Horizons impactor was used to deliver a standard unilateral contusion injury near the spinal cord midline. ⋯ In the third experiment, we also assessed function and found that acute reduction of hemorrhage led to improved functional recovery. Thus, independent replication of the Simard et al. data was achieved. These data illustrate that the injury model and type of trauma can determine the efficacy of pre-clinical pharmacological treatments after SCI.
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Experimental neurology · Feb 2012
Comparative StudyIB4-saporin attenuates acute and eliminates chronic muscle pain in the rat.
The function of populations of nociceptors in muscle pain syndromes remain poorly understood. We compared the contribution of two major classes, isolectin B4-positive (IB4(+)) and IB4-negative (IB4(-)) nociceptors, in acute and chronic inflammatory and ergonomic muscle pain. Baseline mechanical nociceptive threshold was assessed in the gastrocnemius muscle of rats treated with IB4-saporin, which selectively destroys IB4(+) nociceptors. ⋯ And, IB4-saporin treatment completely prevented prolongation of PGE(2)-induced mechanical hyperalgesia. Thus, IB4(+) and IB4(-) neurons contribute to acute muscle hyperalgesia induced by diverse insults. However, only IB4+ nociceptors participate in the long term consequence of acute hyperalgesia.
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Experimental neurology · Feb 2012
Comparative StudyProbucol, a lipid-lowering drug, prevents cognitive and hippocampal synaptic impairments induced by amyloid β peptide in mice.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss and cognitive impairments. The presence of extracellular senile plaques (mainly composed of amyloid-β (Aβ) peptide) is an important molecular hallmark in AD and neuronal damage has been attributed, at least in part, to Aβ-mediated toxicity. Although the molecular mechanisms involved in the pathogenesis of AD are not yet completely understood, several lines of evidence indicate that oxidative stress and cholesterol dyshomeostasis play crucial roles in mediating the synaptic loss and cognitive deficits observed in AD patients. ⋯ In addition, the present results indicate that Probucol is able to counteract the cognitive and biochemical impairments induced by i.c.v. Aβ(1-40) administration in mice. The study is the first to report the protective effects of Probucol (a "non-statin cholesterol-lowering drug") against Aβ(1-40)-induced synaptic and behavioral impairments, rendering this compound a promising molecule for further pharmacological studies on the search for therapeutic strategies to treat or prevent AD.