Neuroscience
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Comparative Study
Glial cell line-derived neurotrophic factor contributes to delayed inflammatory hyperalgesia in adjuvant rat pain model.
Neurotrophic factors, such as nerve growth factor and brain-derived neurotrophic factor, are members of the structurally related neurotrophin family that play important roles in pain modulation. Although there are also indications for the involvement of glial cell line-derived neurotrophic factor (GDNF), it is unclear whether and how GDNF is involved in inflammatory pain. In the present study, we studied the expression pattern of GDNF in dorsal root ganglia (DRG) and spinal cord, using confocal microscopy. ⋯ To assess the impact of this down-regulation on pain transmission, we used a function-blocking antibody against GDNF delivered intrathecally in the same chronic-pain animal models. Injection of this antibody to GDNF produced no immediate effect, but decreased the delayed, bilateral hyperalgesia induced from a unilateral injection of complete Freund's adjuvant. The effect of this antibody coincided with the down-regulation of GDNF immunoreactivity in response to inflammation, suggesting that GDNF supports biochemical changes that contribute to hyperalgesia.
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The formation of edema after traumatic brain injury (TBI) is in part associated with the disruption of the blood-brain barrier. However, the molecular and cellular mechanisms underlying these phenomena have not been fully understood. One possible factor involved in edema formation is vascular endothelial growth factor (VEGF). ⋯ The maximum number of astrocytes expressing VEGF was observed 4 days after TBI, and then the levels of astroglial VEGF expression declined gradually. Early invasion of brain parenchyma by VEGF-secreting neutrophils together with a delayed increase in astrocytic synthesis of this growth factor correlate with the biphasic opening of the blood-brain barrier and formation of edema previously observed after TBI. Therefore, these findings suggest that VEGF plays an important role in promoting the formation of post-traumatic brain edema.
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The heme oxygenase (HO) enzyme system has been shown to participate in nociceptive signaling in a number of different models of pain. In these experiments we investigated the role of the HO type 2 (HO-2) isozyme in tolerance to the analgesic effects of morphine, and the hyperalgesia and allodynia which are measurable upon cessation of administration. Wild type C57Bl/6 wild type mice or HO-2 null mutants in that background strain were treated with morphine for 5 days. ⋯ In pellet-treated mice two- to three-fold increases were observed in the abundance of these species, but very little change was observed in the null-mutant mice. Taken together our results indicate that HO-2 participates in the acquisition of opioid tolerance, the expression of mechanical allodynia after cessation of opioid administration and in gene regulation occurring in the setting of treatment with morphine. Furthermore, these studies suggest that the mechanisms underlying analgesic tolerance and opioid-induced hypersensitivity are at least somewhat distinct.
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Glial cell line-derived neurotrophic factor (GDNF) signals through multisubunit receptor complex consisting of RET tyrosine kinase and a glycosylphosphatidylinositol-anchored coreceptor called GDNF family receptor alpha1 (GFRalpha1). In the current study, we cloned a human SEP1 gene as a GDNF-inducible gene using human neuroblastoma cells that express RET and GFRalpha1. The induction of the SEP1 gene showed two peaks at 0.5-2 h and 24-48 h after GDNF stimulation by Northern blotting and quantitative real-time reverse transcriptase polymerase chain reaction. ⋯ In addition, we found a high level of SEP1 expression in neurons of the dorsal root and superior cervical ganglia and motor neurons of the spinal cord of mice in which RET is also expressed. SEP1 was co-immunoprecipitated with alpha- and beta-tubulins from the lysate of mouse brain. These results thus suggested that SEP1 is a GDNF-inducible and microtubule-associated protein that may play a role in the nervous system.
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Comparative Study
Alzheimer's disease proteins in cerebellar and hippocampal synapses during postnatal development and aging of the rat.
Alzheimer's dementia may be considered a synaptic disease of central neurons: the loss of synapses, reflected by early cognitive impairments, precedes the appearance of extra cellular focal deposits of beta-amyloid peptide in the brain of patients. Distinct immunocytochemical patterns of amyloid precursor proteins (APPs) have previously been demonstrated in the synapses by ultrastructural analysis in the cerebellum and hippocampus of adult rats and mice. Now we show that during postnatal development and during aging in these structures, the immunocytochemical expression of APPs increases in the synapses in parallel with the known up-regulation of total APPs brain levels. ⋯ In addition, double-labelling immunocytofluorescence detects these proteins close to synaptophysin at the growth cones of developing cultured neurons. Thusly, the brain expression of APPs and PSs appears to be regulated synchronously during lifespan in the synaptic compartments where the proteins are colocated. This suggests that PS-dependent processing of important synaptic proteins such as APPs could intervene in age-induced adjustments of synaptic relationships between specific types of neurons.