Neuroscience
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Excess glutamate release from the presynaptic membrane has been thought to be the major cause of ischemic neuronal death. Although both CA1 and CA3 pyramidal neurons receive presynaptic glutamate input, transient cerebral ischemia induces CA1 neurons to die while CA3 neurons remain relatively intact. This suggests that changes in the properties of pyramidal cells may be the main cause related to ischemic neuronal death. ⋯ Furthermore, expression of the GluR2 subunit (calcium impermeable) of the AMPA receptor class significantly decreased while the GluR1 subunit (calcium permeable) remained unchanged at the same examined reperfusion times, which subsequently caused an increase in the GluR1/GluR2 ratio. Despite these notable differences in subunit expression, there were no obvious changes in the density of synapses or expression of NMDAR and AMPAR subunits in the CA3 area after ischemia. These results suggest that delayed CA1 neuronal death may be related to the dramatic fluctuation in the synaptic structure and relative upregulation of NR2B and GluR1 subunits induced by transient global ischemia.
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To better understand the effects of deafness on the brain, these experiments examine how disrupted balance between excitatory and inhibitory neurotransmission following the loss of excitatory input from the auditory nerve alters the central auditory system. In the avian cochlear nucleus, nucleus magnocellularis (NM), deprivation of excitatory input induced by deafness triggers neuronal death. While this neuronal death was previously accredited to the loss of excitatory drive, the present experiments examine an alternative hypothesis: that inhibitory input to NM, which may also be affected by deafness, contributes to neuronal death in NM. ⋯ We found that GABA decreases Y10B-ir, and that GABAA activation is necessary for the GABA-induced effect. We further found that endogenous GABAA activation similarly decreases Y10B-ir and this decrease requires extracellular Ca(2+). Our results suggest that, in the absence of excitatory input, endogenous activation of ionotropic GABAA receptors is detrimental to NM neurons.
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Tissue plasminogen activator (tPA) is the only approved therapy for acute ischemic stroke, but tPA therapy is limited by a short therapeutic window and some adverse side effects. 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside, a salidroside analog (code-named SalA-4g), has shown potent neuroprotective effects. In this study, a rat model of embolic middle cerebral artery occlusion (MCAO) was used to mimic ischemic stroke. ⋯ Our results suggested that additive neuroprotective actions of SalA-4g contributed to widening the therapeutic window of tPA therapy and ameliorating its side effects in treating MCAO rats. The therapeutic benefits of combined treatment with tPA and SalA-4g for ischemic stroke might be associated with its effects on cerebral glucose metabolism.