Journal of neuroscience research
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Peripheral sensitization of skin nociceptors by nerve growth factor (NGF) was explored in pig skin in vivo. As an objective output measure, the area of axon-reflex-mediated erythema was assessed upon mechanical, thermal, chemical, and electrical stimuli delivered at 1, 3, and 7 days after i.d. injection of 1 microg NGF into the pig's back skin (n = 8). Pretreatment with NGF provoked a sensitization to mechanical (600 mN), thermal (10 sec 49 degrees C) and chemical (15 microl, pH 3) stimuli that lasted for 7 days. ⋯ Sensitization of sensory endings by NGF upon mechanical, heat, and chemical stimuli suggests recruitment of sensory transducer molecules [e.g., TRPV1, acid-sensing ion channels (ASICs)]. In contrast, the gradual decrease in electrically induced erythema over 7 days might be attributable to axonal desensitization and possibly activity-dependent down-regulation of sodium channels. Thus, long-lasting sensitization processes of nociceptor endings or axonal sodium channel desensitization mechanisms can be explored in the pig as a translational experimental animal model.
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We evaluated a role of hypoxia-inducible factor-1alpha (HIF-1alpha) and its downstream genes in acute hyperglycemia-induced hemorrhagic transformation in a rat model of focal cerebral ischemia. Male Sprague-Dawley rats weighing 280-300 g (n = 105) were divided into sham, 90 min middle cerebral artery occlusion (MCAO), MCAO plus HIF-1alpha inhibitors, 2-methoxyestradiol (2ME2) or 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), groups. Rats received an injection of 50% dextrose (6 ml/kg intraperitoneally) at 15 min before MCAO. ⋯ Both 2ME2 and YC-1 reduced infarct volume and ameliorated neurological deficits. However, only 2ME2 attenuated hemorrhagic transformation in the ischemic territory. In conclusion, the inhibition of HIF-1alpha and its downstream genes attenuates hemorrhagic conversion of cerebral infarction and ameliorates neurological deficits after focal cerebral ischemia.
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High intracranial pressure (ICP) is a prominent secondary pathology after traumatic brain injury (TBI) and is a major contributor to morbidity and mortality. Currently, there are no clinically proven methods for predicting which TBI patients will develop high ICP. In the present study, we examined whether the serum levels of the copper-binding protein ceruloplasmin are differentially altered in patients with elevated ICP (> or =25 mmHg) vs. those whose ICP remained below 20 mmHg throughout the study period. ⋯ However, prior to this delayed increase, ceruloplasmin levels during the first 24 hr following injury were found to be significantly reduced in patients who subsequently developed high ICP. This decrease was found to have prognostic accuracy in delineating TBI patients based on their ICP status (cutoff of 140 microg/ml; sensitivity: 87%, specificity: 73%), Likewise, low total serum copper (below 1.32 microg/ml) was also found to be predictive of high ICP (sensitivity 86%, specificity 73%). These results suggest that initial serum ceruloplasmin/copper levels may have diagnostic value in predicting patients at risk for developing high intracranial pressure.
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Spinal cord injury (SCI) causes loss of neurological function and, depending on serverity, may cause paralysis. The only recommended pharmacotherapy for the treatment of SCI is high-dose methylprednisolone, and its use is controversial. We have previously shown that estrogen treatment attenuated cell death, axonal and myelin damage, calpain and caspase activities, and inflammation in acute SCI. ⋯ After treatment, animals were sacrificed at the end of 6 weeks following injury, and 1-cm segments of spinal cord (lesion, rostral to lesion, and caudal to lesion) were removed for biochemical analyses. Estrogen treatment reduced COX-2 activity, blocked nuclear factor-kappaB translocation, prevented glial reactivity, attenuated neuron death, inhibited activation and activity of calpain and caspase-3, decreased axonal damage, reduced myelin loss in the lesion and penumbra, and improved locomotor function compared with vehicle-treated animals. These findings suggest that estrogen may be useful as a promising therapeutic agent for prevention of damage and improvement of locomotor function in chronic SCI. (c) 2010 Wiley-Liss, Inc.
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Activated microglia can influence the survival of neural cells through the release of cytotoxic factors. Here, we investigated the interaction between Toll-like receptor 4 (TLR4)-activated microglia and oligodendrocytes or their precursor cells (OPC). Primary rat or N9 microglial cells were activated by exposure to TLR4-specifc lipopolysaccharide (LPS), resulting in mitogen-activated protein kinase activation, increased CD68 and inducible nitric oxide synthase expression, and release of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6). ⋯ Although LPS stimulation of OPC did not induce proinflammatory cytokine release or affect their survival, it did trigger JNK phosphorylation, suggesting that TLR4 signalling in these cells is active. These findings suggest that OPC survival may be influenced not only by factors released from endotoxin-activated microglia but also through a direct response to endotoxins. This may have consequences for myelination under conditions in which microglial activation and cerebral infection are both implicated. , Inc.