Brain research
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In the present study, we examined the effects of OPC-14117, a superoxide radical scavenger, on the secondary cellular damage and cognitive dysfunction occurring in a rat model of cerebral contusion induced by a controlled cortical impact (CCI). Histological examinations revealed that the contusion necrosis volume reached 13.6+/-5.3 mm(3) in non-treated animals and declined to 1.9+/-0.6 mm(3) in OPC-14117-treated animals (P<0.01). The cell number of the CA3 region was 120.0+/-12.4 cells/mm in the normal controls, 73.6+/-9.9 cells/mm in the non-treated animals, and 111.2+/-10.2 cells/mm in the OPC-14117-treated animals, indicating that CCI-induced selective neuronal cell death in the CA3 region was attenuated by the OPC-14117 administration (P<0.01). ⋯ The OPC-14117-treated animals showed a tendency to improve on the Morris water maze performance test. The impairment of the habituation of exploratory activity elicited by CCI was significantly attenuated by OPC-14117 administration (P<0.05). In conclusion, OPC-14117 may have a potential for decreasing secondary cellular damage due to traumatic brain injury since it is as efficacious as any other compound tested in this model.
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Glutamate excitotoxicity plays a key role in inducing neuronal cell death in many neurological diseases. In mice, administration of kainic acid, an analogue of the excitotoxin glutamate, results in hippocampal cell death and seizures. Kainic-acid-induced seizures in mice provide a well-characterized model for studies of human neurodegenerative diseases. ⋯ The hippocampal lesions were associated with a high level of cyclooxygenase-2 production as well as astrogliosis. Administration of kainic acid also altered behavioral responses, with mice showing a significant increase in locomotion and rearing activity as indicated by an open-field test. This animal model could provide a valuable tool for exploring the role of excitotoxicity in neuropathological conditions and should be further evaluated in gene-targeting studies of neurodegenerative diseases.
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Anti-GD(2) antibodies have been shown to be effective for immunotherapy of neuroblastoma and other GD(2) enriched malignancies. Infusion of anti-GD(2) antibodies frequently causes spontaneous pain and allodynia for the duration of the immunotherapy and occasionally longer lasting neuropathic pain. Bolus intravenous injection of anti-GD(2) in rats initiates mechanical allodynia as measured by withdrawal threshold of the hindpaws. ⋯ Intrathecal pretreatment 48--72 h prior to the experiment with capsaicin at doses sufficient to cause a 50% depletion of dorsal horn CGRP, caused a total blockade of the mechanical allodynia indicating an involvement of peptidergic fine afferent fibers. It is likely that the antibody reacts with an antigen on peripheral nerve and/or myelin to initiate its effect. The lack of observed thermal hyperalgesia is surprising especially in light of the capsaicin-associated blockade, however, it is consistent with several other immune system related models of pain.
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Opioid compounds have powerful analgesic properties when administered to the spinal cord. These effects are exerted through mu and delta opioid receptors, and both pre- and postsynaptic mechanisms have been implicated. To specifically address the relative pre- and postsynaptic contribution to spinal opioid analgesia, we have quantitatively assessed the pre- vs. postsynaptic distribution of the mu-opioid (MOR-1, MOP(1)) and delta-opioid receptors (DOR-1, DOP(1)). ⋯ These fibers have a broad rostro-caudal distribution, extending at least three segments rostral and caudal to their segment of entry. Regardless of marker used, the rostral projection was greatest, however, the distribution of CGRP-immunoreactive fibers differed somewhat in that they had a much smaller projection to the most caudal segments examined. Our results suggest that presynaptic delta opioid actions predominate, but that there are mixed pre- and postsynaptic inhibitory effects exerted by opioid analgesics that act at the spinal cord mu opioid receptor.
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Inhibiting Ca(2+) uptake by the sarcoendoplasmic reticular Ca(2+)-ATPase pump (SERCA) causes release of Ca(2+) from the endoplasmic reticulum (ER), increased cytosolic Ca(2+) ([Ca(2+)](cyt)) and depletion of ER Ca(2+) stores. These studies were designed to test the effects of SERCA inhibition on neuronal viability, using as a model the human neuroblastoma cell line, SH-SY5Y. Continuous exposure to the SERCA inhibitor thapsigargin (TG) decreased SH-SY5Y viability to <30% after 48 h exposure, and produced DNA laddering. ⋯ DHBP (20-100 microM) also gave partial protection against TG toxicity, as did ruthenium red (2 microM), but not ryanodine (10 microM). Inhibition of capacitative Ca(2+) entry with EGTA or LaCl(3) or low extracellular Ca(2+), or chelation of [Ca(2+)](cyt) with BAPTA-AM, failed to inhibit TG toxicity, although they prevented increases in [Ca(2+)](cyt) caused by TG. Taken together, these data suggest that toxicity caused by SERCA inhibition in SH-SY5Y cells is caused by ER Ca(2+) depletion, which triggers an apparent apoptotic pathway.